clinical neurophysiology – PushAsRx Athletic Training Centers El Paso, TX Chiropractic Science & Functional Fitness Thu, 02 Aug 2018 22:25:20 +0000 en-US hourly 1 clinical neurophysiology – PushAsRx Athletic Training Centers El Paso, TX 32 32 111105572 The Role of Biomarkers for Depression Thu, 02 Aug 2018 21:19:25 +0000

Depression is one of the most common mental health issues in the United States. Current research suggests that depression results from a combination of genetic, biological, ecological, and psychological aspects. Depression is a major psychiatric disorder worldwide with a significant economic and psychological strain on society. Fortunately, depression, even the most severe cases, may be treated. The earlier that treatment can begin, the more effective it is.


As a result, however, there's a need for robust biomarkers that will aid in improving diagnosis in order to accelerate the drug and/or medication discovery process for each patient with the disorder. These are objective, peripheral physiological indicators which presence can be used to predict the probability of onset or existence of depression, stratify according to severity or symptomatology, indicate predict and prognosis or monitor resp

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Depression is one of the most common mental health issues in the United States. Current research suggests that depression results from a combination of genetic, biological, ecological, and psychological aspects. Depression is a major psychiatric disorder worldwide with a significant economic and psychological strain on society. Fortunately, depression, even the most severe cases, may be treated. The earlier that treatment can begin, the more effective it is.


As a result, however, there’s a need for robust biomarkers that will aid in improving diagnosis in order to accelerate the drug and/or medication discovery process for each patient with the disorder. These are objective, peripheral physiological indicators which presence can be used to predict the probability of onset or existence of depression, stratify according to severity or symptomatology, indicate predict and prognosis or monitor response to therapeutic interventions. The purpose of the following article is to demonstrate recent insights, current challenges and future prospects regarding the discovery of a variety of biomarkers for depression and how these can help improve diagnosis and treatment.


Biomarkers for Depression: Recent Insights, Current Challenges and Future Prospects




A plethora of research has implicated hundreds of putative biomarkers for depression, but has not yet fully elucidated their roles in depressive illness or established what is abnormal in which patients and how biologic information can be used to enhance diagnosis, treatment and prognosis. This lack of progress is partially due to the nature and heterogeneity of depression, in conjunction with methodological heterogeneity within the research literature and the large array of biomarkers with potential, the expression of which often varies according to many factors. We review the available literature, which indicates that markers involved in inflammatory, neurotrophic and metabolic processes, as well as neurotransmitter and neuroendocrine system components, represent highly promising candidates. These may be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomic and neuroimaging assessments. The use of novel approaches and systematic research programs is now required to determine whether, and which, biomarkers can be used to predict response to treatment, stratify patients to specific treatments and develop targets for new interventions. We conclude that there is much promise for reducing the burden of depression through further developing and expanding these research avenues.


Keywords: mood disorder, major depressive disorder, inflammation, treatment response, stratification, personalized medicine




Challenges in Mental Health and Mood Disorders


Although psychiatry has a disease-related burden greater than any single other medical diagnostic category,1 a disparity of esteem is still apparent between physical and mental health across many domains including research funding2 and publication.3 Among the difficulties that mental health faces is a lack of consensus surrounding classification, diagnosis and treatment that stems from an incomplete understanding of the processes underlying these disorders. This is highly apparent in mood disorders, the category which comprises the single largest burden in mental health.3 The most prevalent mood disorder, major depressive disorder (MDD), is a complex, heterogeneous illness in which up to 60% of patients may experience some degree of treatment resistance that prolongs and worsens episodes.4 For mood disorders, and in the broader field of mental health, treatment outcomes would likely be improved by the discovery of robust, homogeneous subtypes within (and across) diagnostic categories, by which treatments could be stratified. In recognition of this, global initiatives to delineate functional subtypes are now in progress, such as the research domain criteria.5 It has been posited that biologic markers are priority candidates for subtyping mental disorders.6


Improving Response to Treatments for Depression


Despite an extensive range of treatment options for major depression, only approximately a third of patients with MDD achieve remission even when receiving optimal antidepressant treatment according to consensus guidelines and using measurement-based care, and rates of treatment response appear to fall with each new treatment.7 Furthermore, treatment-resistant depression (TRD) is associated with increased functional impairment, mortality, morbidity and recurrent or chronic episodes in the long term.8,9 Thus, obtaining improvements in treatment response at any clinical stage would afford wider benefits for overall outcomes in depression. Despite the substantial burden attributable to TRD, research in this area has been sparse. Definitions of TRD are not standardized, in spite of previous attempts:4 some criteria require only one treatment trial that fails to achieve a 50% symptom score reduction (from a validated measure of depression severity), while others require non-achievement of full remission or nonresponse to at least two adequately trialed antidepressants of different classes within an episode to be considered TRD.4,10 Furthermore, the staging and prediction of treatment resistance is improved by adding the key clinical features of severity and chronicity to the number of failed treatments.9,11 Nevertheless, this inconsistency in definition renders interpreting the research literature on TRD an even more complex task.


In order to improve response to treatments, it is clearly helpful to identify predictive risk factors of nonresponse. Some general predictors of TRD have been characterized, including a lack of full remission after previous episodes, comorbid anxiety, suicidality and early onset of depression, as well as personality (particularly low extraversion, low reward dependence and high neuroticism) and genetic factors.12 These findings are corroborated by reviews synthesizing the evidence separately for pharmacologic13 and psychological14 treatment for depression. Antidepressants and cognitive-behavioral therapies show approximately comparable efficacy,15 but due to their differing mechanisms of action might be expected to have different predictors of response. While early-life trauma has long been associated with poorer clinical outcomes and reduced responses to treatment,16 early indications suggest that people with a history of childhood trauma might respond better to psychological than pharmacologic therapies.17 Despite this, uncertainty prevails and little personalization or stratification of treatment has reached clinical practice.18


This review focuses on the evidence supporting the utility of biomarkers as potentially useful clinical tools to enhance treatment response for depression.


Biomarkers: Systems and Sources


Biomarkers provide a potential target for identifying predictors of response to various interventions.19 The evidence to date suggests that markers reflecting the activity of inflammatory, neurotransmitter, neurotrophic, neuroendocrine and metabolic systems may be able to predict mental and physical health outcomes in currently depressed individuals, but there is much inconsistency between findings.20 In this review, we focus on these five biologic systems.


To attain a full understanding of molecular pathways and their contribution in psychiatric disorders, it is now considered important to assess multiple biologic “levels”, in what is popularly referred to as an “omics” approach.21 Figure 1 provides a depiction of the different biologic levels at which each of the five systems can be assessed, and the potential sources of markers on which these assessments can be undertaken. However, note that while each system can be inspected at each omics level, the optimal sources of measurement clearly vary at each level. For example, neuroimaging provides a platform for indirect assessment of brain structure or function, while protein examinations in blood directly assess markers. Transcriptomics22 and metabolomics23 are increasingly popular, offering assessment of potentially huge numbers of markers, and the Human Microbiome Project is now attempting to identify all microorganisms and their genetic composition within humans.24 Novel technologies are enhancing our ability to measure these, including through additional sources; for example, hormones such as cortisol can now be assayed in hair or fingernails (providing a chronic indication) or sweat (providing a continuous measurement),25 as well as in blood, cerebrospinal fluid, urine and saliva.


Figure 1 Potential Biomarkers for Depression


Given the number of putative sources, levels and systems involved in depression, it is not surprising that the scale of biomarkers with translational potential is extensive. Particularly, when interactions between markers are considered, it is perhaps unlikely that examining single biomarkers in isolation will yield findings fruitful for improving clinical practice. Schmidt et al26 proposed the use of biomarker panels and, subsequently, Brand et al27 outlined a draft panel based on prior clinical and preclinical evidence for MDD, identifying 16 “strong” biomarker targets, each of which is rarely a single marker. They comprise reduced gray matter volume (in hippocampal, prefrontal cortex and basal ganglia regions), circadian cycle changes, hypercortisolism and other representations of hypothalamic–pituitary–adrenal (HPA) axis hyperactivation, thyroid dysfunction, reduced dopamine, noradrenaline or 5-hydroxyindoleacetic acid, increased glutamate, increased superoxide dismutase and lipid peroxidation, attenuated cyclic adenosine 3′,5′-monophosphate and mitogen-activated protein kinase pathway activity, increased proinflammatory cytokines, alterations to tryptophan, kynurenine, insulin and specific genetic polymorphisms. These markers have not been agreed by consensus and could be measured in various ways; it is clear that focused and systematic work must address this enormous task in order to prove their clinical benefits.


Aims of this Review


As a deliberately broad review, this article seeks to determine the overall needs for biomarker research in depression and the extent to which biomarkers hold real translational potential for enhancing response to treatments. We begin by discussing the most important and exciting findings in this field and direct the reader to more specific reviews pertaining to relevant markers and comparisons. We outline the current challenges faced in light of the evidence, in combination with needs for reducing the burden of depression. Finally, we look ahead to the important research pathways for meeting current challenges and their implications for clinical practice.


Recent Insights


The search for clinically useful biomarkers for people with depression has generated extensive investigation over the last half a century. The most commonly used treatments were conceived from the monoamine theory of depression; subsequently, neuroendocrine hypotheses gained much attention. In more recent years, the most prolific research has surrounded the inflammatory hypothesis of depression. However, a large number of relevant review articles have focused across all five systems; see Table 1 and below for a collection of recent insights across biomarker systems. While measured at many levels, blood-derived proteins have been examined most widely and provide a source of biomarker that is convenient, cost-effective and may be closer to translational potential than other sources; thus, more detail is given to biomarkers circulating in blood.


Table 1 Overview on Biomarkers for Depression


In a recent systematic review, Jani et al20 examined peripheral blood-based biomarkers for depression in association with treatment outcomes. Of only 14 studies included (searched up until early 2013), 36 biomarkers were studied of which 12 were significant predictors of mental or physical response indices in at least one investigation. Those identified as potentially representing risk factors for nonresponse included inflammatory proteins: low interleukin (IL)-12p70, ratio of lymphocyte to monocyte count; neuroendocrine markers (dexamethasone nonsuppression of cortisol, high circulating cortisol, reduced thyroid-stimulating hormone); neurotransmitter markers (low serotonin and noradrenaline); metabolic (low high-density lipoprotein cholesterol) and neurotrophic factors (reduced S100 calcium-binding protein B). Further to this, other reviews have reported on associations between additional biomarkers and treatment outcomes.19,28–30 A brief description of putative markers in each system is outlined in the subsequent sections and in Table 2.


Table 2 Biomarkers with Potential use for Depression


Inflammatory Findings in Depression


Since Smith’s seminal paper outlining the macrophage hypothesis,31 this established literature has found increased levels of various proinflammatory markers in depressed patients, which have been reviewed widely.32–37 Twelve inflammatory proteins have been evaluated in meta-analyses comparing depressed and healthy control populations.38–43


IL-6 (P<0.001 in all meta-analyses; 31 studies included) and CRP (P<0.001; 20 studies) appear frequently and reliably elevated in depression.40 Elevated tumor necrosis factor alpha (TNFα) was identified in early studies (P<0.001),38 but substantial heterogeneity rendered this inconclusive when accounting for more recent investigations (31 studies).40 IL-1β is even more inconclusively associated with depression, with meta-analyses suggesting higher levels in depression (P=0.03),41 high levels only in European studies42 or no differences from controls.40 Despite this, a recent article suggested particular translational implications for IL-1β,44 supported by an extremely significant effect of elevated IL-1β ribonucleic acid predicting a poor response to antidepressants;45 other findings above pertain to circulating blood-derived cytokines. The chemokine monocyte chemoattractant protein-1 has shown elevations in depressed participants in one meta-analysis.39 Interleukins IL-2, IL-4, IL-8, IL-10 and interferon gamma were not significantly different between depressed patients and controls at a meta-analytic level, but have nonetheless demonstrated potential in terms of altering with treatment: IL-8 has been reported as elevated in those with severe depression prospectively and cross-sectionally,46 different patterns of change in IL-10 and interferon gamma during treatment have occurred between early responders versus nonresponders,47 while IL-4 and IL-2 have decreased in line with symptom remission.48 In meta-analyses, small decreases alongside treatment have been demonstrated for IL-6, IL-1β, IL-10 and CRP.43,49,50 Additionally, TNFα may only reduce with treatment in responders, and a composite marker index may indicate increased inflammation in patients who subsequently do not respond to treatment.43 It is notable, however, that almost all of the research examining inflammatory proteins and treatment response utilize pharmacologic treatment trials. Thus, at least some inflammatory alterations during treatment are likely attributable to antidepressants. The precise inflammatory effects of different antidepressants have not yet been established, but evidence using CRP levels suggests individuals respond differently to specific treatments based on baseline inflammation: Harley et al51 reported elevated pretreatment CRP predicting a poor response to psychological therapy (cognitive–behavioral or interpersonal psychotherapy), but a good response to nortriptyline or fluoxetine; Uher et al52 replicated this finding for nortriptyline and identified the opposite effect for escitalopram. In contrast, Chang et al53 found higher CRP in early responders to fluoxetine or venlafaxine than nonresponders. Furthermore, patients with TRD and high CRP have responded better to the TNFα antagonist infliximab than those with levels in the normal range.54


Together, the evidence suggests that even when controlling for factors such as body mass index (BMI) and age, inflammatory responses appear aberrant in approximately one-third of patients with depression.55,56 The inflammatory system, however, is extremely complex, and there are numerous biomarkers representing different aspects of this system. Recently, additional novel cytokines and chemokines have yielded evidence of abnormalities in depression. These include: macrophage inhibitory protein 1a, IL-1a, IL-7, IL-12p70, IL-13, IL-15, eotaxin, granulocyte macrophage colony-stimulating factor,57 IL-5,58 IL-16,59 IL-17,60 monocyte chemoattractant protein-4,61 thymus and activation-regulated chemokine,62 eotaxin-3, TNFb,63 interferon gamma-induced protein 10,64 serum amyloid A,65 soluble intracellular adhesion molecule66 and soluble vascular cell adhesion molecule 1.67


Growth Factor Findings in Depression


In light of the potential importance of non-neurotrophic growth factors (such as those relating to angiogenesis), we refer to neurogenic biomarkers under the broader definition of growth factors.


Brain-derived neurotrophic factor (BDNF) is the most frequently studied of these. Multiple meta-analyses demonstrate attenuations of the BDNF protein in serum, which appear to increase alongside antidepressant treatment.68–71 The most recent of these analyses suggests that these BDNF aberrations are more pronounced in the most severely depressed patients, but that antidepressants appear to increase the levels of this protein even in the absence of clinical remission.70 proBDNF has been less widely studied than the mature form of BDNF, but the two appear to differ functionally (in terms of their effects on tyrosine receptor kinase B receptors) and recent evidence suggests that while mature BDNF may be reduced in depression, proBDNF may be overproduced.72 Nerve growth factor assessed peripherally has also been reported as lower in depression than in controls in a meta-analysis, but may not be altered by antidepressant treatment despite being most attenuated in patients with more severe depression.73 Similar findings have been reported in a meta-analysis for glial cell line-derived neurotrophic factor.74


Vascular endothelial growth factor (VEGF) has a role in promoting angiogenesis and neurogenesis along with other members of the VEGF family (eg, VEGF-C, VEGF-D) and has promise for depression.75 Despite inconsistent evidence, two meta-analyses have recently indicated elevations of VEGF in blood of depressed patients compared to controls (across 16 studies; P<0.001).76,77 However, low VEGF has been identified in TRD78 and higher levels have predicted nonresponse to antidepressant treatment.79 It is not understood why the levels of VEGF protein would be elevated, but it may partly be attributable to proinflammatory activity and/or increases in blood–brain barrier permeability in depressed states that causes reduced expression in cerebrospinal fluid.80 The relationship between VEGF and treatment response is unclear; a recent study found no relationship between either serum VEGF or BDNF with response or depression severity, despite decreases alongside antidepressant treatment.81 Insulin-like growth factor-1 is an additional factor with neurogenic functions that may be increased in depression, reflecting an imbalance in neurotrophic processes.82,83 Basic fibroblast growth factor (or FGF-2) is a member of the fibroblast growth factor family and appears higher in depressed than control groups.84 However, reports are not consistent; one found that this protein was lower in MDD than healthy controls, but reduced further alongside antidepressant treatment.85


Further growth factors that have not been sufficiently explored in depression include tyrosine kinase 2 and soluble fms-like tyrosine kinase-1 (also termed sVEGFR-1) which act in synergy with VEGF, and tyrosine kinase receptors (that bind BDNF) may be attenuated in depression.86 Placental growth factor is also part of the VEGF family, but has not been studied in systematically depressed samples to our knowledge.


Metabolic Biomarker Findings in Depression


The main biomarkers associated with metabolic illness include leptin, adiponectin, ghrelin, triglycerides, high-density lipoprotein (HDL), glucose, insulin and albumin.87 The associations between many of these and depression have been reviewed: leptin88 and ghrelin89 appear lower in depression than controls in the periphery and may increase alongside antidepressant treatment or remission. Insulin resistance may be increased in depression, albeit by small amounts.90 Lipid profiles, including HDL-cholesterol, appear altered in many patients with depression, including those without comorbid physical illness, though this relationship is complex and requires further elucidation.91 Additionally, hyperglycemia92 and hypoalbuminemia93 in depression have been reported in reviews.


Investigations of overall metabolic states are becoming more frequent using metabolomics panels of small molecules with the hope of finding a robust biochemical signature for psychiatric disorders. In a recent study using artificial intelligence modeling, a set of metabolites illustrating increased glucose–lipid signaling was highly predictive of an MDD diagnosis,94 supportive of previous studies.95


Neurotransmitter Findings in Depression


While the attention paid to monoamines in depression has yielded relatively successful treatments, no robust neurotransmitter markers have been identified to optimize treatment based on the selectivity of monoamine targets of antidepressants. Recent work points toward the serotonin (5-hydroxytryptamine) 1A receptor as potentially important for both diagnosis and prognosis of depression, pending new genetic and imaging techniques.96 There are new potential treatments targeting 5-hydroxytryptamine; for example, using a slow-release administration of 5-hydroxytryptophan.97 Increased transmission of dopamine interacts with other neurotransmitters to improve cognitive outcomes such as decision making and motivation.98 Similarly, the neurotransmitters glutamate, noradrenaline, histamine and serotonin may interact and activate as part of a depression-related stress response; this might decrease 5-hydroxytryptamine production through “flooding”. A recent review sets out this theory and suggests that in TRD, this could be reversed (and 5-HT restored) through multimodal treatment targeting multiple neurotransmitters.99 Interestingly, increases in serotonin do not always occur conjunctively with therapeutic antidepressant benefits.100 Despite this, neurotransmitter metabolites such as 3-methoxy-4-hydroxyphenylglycol, of noradrenaline, or homovanillic acid, of dopamine, have often been found to increase alongside reduction in depression with antidepressant treatment101,102 or that low levels of these metabolites predict a better response to SSRI treatment.102,103


Neuroendocrine Findings in Depression


Cortisol is the most common HPA axis biomarker to have been studied in depression. Numerous reviews have focused on the various assessments of HPA activity; overall, these suggest that depression is associated with hypercortisolemia and that the cortisol awakening response is often attenuated.104,105 This is supported by a recent review of chronic cortisol levels measured in hair, supporting the hypothesis of cortisol hyperactivity in depression but hypoactivity in other illnesses such as panic disorder.106 Furthermore, particularly, elevated cortisol levels may predict a poorer response to psychological107 and antidepressant108 treatment. Historically, the most promising neuroendocrine marker of prospective treatment response has been the dexamethasone suppression test, where cortisol nonsuppression following dexamethasone administration is associated with a lower likelihood of subsequent remission. However, this phenomenon has not been considered sufficiently robust for clinical application. Related markers corticotrophin-releasing hormone and adrenocorticotropin hormone as well as vasopressin are inconsistently found to be overproduced in depression and dehydroepiandrosterone is found to be attenuated; the ratio of cortisol to dehydroepiandrosterone may be elevated as a relatively stable marker in TRD, persisting after remission.109 Neuroendocrine hormone dysfunctions have long been associated with depression, and hypothyroidism may also play a causal role in depressed mood.110 Furthermore, thyroid responses can normalize with successful treatment for depression.111


Within the above, it is important also to consider signaling pathways across systems, such as glycogen synthase kinase-3, mitogen-activated protein kinase and cyclic adenosine 3′,5′-monophosphate, involved in synaptic plasticity112 and modified by antidepressants.113 Further potential biomarker candidates that span biologic systems particularly are measured using neuroimaging or genetics. In response to the lack of robust and meaningful genomic differences between depressed and nondepressed populations,114 novel genetic approaches such as polygenic scores115 or telomere length116,117 could prove more useful. Additional biomarkers gaining popularity are examining circadian cycles or chronobiologic biomarkers utilizing different sources. Actigraphy can provide an objective assessment of sleep and wake activity and rest through an accelerometer, and actigraphic devices can increasingly measure additional factors such as light exposure. This may be more useful for detection than commonly used subjective reports of patients and could provide novel predictors of treatment response.118 The question of which biomarkers are the most promising for translational use is a challenging one, which is expanded upon below.


Current Challenges


For each of these five neurobiological systems reviewed, the evidence follows a similar narrative: there are many biomarkers that exist that are associated in some respects with depression. These markers are frequently interrelated in a complex, difficult-to-model fashion. The evidence is inconsistent, and it is likely that some are epiphenomena of other factors and some are important in only a subset of patients. Biomarkers are likely to be useful through a variety of routes (eg, those that predict subsequent response to treatment, those indicating specific treatments as more likely to be effective or those that alter with interventions regardless of clinical improvements). Novel methods are required to maximize consistency and clinical applicability of biologic assessments in psychiatric populations.


Biomarker Variability


Variation of biomarkers over time and across situations pertains more to some types (eg, proteomics) than others (genomics). Standardized norms for many do not exist or have not been widely accepted. Indeed, the influence of environmental factors on markers frequently depends on genetic composition and other physiologic differences between people that cannot all be accounted for. This makes the assessment of biomarker activity, and identifying biologic abnormalities, difficult to interpret. Due to the number of potential biomarkers, many have not been measured widely or in a complete panel alongside other relevant markers.


Many factors have been reported to alter the protein levels across biologic systems in patients with affective disorders. Along with research-related factors such as duration and conditions of storage (which may cause degradation of some compounds), these include time of day measured, ethnicity, exercise,119 diet (eg, microbiome activity, especially provided that most blood biomarker studies do not require a fasting sample),120 smoking and substance use,121 as well as health factors (such as comorbid inflammatory, cardiovascular or other physical illnesses). For example, although heightened inflammation is observed in depressed but otherwise healthy individuals compared to nondepressed groups, depressed individuals who also have a comorbid immune-related condition frequently have even higher levels of cytokines than either those without depression or illness.122 Some prominent factors with probable involvement in the relationship between biomarkers, depression and treatment response are outlined below.


Stress. Both endocrine and immune responses have well-known roles in responding to stress (physiologic or psychological), and transient stress at the time of biologic specimen collection is rarely measured in research studies despite the variability of this factor between individuals that may be accentuated by current depressive symptoms. Both acute and chronic psychological stressors act as an immune challenge, accentuating inflammatory responses in the short and longer term.123,124 This finding extends to the experience of early-life stress, which has been associated with adult inflammatory elevations that are independent of stress experienced as an adult.125,126 During childhood traumatic experience, heightened inflammation has also been reported only in those children who were currently depressed.127 Conversely, people with depression and a history of childhood trauma may have blunted cortisol responses to stress, compared to those with depression and no early-life trauma.128 Stress-induced HPA axis alterations appear interrelated with cognitive function,129 as well as depression subtype or variation in HPA-related genes.130 Stress also has short- and long-term impairing effects on neurogenesis131 and other neural mechanisms.132 It is unclear precisely how childhood trauma affects biologic markers in depressed adults, but it is possible that early-life stress predisposes some individuals to enduring stress reactions in adulthood that are amplified psychologically and/or biologically.


Cognitive functioning. Neurocognitive dysfunctions occur frequently in people with affective disorders, even in unmedicated MDD.133 Cognitive deficits appear cumulative alongside treatment resistance.134 Neurobiologically, the HPA axis129 and neurotrophic systems135 are likely to play a key role in this relationship. Neurotransmitters noradrenaline and dopamine are likely important for cognitive processes such as learning and memory.136 Elevated inflammatory responses have been linked with cognitive decline, and likely affect cognitive functioning in depressive episodes,137 and in remission, through a variety of mechanisms.138 Indeed, Krogh et al139 proposed that CRP is more closely related to cognitive performance than to the core symptoms of depression.


Age, gender and BMI. The absence or presence, and direction of biologic differences between men and women has been particularly variable in the evidence to date. Neuroendocrine hormone variation between men and women interacts with depression susceptibility.140 A review of inflammation studies reported that controlling for age and gender did not affect patient-control differences in inflammatory cytokines (although the association between IL-6 and depression reduced as age increased, which is consistent with theories that inflammation generally heightens with age).41,141 VEGF differences between patients and controls are larger in studies assessing younger samples, while gender, BMI and clinical factors did not affect these comparisons at a meta-analytic level.77 However, the lack of adjustment for BMI in previous examinations of inflammation and depression appears to confound highly significant differences reported between these groups.41 Enlarged adipose tissue has been definitively demonstrated to stimulate cytokine production as well as being closely linked to metabolic markers.142 Because psychotropic medications may be associated with weight gain and a higher BMI, and these have been associated with treatment resistance in depression, this is an important area to examine.


Medication. Many biomarker studies in depression (both cross-sectional and longitudinal) have collected baseline specimens in unmedicated participants to reduce heterogeneity. However, many of these assessments are taken after a wash-out period from medication, which leaves the potentially significant confounding factor of residual changes in physiology, exacerbated by the extensive range of treatments available that may have had differing effects on inflammation. Some studies have excluded psychotropic, but not other medication use: in particular, the oral contraceptive pill is frequently permitted in research participants and not controlled for in analyses, which has recently been indicated to increase hormone and cytokine levels.143,144 Several studies indicate that antidepressant medications have effects on the inflammatory response,34,43,49,145–147 HPA-axis,108 neurotransmitter,148 and neurotrophic149 activity. However, the numerous potential treatments for depression have distinct and complex pharmacologic properties, suggesting there may be discrete biologic effects of different treatment options, supported by current data. It has been theorized that in addition to monoamine effects, specific serotonin-targeting medications (ie, SSRIs) are likely to target Th2 shifts in inflammation, and noradrenergic antidepressants (eg, SNRIs) effect a Th1 shift.150 It is not yet possible to determine the effects of individual or combination medications on biomarkers. These are likely mediated by other factors including the length of treatment (few trials assess long-term medication use), sample heterogeneity and not stratifying participants by response to treatment.




Methodological. As alluded to above, differences (between and within studies) in terms of which treatments (and combinations) the participants are taking and have taken previously are bound to introduce heterogeneity into research findings, particularly in biomarker research. In addition to this, many other design and sample characteristics vary across studies, thus augmenting the difficulty with interpreting and attributing findings. These include biomarker measurement parameters (eg, assay kits) and methods of collecting, storing, processing and analyzing markers in depression. Hiles et al141 examined some sources of inconsistency in the literature on inflammation and found that accuracy of depression diagnosis, BMI and comorbid illnesses were most important to account for in assessing peripheral inflammation between depressed and nondepressed groups.


Clinical. The extensive heterogeneity of depressed populations is well documented151 and is a critical contributor to contrasting findings within the research literature. It is probable that even within diagnoses, abnormal biologic profiles are confined to subsets of individuals that may not be stable over time. Cohesive subgroups of people suffering with depression may be identifiable through a combination of psychological and biologic factors. Below, we outline the potential for exploring subgroups in meeting the challenges that biomarker variability and heterogeneity pose.


Subtypes within Depression


Thus far, no homogenous subgroups within depression episodes or disorders have been reliably able to distinguish between patients based on symptom presentations or treatment responsiveness.152 The existence of a subgroup in whom biologic aberrations are more pronounced would help to explain the heterogeneity between previous studies and could catalyze the path toward stratified treatment. Kunugi et al153 have proposed a set of four potential subtypes based on the role of different neurobiological systems displaying clinically relevant subtypes in depression: those with hypercortisolism presenting with melancholic depression, or hypocortisolism reflecting an atypical subtype, a dopamine-related subset of patients who may present prominently with anhedonia (and could respond well to, eg, aripiprazole) and an inflammatory subtype characterized by elevated inflammation. Many articles focusing on inflammation have specified the case for the existence of an “inflammatory subtype” within depression.55,56,154,155 Clinical correlates of elevated inflammation are as yet undetermined and few direct attempts have been made to discover which participants may comprise this cohort. It has been proposed that people with atypical depression could have higher levels of inflammation than the melancholic subtype,156 which is perhaps not in line with findings regarding the HPA axis in melancholic and atypical subtypes of depression. TRD37 or depression with prominent somatic symptoms157 has also been posited as a potential inflammatory subtype, but neurovegetative (sleep, appetite, libido loss), mood (including low mood, suicidality and irritability) and cognitive symptoms (including affective bias and guilt)158 all appear related to biologic profiles. Further potential candidates for an inflammatory subtype involve the experience of sickness behavior-like symptoms159,160 or a metabolic syndrome.158


The propensity toward (hypo) mania may distinguish biologically between patients suffering from depression. Evidence now suggests that bipolar illnesses are a multifaceted group of mood disorders, with bipolar subsyndromal disorder found more prevalently than was previously recognized.161 Inaccurate and/or delayed detection of bipolar disorder has recently been highlighted as a major problem in clinical psychiatry, with the average time to correct diagnosis frequently exceeding a decade162 and this delay causing greater severity and cost of overall illness.163 With the majority of patients with bipolar disorder presenting initially with one or more depressive episodes and unipolar depression being the most frequent misdiagnosis, the identification of factors that might differentiate between unipolar and bipolar depression has substantial implications.164 Bipolar spectrum disorders likely have been undetected in some previous MDD biomarker investigations, and smatterings of evidence have indicated differentiation of HPA axis activity109 or inflammation165,166 between bipolar and unipolar depression. However, these comparisons are scarce, possess small sample sizes, identified nonsignificant trend effects or recruited populations that were not well characterized by diagnosis. These investigations also do not examine the role of treatment responsiveness in these relationships.


Both bipolar disorders167 and treatment resistance168 are not dichotomous constructs and lie on continua, which increases the challenge of subtype identification. Apart from subtyping, it is worth noting that many biologic abnormalities observed in depression are similarly found in patients with other diagnoses. Thus, transdiagnostic examinations are also potentially important.


Biomarker Measurement Challenges


Biomarker selection. The large number of potentially useful biomarkers presents a challenge for psychobiology in determining which markers are implicated in which way and for whom. To increase the challenge, relatively few of these biomarkers have been subject to sufficient investigation in depression, and for most, their precise roles in healthy and clinical populations are not well understood. Despite this, a number of attempts have been made to propose promising biomarker panels. In addition to Brand et al’s 16 sets of markers with strong potential,27 Lopresti et al outline an additional extensive set of oxidative stress markers with potential for improving treatment response.28 Papakostas et al defined a priori a set of nine serum markers spanning biologic systems (BDNF, cortisol, soluble TNFα receptor type II, alpha1 antitrypsin, apolipoprotein CIII, epidermal growth factor, myeloperoxidase, prolactin and resistin) in validation and replication samples with MDD. Once combined, a composite measure of these levels was able to distinguish between MDD and control groups with 80%–90% accuracy.169 We propose that even these do not cover all potential candidates in this field; see Table 2 for a nonexhaustive delineation of biomarkers with potential for depression, containing both those with an evidence base and promising novel markers.


Technology. Due to technologic advances, it is now possible (indeed, convenient) to measure a large array of biomarkers simultaneously at a lower cost and with higher sensitivity than has been the case previously. At present, this capability to measure numerous compounds is ahead of our ability to effectively analyze and interpret the data,170 something that will continue with the rise in biomarker arrays and new markers such as with metabolomics. This is largely due to a lack of understanding about the precise roles of and the interrelationships between markers, and an insufficient grasp of how related markers associate across different biologic levels (eg, genetic, transcription, protein) within and between individuals. Big data using new analytical approaches and standards will assist with addressing this, and new methodologies are being proposed; one example is the development of a statistical approach grounded in flux-based analysis to discover new potential metabolic markers based on their reactions between networks and integrate gene expression with metabolite data.171 Machine learning techniques are already being applied and will assist with models using biomarker data to predict treatment outcomes in studies with big data.172


Aggregating biomarkers. Examining an array of biomarkers simultaneously is an alternative to inspecting isolated markers that could provide a more accurate viewpoint into the complex web of biologic systems or networks.26 Also, to assist with disentangling contrasting evidence in this literature to date (particularly, where biomarker networks and interactions are well understood), biomarker data can then be aggregated or indexed. One challenge is in identifying the optimum method of conducting this, and it may require enhancements in technology and/or novel analytical techniques (see the “Big data” section). Historically, ratios between two distinct biomarkers have yielded interesting findings.109,173 Few attempts have been made to aggregate biomarker data on a larger scale, such as those using principal component analysis of proinflammatory cytokine networks.174 In a meta-analysis, proinflammatory cytokines have been converted into a single-effect size score for each study, and overall showed significantly higher inflammation before antidepressant treatment, predicting subsequent nonresponse in outpatient studies. Composite biomarker panels are both a challenge and opportunity for future research to identify meaningful and reliable findings that can be applied to improve treatment outcomes.43 A study by Papakostas et al took an alternative approach, selecting a panel of heterogeneous serum biomarkers (of inflammatory, HPA axis and metabolic systems) that had been indicated to differ between depressed and control individuals in a previous study and composited these into a risk score which differed in two independent samples and a control group with >80% sensitivity and specificity.169


Big data. The use of big data is probably necessary for addressing the current challenges outlined surrounding heterogeneity, biomarker variability, identifying the optimal markers and bringing the field toward translational, applied research in depression. However, as outlined above, this brings technological and scientific challenges.175 The health sciences have only recently begun using big data analytics, a decade or so later than in the business sector. However, studies such as iSPOT-D152 and consortia such as the Psychiatric Genetics Consortium176 are progressing with our understanding of biologic mechanisms in psychiatry. Machine-learning algorithms have, in very few studies, started to be applied to biomarkers for depression: a recent investigation pooled data from >5,000 participants of 250 biomarkers; after multiple imputation of data, a machine-learning boosted regression was conducted, indicating 21 potential biomarkers. Following further regression analyses, three biomarkers were selected as associating most strongly with depressive symptoms (highly variable red blood cell size, serum glucose and bilirubin levels). The authors conclude that big data can be used effectively for generating hypotheses.177 Larger biomarker phenotyping projects are now underway and will help to advance our journey into the future of the neurobiology of depression.


Future Prospects


Biomarker Panel Identification


The findings in the literature to date require replication in large-scale studies. This is particularly true for novel biomarkers, such as the chemokine thymus and activation-regulated chemokine and the growth factor tyrosine kinase 2 which, to our knowledge, have not been investigated in clinically depressed and healthy control samples. Big data studies must assay comprehensive biomarker panels and use sophisticated analysis techniques to fully ascertain the relationships between markers and those factors which modify them in clinical and nonclinical populations. Additionally, large-scale replications of principal component analysis might establish highly correlated groups of biomarkers and could also inform the use of “composites” in biologic psychiatry, which may enhance the homogeneity of future findings.


Discovery of Homogenous Subtypes


Regarding biomarker selection, multiple panels may be required for different potential pathways that research could implicate. Taken together, the current evidence indicates that biomarker profiles are assuredly, but abstrusely altered in a subpopulation of individuals currently suffering from depression. This may be established within or across diagnostic categories, which would account for some inconsistency of findings that can be observed in this literature. Quantifying a biologic subgroup (or subgroups) may most effectively be facilitated by a large cluster analysis of biomarker network panels in depression. This would illustrate within-population variability; latent class analyses could exhibit distinct clinical characteristics based on, for example, inflammation.


Specific Treatment Effects on Inflammation and Response


All commonly prescribed treatments for depression should be comprehensively assessed for their specific biologic effects, also accounting for the effectiveness of treatment trials. This may enable constructs relating to biomarkers and symptom presentations to predict outcomes to a variety of antidepressant treatments in a more personalized fashion, and may be possible in the context of both unipolar and bipolar depression. This is likely to be useful for new potential treatments as well as currently indicated treatments.


Prospective Determination of Treatment Response


Use of the above techniques is likely to result in an improved ability to forecast treatment resistance prospectively. More authentic and persistent (eg, long-term) measures of treatment response may contribute to this. Assessment of other valid measures of patient well-being (such as quality of life and everyday functioning) could provide a more holistic assessment of treatment outcome that may associate more closely with biomarkers. While biologic activity alone might not be able to distinguish treatment responders from nonresponders, concurrent measurement of biomarkers with psychosocial or demographic variables could be integrated with biomarker information in developing a predictive model of insufficient treatment response. If a reliable model is developed to predict response (either for the depressed population or a subpopulation) and is validated retrospectively, a translational design can establish its applicability in a large controlled trial.


Toward Stratified Treatments


At present, patients with depression are not systematically directed to receive an optimized intervention program. If validated, a stratified trial design could be employed to test a model to predict nonresponse and/or to determine where a patient needs to be triaged in a stepped care model. This could be useful in both standardized and naturalistic treatment settings, across different types of intervention. Ultimately, a clinically viable model could be developed to provide individuals with the most appropriate treatment, to recognize those who are likely to develop refractory depression and supply enhanced care and monitoring to these patients. Patients identified as being at risk for treatment resistance may be prescribed a concomitant psychological and pharmacologic therapy or combination pharmacotherapy. As a speculative example, participants with no proinflammatory cytokine elevations might be indicated to receive psychological rather than pharmacologic therapy, while a subset of patients with particularly high inflammation could receive an anti-inflammatory agent in augmentation to standard treatment. Similar to stratification, personalized treatment-selection strategies may be possible in the future. For example, a particular depressed individual might have markedly high TNFα levels, but no other biologic abnormalities, and could benefit from short-term treatment with a TNFα antagonist.54 Personalized treatment may also entail monitoring biomarker expression during treatment to inform possible intervention changes, the length of continuation therapy required or to detect early markers of relapse.


Novel Treatment Targets


There are a huge number of potential treatments that could be effective for depression, which have not been adequately examined, including novel or repurposed interventions from other medical disciplines. Some of the most popular targets have been in anti-inflammatory medications such as celecoxib (and other cyclooxygenase-2 inhibitors), TNFα antagonists etanercept and infliximab, minocycline or aspirin. These appear promising.178 Antiglucocorticoid compounds, including ketoconazole179 and metyrapone,180 have been investigated for depression, but both have drawbacks with their side effect profile and the clinical potential of metyrapone is uncertain. Mifepristone181 and the corticosteroids fludrocortisone and spironolactone,182 and dexamethasone and hydrocortisone183 may also be effective in treating depression in the short term. Targeting glutamate N-methyl-d-aspartate receptor antagonists, including ketamine, might represent efficacious treatments in depression.184 Omega-3 polyunsaturated fatty acids influence inflammatory and metabolic activity and appear to demonstrate some effectiveness for depression.185 It is possible that statins may have antidepressant effects186 through relevant neurobiological pathways.187


In this way, the biochemical effects of antidepressants (see the “Medication” section) have been utilized for clinical benefits in other disciplines: particularly gastroenterological, neurologic and nonspecific symptom illnesses.188 Anti-inflammatory effects of antidepressants may represent part of the mechanism for these benefits. Lithium has also been suggested to reduce inflammation, critically through glycogen synthase kinase-3 pathways.189 A focus on these effects could prove informative for a depression biomarker signature and, in turn, biomarkers could represent surrogate markers for novel drug development.



Dr. Alex Jimenez’s Insight

Depression is a mental health disorder characterized by severe symptoms which affect mood, including loss of interest in activities. Recent research studies, however, have found that it may be possible to diagnose depression using more than just a patient’s behavioral symptoms. According to the researchers, identifying easily obtainable biomarkers which could more accurately diagnose depression is fundamental towards improving a patient’s overall health and wellness. By way of instance, clinical findings suggest that individuals with major depressive disorder, or MDD, have lower levels of the molecule acetyl-L-carnitine, or LAC, in their blood than healthy controls. Ultimately, establishing biomarkers for depression could potentially help better determine who is at risk of developing the disorder as well as help healthcare professionals determine the best treatment option for a patient with depression.




The literature indicates that approximately two-thirds of patients with depression do not achieve remission to an initial treatment and that the likelihood of nonresponse increases with the number of treatments trialed. Providing ineffective therapies has substantial consequences for individual and societal cost, including persistent distress and poor well-being, risk of suicide, loss of productivity and wasted health care resources. The vast literature in depression indicates a huge number of biomarkers with the potential to improve treatment for people with depression. In addition to neurotransmitter and neuroendocrine markers which have been subject to widespread study for many decades, recent insights highlight the inflammatory response (and the immune system more generally), metabolic and growth factors as importantly involved in depression. However, excessive contrasting evidence illustrates that there are a number of challenges needing to be tackled before biomarker research can be applied in order to improve the management and care of people with depression. Due to the sheer complexity of biologic systems, simultaneous examinations of a comprehensive range of markers in large samples are of considerable benefit in discovering interactions between biologic and psychological states across individuals. Optimizing the measurement of both neurobiological parameters and clinical measures of depression is likely to facilitate greater understanding. This review also highlights the importance of examining potentially modifying factors (such as illness, age, cognition and medication) in gleaning a coherent understanding of the biology of depression and mechanisms of treatment resistance. It is likely that some markers will show most promise for predicting treatment response or resistance to specific treatments in a subgroup of patients, and the concurrent measurement of biologic and psychological data may enhance the ability to prospectively identify those at risk for poor treatment outcomes. Establishing a biomarker panel has implications for boosting diagnostic accuracy and prognosis, as well as for individualizing treatments at the earliest practicable stage of depressive illness and developing effective novel treatment targets. These implications may be confined to subgroups of depressed patients. The pathways toward these possibilities complement recent research strategies to link clinical syndromes more closely to underlying neurobiological substrates.6 Apart from reducing heterogeneity, this may facilitate a shift toward parity of esteem between physical and mental health. It is clear that although much work is needed, establishment of the relationship between relevant biomarkers and depressive disorders has substantial implications for reducing the burden of depression at an individual and societal level.




This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.




Disclosure. AHY has in the last 3 years received honoraria for speaking from Astra Zeneca (AZ), Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen and UK funding agencies (NIHR, MRC, Wellcome Trust). AJC has in the last 3 years received honoraria for speaking from Astra Zeneca (AZ), honoraria for consulting from Allergan, Livanova and Lundbeck, and research grant support from Lundbeck and UK funding agencies (NIHR, MRC, Wellcome Trust).


The authors report no other conflicts of interest in this work.


In conclusion, while numerous research studies have found hundreds of biomarkers for depression, not many have established their role in depressive illness or how exactly biologic information could be utilized to enhance diagnosis, treatment and prognosis. However, the article above reviews the available literature on the biomarkers involved during other processes and compares the clinical findings to that of depression. Furthermore, new findings on biomarkers for depression may help better diagnose depression in order to follow up with better treatment. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


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Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment

The post The Role of Biomarkers for Depression appeared first on PushAsRx Athletic Training Centers El Paso, TX.

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Lab Biomarkers for Chronic Pain Wed, 01 Aug 2018 22:53:36 +0000

Biomarkers (short for biological markers) are biological measurements of a biological condition. By definition, a biomarker is "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention" Biomarkers are the measurements utilized to perform a clinical evaluation like blood pressure or cholesterol level and therefore are used to monitor and forecast health conditions in individuals or across populations so that appropriate treatment options could be proposed. Biomarkers may be used by itself or in combination to assess the health or disease state of an individual.


Variety of Biomarkers


A wide selection of biomarkers are used now. Every biological system, suc

The post Lab Biomarkers for Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.


Biomarkers (short for biological markers) are biological measurements of a biological condition. By definition, a biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention” Biomarkers are the measurements utilized to perform a clinical evaluation like blood pressure or cholesterol level and therefore are used to monitor and forecast health conditions in individuals or across populations so that appropriate treatment options could be proposed. Biomarkers may be used by itself or in combination to assess the health or disease state of an individual.


Variety of Biomarkers


A wide selection of biomarkers are used now. Every biological system, such as the cardiovascular system, metabolic system or the immune system, has its own specific biomarkers. Many of these biomarkers are rather easy to quantify and form part of regular medical examinations. By way of instance, a general health check may include assessment of blood pressure, heart rate, cholesterol, triglycerides and fasting glucose levels. Body dimensions such as weight, body mass index, or BMI, and waist-to-hip ratio are routinely used for assessing conditions like obesity and metabolic disorders, among others. These varieties in biomarkers can ultimately be useful in the diagnosis of a variety of health issues.


Attributes of a Perfect Biomarker


An ideal biomarker has particular characteristics that make it suitable for assessing a particular disease or condition. Ideally, an ideal marker should possess the following features, as it should be:


  • Safe and simple to measure
  • Cost effective to follow up
  • Modifiable with treatment
  • Consistent across gender and cultural groups


Biomarkers as Health and Disease Predictors


Biomarkers are used to predict significant ailments like diabetes and cardiovascular disease, among others. Each individual biomarker indicates whether there’s a disease or health condition and can be combined to offer a thorough demonstration of how healthy an individual is and whether further diagnosis needs to be made. Biomarkers ultimately serve as health and disease predictors, capable of determining a potential onset of disease or illness, such as that of cancer.


Biomarkers in Cancer Detection and Drug Development


The principles of biomarkers in disease have been applied to the discovery, screening, diagnosis, treatment and monitoring of cancer. Traditionally, anti-cancer drugs and/or medications were agents that eliminated both cancer cells and healthy cells. However, more targeted therapies have now been developed that can be instructed to kill cancer cells only, while sparing healthy cells. The evaluation of a typical biomarker in cancer will help in the development of therapies that may target the biomarker. This can minimize the risk of toxicity and reduce the cost of treatment. In cancer research, genetic studies are valuable because genetic abnormalities so often underlie the evolution of cancer. Certain DNA or RNA markers might therefore help in the treatment and detection of specific cancers. The purpose of the following article, however, is to demonstrate the biomarkers involved in low back pain, disc degeneration and other chronic pain health issues, such as neuropathic pain.


Inflammatory Biomarkers of Low Back Pain and Disc Degeneration: a Review




Biomarkers are biological characteristics that can be used to indicate health or disease. This paper reviews studies on biomarkers of low back pain (LBP) in human subjects. LBP is the leading cause of disability, caused by various spine-related disorders, including intervertebral disc degeneration, disc herniation, spinal stenosis, and facet arthritis. The focus of these studies is inflammatory mediators, because inflammation contributes to the pathogenesis of disc degeneration and associated pain mechanisms. Increasingly, studies suggest that the presence of inflammatory mediators can be measured systemically in the blood. These biomarkers may serve as novel tools for directing patient care. Currently, patient response to treatment is unpredictable with a significant rate of recurrence, and, while surgical treatments may provide anatomical correction and pain relief, they are invasive and costly. The review covers studies performed on populations with specific diagnoses and undefined origins of LBP. Since the natural history of LBP is progressive, the temporal nature of studies is categorized by duration of symptomology/disease. Related studies on changes in biomarkers with treatment are also reviewed. Ultimately, diagnostic biomarkers of LBP and spinal degeneration have the potential to shepherd an era of individualized spine medicine for personalized therapeutics in the treatment of LBP.


Keywords: back pain; biomarkers; inflammation; intervertebral disc degeneration; spine


Biomarkers for Chronic Neuropathic Pain and their Potential Application in Spinal Cord Stimulation: a Review




This review was focused on understanding which substances inside the human body increase and decrease with increasing neuropathic pain. We reviewed various studies, and saw correlations between neuropathic pain and components of the immune system (this system defends the body against diseases and infections). Our findings will especially be useful for understanding ways to reduce or eliminate the discomfort, chronic neuropathic pain brings with it. Spinal cord stimulation (SCS) procedure is one of the few fairly efficient remedial treatments for pain. A follow-up study will apply our findings from this review to SCS, in order to understand the mechanism, and further optimize efficaciousness.


Keywords: spinal cord stimulation, pain biomarkers, chronic neuropathic pain, cytokines




Chronic neuropathic pain disorders represent a common long-term disability in the United States, as well as, globally. They affect 1 in 4 Americans. Chronic neuropathic pain treatment has limited success because of poor understanding of the mechanisms that lead to the initiation and maintenance. Additionally, the effectiveness of neuropathic pain management regimens and procedures has been difficult to determine in the past, due to the subjectivity related to pain perception, and a lack of standardized assessment of neuropathic pain. However, one of the most effective management strategies in recent times is spinal cord stimulation (SCS). The main goals of spinal cord stimulation are to improve physical function and quality of life in the patients afflicted with chronic neuropathic pain associated with complex regional pain syndrome (CRPS), failed back syndrome, and other chronic neuropathic pain syndromes [1–2]. Despite limited knowledge of how people benefit from SCS, more than 20,000 stimulators are implanted each year, with more than a half-billion dollars in revenue [3]. While it is generally believed that spinal cord stimulation inhibits pain transmission in the dorsal horn, the exact mechanisms by which SCS relieves neuropathic pain is unknown. Chronic neuropathic pain is caused often by inflammation and/or nerve injury. The advances have shown that inflammation and nerve injury produce changes in the expression of cytokines, neurotransmitters, and structural proteins [4]. It is very likely that there are changes in the body’s serum biomarkers of neuropathic pain before SCS and after SCS. Such a study would contribute greatly to the field of neuromodulation, as objective quantifiers of neuropathic pain control before and after SCS have not yet been investigated. Such definitive data regarding the effectiveness of SCS in relieving neuropathic pain and improving function will be important in future use of SCS.


In preparation for the launching of this study, the authors’ goal with this transcript is to provide a review of the literature regarding known biomarkers for chronic neuropathic pain, and then prepare a role for biomarker analysis in the prediction of therapy success in SCS.




The expression of certain genes is altered under chronic pain conditions. This alteration has helped provide an insight into the identification of potential biomarkers [5]. Current advanced research suggests that genetic expression of cytokines, positively or negatively, correlates with the experience of chronic pain. This negative or positive correlation primarily depends on the nature of the cytokine. Cytokines are signaling proteins which mediate the activation, differentiation, and proliferation of immune cells. They can be pro-inflammatory or anti-inflammatory. A misaligned balance between pro-inflammatory and anti-inflammatory cytokines has been common in most of the studies conducted (Table 1). Pro-inflammatory cytokines such as IL-1β, IL-6, IL-2, IL-33, CCL3, CXCL1, CCR5, and TNF-α, have been found to play significant roles in the amplification of chronic pain states. In studies involving discogenic pain, Complete Freund’s adjuvant (CFA)-induced discogenic pain in animal models has been observed to coincide with a sustained up-regulation of the above named cytokines [6]. In a more recent study, chronic constriction injury (CCI)-induced rats (neuropathic pain induction) were shown to have increased serum levels of CCL3 and CCR5. Even more interesting, an intrathecal injection of the anti-inflammatory cytokine, IL-4, and the CCL3-neutralizing antibody, reduced the CCI-induced neuropathic pain, estimated by a plantar test [7]. Other studies have also shown that the selective genetic impairment of the highlighted pro-inflammatory cytokines attenuated nerve-injury induced pain behavior, observed in neuropathic pain models [8]. Particularly, Zarpelon et al. revealed that CCI-induced rats showed reduced mechanical hyperalgesia when the IL-33 receptor gene, IL-33R (ST2), was knocked out, compared to the wild-type mice [9].


Table 1 Cytokines and Hormones in Various Studies


On the other hand, one study showed that blood levels of anti-inflammatory cytokines (such as IL-10 and IL-4) of Complex Regional Pain Syndrome (CRPS) patients were lower compared to the control [10]. A recent study also shows a distinction of the significant increases of pro-inflammatory cytokines based on the part of the back affected. There were more significant elevations (p<0.05, student’s t test) of pro-inflammatory cytokines in the plasma of lower back pain patients than in upper back patients, when compared to controls [11]. There has also been a study focusing on the levels of the aforementioned cytokines in patients with painful neuropathy in contrast with painless neuropathy and healthy control subjects. Patients with a painful neuropathy had about double the level of IL-2 expression (p = 0.001), TNF expression (p < 0.0001) and protein levels (p = 0.009) than the controls. The study further indicated there was about double the IL-2 and TNF level expression (p = 0.03; p = 0.001) and protein levels in painful neuropathy (p = 0.04; p = 0.04) than patients with painless neuropathy. On the contrary, levels of mRNA expression of the anti-inflammatory cytokines, IL-10 and IL-4 were considerably lower in patients with painful neuropathy than in patients with painless neuropathy (p =0.001) [12].


Several other studies, focused on the antagonist and agonist effects of some drugs targeting pro-inflammatory and anti-inflammatory cytokines, also have pointed out their significance with pain. Certain known analgesics were seen to reduce the levels of pro-inflammatory cytokines in the studies reviewed. There was a study about (CCI)-induced rats, in which case, this induced injury significantly, elevated the levels of pro-inflammatory cytokines, and decreased the serum levels of anti-inflammatory cytokines. Omeprazole, a known remedy for stomach pain, was observed to reduce the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) to normal, compared with the CCI control. It is important to note that this was while curbing the CCI-induced neuropathic pain, measured with the paw withdrawal latency [13]. Zhou et al. also highlighted the significance of certain drugs in determining the correlation between cytokines and neuropathic pain. CCI was again, used to induce neuropathic pain on rat models; and in turn, Paenoflorin, an established analgesic [14] was administered. Once Paenoflorin was introduced, significant decreases in serum levels of pro-inflammatory cytokines of CCI-induced rats (IL-1β, IL-6, TNF-α, and CXCL1) were observed, compared to the CCI-control [15]. The cytokines identified here, are the ones that showed correlation in various studies reviewed.


Even though cytokines are the key chronic pain biomarkers, according to the studies reviewed, there are still other proteins and nucleotides that have been observed to associate with chronic pain disorder. Two studies laid emphasis on regulatory microRNAs (miRNAs), which are small non-coding RNA molecules involved in post-transcriptional gene regulation. miRNAs achieve this by binding to mRNAs and degrading them or repressing their functions. Orlova et al. showed that 60% of CRPS patients in their study showed a significant down-regulation of 18 different miRNAs. The rest of the patients, however, showed variable (contradicting) miRNA levels. miRNA levels show variability, depending on the gene being regulated [5]. Tao et al. revealed that an increased inflammatory stimulation by the cytokine IL-1β in normal and osteoarthritis chondrocytes produced a significant down-regulation of the miRNA, miR-558, and a significant up-regulation of miR-21 in DRG neurons. A connection between IL-1β and miR-21 was attributed to AP-1, which is a transcription factor located in the promoter site of the mRNA, and is activated by IL-1β [4]. siRNAs have the same features as miRNAs, in the sense, that they are regulatory nucleotides. They also show variability, depending on the gene being regulated. SIRT1, a deacetylase, functions in regulating various pathways, including inflammation. It was observed that an intrathecal injection of SRT170, an SIRT1 agonist, reduced serum levels of NF-κB, a transcription factor for pro-inflammatory cytokines, in CCI-induced rat models. When SRT170-siRNA (a regulator of the regulator) was administered before SRT170, there was no agonistic effect [16].



Dr. Alex Jimenez’s Insight

A biomarker is most accurately defined as any measurement which demonstrates an interaction between a biological system and the possibility of a chemical, physical or biological hazard. However, biomarkers are often most commonly associated with medicine. In this setting, these can be utilized to determine the effects a particular treatment may have on a patient as well as for determining the risk a patient may have of developing certain health issues. An example of a diagnostic use of biomarkers includes the measurement of biomarkers in blood to evaluate the severity of a heart attack. In the same manner, blood samples can be analyzed and biomarkers can be measured in the instance of chronic pain.




Chronic neuropathic pain affects a tremendous amount of the population. There are few effective therapies. However, outcomes are hard to determine due to the subjective nature of pain. We would like to devise a strategy that would establish objectivity of pain assessment. After review of various studies relating to pain biomarkers, we found that serum levels of pro-inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-2, IL-33, CCL3, CXCL1, CCR5, and TNF-α, were significantly up-regulated during chronic pain experience. On the other hand, anti-inflammatory cytokines such as IL-10 and IL-4 were found to show significant down-regulation during chronic pain state. Regulatory miRNAs, siRNAs, and deacetylases that coincide with these cytokines, also showed negative correlation, corresponding to the cytokine they were regulating.


The authors would like to apply this knowledge to SCS, a therapy for chronic neuropathic pain, in an attempt to develop a biomarker profile to help predict success. This study will be a prospective study including patients scheduled for SCS. One month before SCS surgery, patients will complete a survey assessing their subjective level of pain on the visual analog scale and subjective level of function. Patients will also have venipuncture performed, and serum will be analyzed for levels of pain biomarkers. After SCS surgery, patients will be followed at 6 more time points: 2 weeks, 1 month, 3 months, 6 months, 1 year, and 2 years. At each time point, the survey will be re-administered and blood work will be repeated. By evaluating patients pre-operatively and post-operatively, we will be able to assess subjective and objective levels of pain, allowing us to analyze trends in pain biomarkers in the context of patient-reported pain measurement. The duration of this study will be 4 years. Each subject will participate in this study for a total period of 25 months, which will allow us to follow these patients for 2 years postoperatively.




The review of various studies relating to inflammation- and/or nerve injury-induced chronic pain disorder led us to hypothesize that the application of the spinal cord stimulation procedure should relatively reduce serum pro-inflammatory cytokines, and relatively increase serum levels of anti-inflammatory cytokines. This should, in turn, help us understand the mechanism of spinal cord stimulation, thereby optimizing the efficaciousness of the procedure, and perhaps allow us to make predictions regarding therapy success. A follow-up prospective study regarding serum biomarker profile in SCS patients is currently being undertaken.




Author Disclosure: The authors declare no conflicts of interest.


Disclosure of Funding: This work was supported by grants from the University of Medicine and Dentistry of New Jersey and the National Institutes of Health, Bethesda, Maryland (grant numbers: NS072206, HL117684, and DA033390).


In conclusion, diagnostic biomarkers have the potential of leading new personalized therapeutics in the treatment of chronic pain health issues, such as low back pain, disc degeneration and neuropathic pain. Several research studies like the ones above have been established to ultimately help healthcare professionals understand better ways to reduce or eliminate the pain and discomfort associated with these chronic pain problems. Furthermore, biomarkers can be essential diagnostic tools for the evaluation and treatment of a variety of health issues. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


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2. Kumar K, Hunter G, Demeria D. Spinal Cord Stimulation in Treatment of Chronic Benign Pain: Challenges in Treatment Planning and Present Status, a 22-year Experience. Neurosurgery. 2006;58:481–491. [PubMed]
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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment

The post Lab Biomarkers for Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.

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Safety and Side Effects of Cannabidiol Fri, 13 Jul 2018 22:02:41 +0000

Cannabidiol is a compound in the Cannabis sativa plant, also known as marijuana. More than 80 chemicals, called cannabinoids, have been identified in the Cannabis sativa plant. Even though delta-9-tetrahydrocannabinol, or THC, is the major active ingredient, cannabidiol constitutes about 40 percent of cannabis extracts and has been analyzed for many distinct uses. According to the U.S. Food and Drug Administration, or the FDA, because cannabidiol was analyzed as a new drug, products containing cannabidiol are not defined as dietary supplements. But there are still products labeled as dietary supplements available on the marketplace which contain cannabidiol.


Cannabidiol has antipsychotic results. The exact cause for these effects isn't clear. However, cannabidiol appears to protect against the breakdown of a

The post Safety and Side Effects of Cannabidiol appeared first on PushAsRx Athletic Training Centers El Paso, TX.


Cannabidiol is a compound in the Cannabis sativa plant, also known as marijuana. More than 80 chemicals, called cannabinoids, have been identified in the Cannabis sativa plant. Even though delta-9-tetrahydrocannabinol, or THC, is the major active ingredient, cannabidiol constitutes about 40 percent of cannabis extracts and has been analyzed for many distinct uses. According to the U.S. Food and Drug Administration, or the FDA, because cannabidiol was analyzed as a new drug, products containing cannabidiol are not defined as dietary supplements. But there are still products labeled as dietary supplements available on the marketplace which contain cannabidiol.


Cannabidiol has antipsychotic results. The exact cause for these effects isn’t clear. However, cannabidiol appears to protect against the breakdown of a chemical in the brain that affects pain, mood, and mental function. Preventing the breakdown of this compound and raising its levels in the blood seems to decrease psychotic symptoms related to conditions such as schizophrenia. Cannabidiol may also block some of the untoward effects of delta-9-tetrahydrocannabinol, or THC. Additionally, cannabidiol appears to decrease pain and anxiety. The purpose of the following article is to demonstrate an update on the safety and side effects of cannabidiol involving clinical data and relevant animal studies.


An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies




  • Introduction: This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.
  • Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.
  • Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.
  • Keywords: cannabidiol, cannabinoids, medical uses, safety, side effects, toxicity




Since several years, other pharmacologically relevant constituents of the Cannabis plant, apart from Δ9-THC, have come into the focus of research and legislation. The most prominent of those is cannabidiol (CBD). In contrast to Δ9-THC, it is nonintoxicating, but exerts a number of beneficial pharmacological effects. For instance, it is anxiolytic, anti-inflammatory, antiemetic, and antipsychotic. Moreover, neuroprotective properties have been shown.1,2 Consequently, it could be used at high doses for the treatment of a variety of conditions ranging in psychiatric disorders such as schizophrenia and dementia, as well as diabetes and nausea.1,2


At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne.3,4


The comprehensive review of 132 original studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells. Chronic use and high doses of up to 1500 mg per day have been repeatedly shown to be well tolerated by humans.1


Nonetheless, some side effects have been reported for CBD, but mainly in vitro or in animal studies. They include alterations of cell viability, reduced fertilization capacity, and inhibition of hepatic drug metabolism and drug transporters (e.g., p-glycoprotein).1 Consequently, more human studies have to be conducted to see if these effects also occur in humans. In these studies, a large enough number of subjects have to be enrolled to analyze long-term safety aspects and CBD possible interactions with other substances.


This review will build on the clinical studies mentioned by Bergamaschi et al. and will update their survey with new studies published until September 2016.



Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a cannabis compound which is believed to have significant health benefits and can counteract the psychoactivity of THC. Because CBD is non-psychoactive or less psychoactive than THC-dominant strains, it has become an appealing treatment option for patients experiencing chronic pain, inflammation, anxiety, seizures, psychosis and other conditions without the common side effects. associated with THC. Numerous research studies have been conducted to demonstrate evidence on the health benefits of cannabidiol, or CBD, on the human body.


Relevant Preclinical Studies


Before we discuss relevant animal research on CBD possible effects on various parameters, several important differences between route of administration and pharmacokinetics between human and animal studies have to be mentioned. First, CBD has been studied in humans using oral administration or inhalation. Administration in rodents often occures either via intraperitoneal injection or via the oral route. Second, the plasma levels reached via oral administration in rodents and humans can differ. Both these observations can lead to differing active blood concentrations of CBD.1,5,6


In addition, it is possible that CBD targets differ between humans and animals. Therefore, the same blood concentration might still lead to different effects. Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.


The following study, which showed a positive effect of CBD on obsessive compulsive behavior in mice and reported no side effects, exemplifies the existing pharmacokinetic differences.5 When mice and humans are given the same CBD dose, more of the compound becomes available in the mouse organism. This higher bioavailability, in turn, can cause larger CBD effects.


Deiana et al. administered 120 mg/kg CBD either orally or intraperitoneally and measured peak plasma levels.5 The group of mice, which received oral CBD, had plasma levels of 2.2 μg/ml CBD. In contrast, i.p. injections resulted in peak plasma levels of 14.3 μg/ml. Administering 10 mg/kg oral CBD to humans leads to blood levels of 0.01 μg/ml.6 This corresponds to human blood levels of 0.12 μg/ml, when 120 mg/kg CBD was given to humans. This calculation was performed assuming the pharmacokinetics of a hydrophilic compound, for simplicity’s sake. We are aware that the actual levels of the lipophilic CBD will vary.


A second caveat of preclinical studies is that supraphysiological concentrations of compounds are often used. This means that the observed effects, for instance, are not caused by a specific binding of CBD to one of its receptors but are due to unspecific binding following the high compound concentration, which can inactivate the receptor or transporter.


The following example and calculations will demonstrate this. In vitro studies have shown that CBD inhibits the ABC transporters P-gp (P glycoprotein also referred to as ATP-binding cassette subfamily B member 1=ABCB1; 3–100 μM CBD) and Bcrp (Breast Cancer Resistance Protein; also referred to as ABCG2=ATP-binding cassette subfamily G member 2).7 After 3 days, the P-gp protein expression was altered in leukemia cells. This can have several implications because various anticancer drugs also bind to these membrane-bound, energy-dependent efflux transporters.1 The used CBD concentrations are supraphysiological, however, 3 μM CBD approximately corresponds to plasma concentrations of 1 μg/ml. On the contrary, a 700 mg CBD oral dose reached a plasma level of 10 ng/ml.6 This means that to reach a 1 μg/ml plasma concentration, one would need to administer considerably higher doses of oral CBD. The highest ever applied CBD dose was 1500 mg.1 Consequently, more research is warranted, where the CBD effect on ABC transporters is analyzed using CBD concentrations of, for example, 0.03–0.06 μM. The rationale behind suggesting these concentrations is that studies summarized by Bih et al. on CBD effect on ABCC1 and ABCG2 in SF9 human cells showed that a CBD concentration of 0.08 μM elicited the first effect.7


Using the pharmacokinetic relationships mentioned above, one would need to administer an oral CBD dose of 2100 mg CBD to affect ABCC1 and ABCG2. We used 10 ng/ml for these calculations and the ones in Table 1,6,8 based on a 6-week trial using a daily oral administration of 700 mg CBD, leading to mean plasma levels of 6–11 ng/ml, which reflects the most realistic scenario of CBD administration in patients.6 That these levels seem to be reproducible, and that chronic CBD administration does not lead to elevated mean blood concentrations, was shown by another study. A single dose of 600 mg led to reduced anxiety and mean CBD blood concentrations of 4.7–17 ng/ml.9


Table 1 Inhibition of Human Metabolic Enzymes


It also seems warranted to assume that the mean plasma concentration exerts the total of observed CBD effects, compared to using peak plasma levels, which only prevail for a short amount of time. This is not withstanding, that a recent study measured Cmax values for CBD of 221 ng/ml, 3 h after administration of 1 mg/kg fentanyl concomitantly with a single oral dose of 800 mg CBD.10


CBD-Drug Interactions


Cytochrome P450-complex enzymes. This paragraph describes CBD interaction with general (drug)-metabolizing enzymes, such as those belonging to the cytochrome P450 family. This might have an effect for coadministration of CBD with other drugs.7 For instance, CBD is metabolized, among others, via the CYP3A4 enzyme. Various drugs such as ketoconazol, itraconazol, ritonavir, and clarithromycin inhibit this enzyme.11 This leads to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active. In contrast, phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, causing reduced CBD bioavailability.11 Approximately 60% of clinically prescribed drugs are metabolized via CYP3A4.1 Table 1 shows an overview of the cytochrome inhibiting potential of CBD. It has to be pointed out though, that the in vitro studies used supraphysiological CBD concentrations.


Studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short term, but can induce them after repeated administration. This is similar to their induction by phenobarbital, thereby implying the 2b subfamily of isozymes.1 Another study showed this effect to be mediated by upregulation of mRNA for CYP3A, 2C, and 2B10, after repeated CBD administration.1


Hexobarbital is a CYP2C19 substrate, which is an enzyme that can be inhibited by CBD and can consequently increase hexobarbital availability in the organism.12,13 Studies also propose that this effect might be caused in vivo by one of CBD metabolites.14,15 Generally, the metabolite 6a-OH-CBD was already demonstrated to be an inducer of CYP2B10. Recorcinol was also found to be involved in CYP450 induction. The enzymes CYP3A and CYP2B10 were induced after prolonged CBD administration in mice livers, as well as for human CYP1A1 in vitro.14,15 On the contrary, CBD induces CYP1A1, which is responsible for degradation of cancerogenic substances such as benzopyrene. CYP1A1 can be found in the intestine and CBD-induced higher activity could therefore prevent absorption of cancerogenic substances into the bloodstream and thereby help to protect DNA.2


Effects on P-glycoprotein activity and other drug transporters. A recent study with P-gp, Bcrp, and P-gp/Bcrp knockout mice, where 10 mg/kg was injected subcutaneously, showed that CBD is not a substrate of these transporters itself. This means that they do not reduce CBD transport to the brain.16 This phenomenon also occurs with paracetamol and haloperidol, which both inhibit P-gp, but are not actively transported substrates. The same goes for gefitinib inhibition of Bcrp.


These proteins are also expressed at the blood–brain barrier, where they can pump out drugs such as risperidone. This is hypothesized to be a cause of treatment resistance.16 In addition, polymorphisms in these genes, making transport more efficient, have been implied in interindividual differences in pharmacoresistance.10 Moreover, the CBD metabolite 7-COOH CBD might be a potent anticonvulsant itself.14 It will be interesting to see whether it is a P-gp substrate and alters pharmacokinetics of coadministered P-gp-substrate drugs.


An in vitro study using three types of trophoblast cell lines and ex vivo placenta, perfused with 15 μM CBD, found BCRP inhibition leading to accumulation of xenobiotics in the fetal compartment.17 BCRP is expressed at the apical side of the syncytiotrophoblast and removes a wide variety of compounds forming a part of the placental barrier. Seventy-two hours of chronic incubation with 25 μM CBD also led to morphological changes in the cell lines, but not to a direct cytotoxic effect. In contrast, 1 μM CBD did not affect cell and placenta viability.17 The authors consider this effect cytostatic. Nicardipine was used as the BCRP substrate in the in vitro studies, where the Jar cell line showed the largest increase in BCRP expression correlating with the highest level of transport.17,and references therein


The ex vivo study used the antidiabetic drug and BCRP substrate glyburide.17 After 2 h of CBD perfusion, the largest difference between the CBD and the placebo placentas (n=8 each) was observed. CBD inhibition of the BCRP efflux function in the placental cotyledon warrants further research of coadministration of CBD with known BCRP substrates such as nitrofurantoin, cimetidine, and sulfasalazine. In this study, a dose–response curve should be established in male and female subjects (CBD absorption was shown to be higher in women) because the concentrations used here are usually not reached by oral or inhaled CBD administration. Nonetheless, CBD could accumulate in organs physiologically restricted via a blood barrier.17


Physiological Effects


CBD treatment of up to 14 days (3–30 mg/kg b.w. i.p.) did not affect blood pressure, heart rate, body temperature, glucose levels, pH, pCO2, pO2, hematocrit, K+ or Na+ levels, gastrointestinal transit, emesis, or rectal temperature in a study with rodents.1


Mice treated with 60 mg/kg b.w. CBD i.p. for 12 weeks (three times per week) did not show ataxia, kyphosis, generalized tremor, swaying gait, tail stiffness, changes in vocalization behavior or open-field physiological activity (urination, defecation).1


Neurological and Neurospychiatric Effects


Anxiety and depression. Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated 14-day administration of CBD.2 However, this finding might depend on the used animal model of anxiety or depression. This is supported by a study, where CBD was administered in an acute and “chronic” (2 weeks) regimen, which measured anxiolytic/antidepressant effects, using behavioral and operative models (OBX=olfactory bulbectomy as model for depression).18 The only observed side effects were reduced sucrose preference, reduced food consumption and body weight in the nonoperated animals treated with CBD (50 mg/kg). Nonetheless, the behavioral tests (for OBX-induced hyperactivity and anhedonia related to depression and open field test for anxiety) in the CBD-treated OBX animals showed an improved emotional response. Using microdialysis, the researchers could also show elevated 5-HT and glutamate levels in the prefrontal cortex of OBX animals only. This area was previously described to be involved in maladaptive behavioral regulation in depressed patients and is a feature of the OBX animal model of depression. The fact that serotonin levels were only elevated in the OBX mice is similar to CBD differential action under physiological and pathological conditions.


A similar effect was previously described in anxiety experiments, where CBD proved to be only anxiolytic in subjects where stress had been induced before CBD administration. Elevated glutamate levels have been proposed to be responsible for ketamine’s fast antidepressant function and its dysregulation has been described in OBX mice and depressed patients. Chronic CBD treatment did not elicit behavioral changes in the nonoperated mice. In contrast, CBD was able to alleviate the affected functionality of 5HT1A receptors in limbic brain areas of OBX mice.18 and references therein.


Schiavon et al. cite three studies that used chronic CBD administration to demonstrate its anxiolytic effects in chronically stressed rats, which were mostly mediated via hippocampal neurogenesis.19 and references therein For instance, animals received daily i.p. injections of 5 mg/kg CBD. Applying a 5HT1A receptor antagonist in the DPAG (dorsal periaqueductal gray area), it was implied that CBD exerts its antipanic effects via these serotonin receptors. No adverse effects were reported in this study.


Psychosis and bipolar disorder. Various studies on CBD and psychosis have been conducted.20 For instance, an animal model of psychosis can be created in mice by using the NMDAR antagonist MK-801. The behavioral changes (tested with the prepulse inhibition [PPI] test) were concomitant with decreased mRNA expression of the NMDAR GluN1 subunit gene (GRN1) in the hippocampus, decreased parvalbumin expression (=a calcium-binding protein expressed in a subclass of GABAergic interneurons), and higher FosB/ΔFosB expression (=markers for neuronal activity). After 6 days of MK-801 treatment, various CBD doses were injected intraperitoneally (15, 30, 60 mg/kg) for 22 days. The two higher CBD doses had beneficial effects comparable to the atypical antipsychotic drug clozapine and also attenuated the MK-801 effects on the three markers mentioned above. The publication did not record any side effects.21


One of the theories trying to explain the etiology of bipolar disorder (BD) is that oxidative stress is crucial in its development. Valvassori et al. therefore used an animal model of amphetamine-induced hyperactivity to model one of the symptoms of mania. Rats were treated for 14 days with various CBD concentrations (15, 30, 60 mg/kg daily i.p.). Whereas CBD did not have an effect on locomotion, it did increase brain-derived neurotrophic factor (BDNF) levels and could protect against amphetamine-induced oxidative damage in proteins of the hippocampus and striatum. No adverse effects were recorded in this study.22


Another model for BD and schizophrenia is PPI of the startle reflex both in humans and animals, which is disrupted in these diseases. Peres et al., list five animal studies, where mostly 30 mg/kg CBD was administered and had a positive effect on PPI.20 Nonetheless, some inconsistencies in explaining CBD effects on PPI as model for BD exist. For example, CBD sometimes did not alter MK-801-induced PPI disruption, but disrupted PPI on its own.20 If this effect can be observed in future experiments, it could be considered to be a possible side effect.


Addiction. CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. This was shown in an animal heroin self-administration study, where mice received 5 mg/kg CBD i.p. injections. The observed effect lasted for 2 weeks after CBD administration and could normalize the changes seen after stimulus cue-induced heroin seeking (expression of AMPA, GluR1, and CB1R). In addition, the described study was able to replicate previous findings showing no CBD side effects on locomotor behavior.23


Neuroprotection and neurogenesis. There are various mechanisms underlying neuroprotection, for example, energy metabolism (whose alteration has been implied in several psychiatric disorders) and proper mitochondrial functioning.24 An early study from 1976 found no side effects and no effect of 0.3–300 μg/mg protein CBD after 1 h of incubation on mitochondrial monoamine oxidase activity in porcine brains.25 In hypoischemic newborn pigs, CBD elicited a neuroprotective effect, caused no side effects, and even led to beneficial effects on ventilatory, cardiac, and hemodynamic functions.26


A study comparing acute and chronic CBD administration in rats suggests an additional mechanism of CBD neuroprotection: Animals received i.p. CBD (15, 30, 60 mg/kg b.w.) or vehicle daily, for 14 days. Mitochondrial activity was measured in the striatum, hippocampus, and the prefrontal cortex.27 Acute and chronic CBD injections led to increased mitochondrial activity (complexes I-V) and creatine kinase, whereas no side effects were documented. Chronic CBD treatment and the higher CBD doses tended to affect more brain regions. The authors hypothesized that CBD changed the intracellular Ca2+ flux to cause these effects. Since the mitochondrial complexes I and II have been implied in various neurodegenerative diseases and also altered ROS (reactive oxygen species) levels, which have also been shown to be altered by CBD, this might be an additional mechanism of CBD-mediated neuroprotection.1,27


Interestingly, it has recently been shown that the higher ROS levels observed after CBD treatment were concomitant with higher mRNA and protein levels of heat shock proteins (HSPs). In healthy cells, this can be interpreted as a way to protect against the higher ROS levels resulting from more mitochondrial activity. In addition, it was shown that HSP inhibitors increase the CBD anticancer effect in vitro.28 This is in line with the studies described by Bergamaschi et al., which also imply ROS in CBD effect on (cancer) cell viability in addition to, for example, proapoptotic pathways such as via caspase-8/9 and inhibition of the procarcinogenic lipoxygenase pathway.1


Another publication studied the difference of acute and chronic administration of two doses of CBD in nonstressed mice on anxiety. Already an acute i.p. administration of 3 mg/kg was anxiolytic to a degree comparable to 20 mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3 mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus. Interestingly, the repeated administration of 30 mg/kg also led to anxiolytic effects. However, the higher dose caused a decrease in neurogenesis and cell proliferation, indicating dissociation of behavioral and proliferative effects of chronic CBD treatment. The study does not mention adverse effects.19


Immune System


Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes. These animal and human ex vivo studies have been reviewed extensively elsewhere, but studies with pure CBD are still lacking. Often combinations of THC and CBD were used. It would be especially interesting to study when CBD is proinflammatory and under which circumstances it is anti-inflammatory and whether this leads to side effects (Burstein, 2015: Table 1 shows a summary of its anti-inflammatory actions; McAllister et al. give an extensive overview in Table 1 of the interplay between CBD anticancer effects and inflammation signaling).29,30


In case of Alzheimer’s disease (AD), studies in mice and rats showed reduced amyloid beta neuroinflammation (linked to reduced interleukin [IL]-6 and microglial activation) after CBD treatment. This led to amelioration of learning effects in a pharmacological model of AD. The chronic study we want to describe in more detail here used a transgenic mouse model of AD, where 2.5-month-old mice were treated with either placebo or daily oral CBD doses of 20 mg/kg for 8 months (mice are relatively old at this point). CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.


Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment. Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. Also, CBD increased cholesterol levels in WT mice but not in CBD-treated transgenic mice. This was probably due to already elevated cholesterol in the transgenic mice. The study observed no side effects.31 and references within


In nonobese diabetes-prone female mice (NOD), CBD was administered i.p. for 4 weeks (5 days a week) at a dose of 5 mg/kg per day. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD treatment lead to considerable reduction of diabetes development (32% developed glucosuria in the CBD group compared to 100% in untreated controls) and to more intact islet of Langerhans cells. CBD increased IL-10 levels, which is thought to act as an anti-inflammatory cytokine in this context. The IL-12 production of splenocytes was reduced in the CBD group and no side effects were recorded.32


After inducing arthritis in rats using Freund’s adjuvant, various CBD doses (0.6, 3.1, 6.2, or 62.3 mg/day) were applied daily in a gel for transdermal administration for 4 days. CBD reduced joint swelling, immune cell infiltration. thickening of the synovial membrane, and nociceptive sensitization/spontaneous pain in a dose-dependent manner, after four consecutive days of CBD treatment. Proinflammatory biomarkers were also reduced in a dose-dependent manner in the dorsal root ganglia (TNF alpha) and spinal cord (CGRP, OX42). No side effects were evident and exploratory behavior was not altered (in contrast to Δ9-THC, which caused hypolocomotion).33


Cell Migration


Embryogenesis. CBD was shown to be able to influence migratory behavior in cancer, which is also an important aspect of embryogenesis.1 For instance, it was recently shown that CBD inhibits Id-1. Helix-loop-helix Id proteins play a role in embryogenesis and normal development via regulation of cell differentiation. High Id1-levels were also found in breast, prostate, brain, and head and neck tumor cells, which were highly aggressive. In contrast, Id1 expression was low in noninvasive tumor cells. Id1 seems to influence the tumor cell phenotype by regulation of invasion, epithelial to mesenchymal transition, angiogenesis, and cell proliferation.34


There only seems to exist one study that could not show an adverse CBD effect on embryogenesis. An in vitro study could show that the development of two-cell embryos was not arrested at CBD concentrations of 6.4, 32, and 160 nM.35


Cancer. Various studies have been performed to study CBD anticancer effects. CBD anti-invasive actions seem to be mediated by its TRPV1 stimulation and its action on the CB receptors. Intraperitoneal application of 5 mg/kg b.w. CBD every 3 days for a total of 28 weeks, almost completely reduced the development of metastatic nodules caused by injection of human lung carcinoma cells (A549) in nude mice.36 This effect was mediated by upregulation of ICAM1 and TIMP1. This, in turn, was caused by upstream regulation of p38 and p42/44 MAPK pathways. The typical side effects of traditional anticancer medication, emesis, and collateral toxicity were not described in these studies. Consequently, CBD could be an alternative to other MMP1 inhibitors such as marimastat and prinomastat, which have shown disappointing clinical results due to these drugs’ adverse muscoskeletal effects.37,38


Two studies showed in various cell lines and in tumor-bearing mice that CBD was able to reduce tumor metastasis.34,39 Unfortunately, the in vivo study was only described in a conference abstract and no route of administration or CBD doses were mentioned.36 However, an earlier study used 0.1, 1.0, or 1.5 μmol/L CBD for 3 days in the aggressive breast cancer cells MDA-MB231. CBD downregulated Id1 at promoter level and reduced tumor aggressiveness.40


Another study used xenografts to study the proapoptotic effect of CBD, this time in LNCaP prostate carcinoma cells.36 In this 5-week study, 100 mg/kg CBD was administered daily i.p. Tumor volume was reduced by 60% and no adverse effects of treatment were described in the study. The authors assumed that the observed antitumor effects were mediated via TRPM8 together with ROS release and p53 activation.41 It has to be pointed out though, that xenograft studies only have limited predictive validity to results with humans. Moreover, to carry out these experiments, animals are often immunologically compromised, to avoid immunogenic reactions as a result to implantation of human cells into the animals, which in turn can also affect the results.42


Another approach was chosen by Aviello et al.43 They used the carcinogen azoxymethane to induce colon cancer in mice. Treatment occurred using IP injections of 1 or 5 mg/kg CBD, three times a week for 3 weeks (including 1 week before carcinogen administration). After 3 months, the number of aberrant crypt foci, polyps, and tumors was analyzed. The high CBD concentration led to a significant decrease in polyps and a return to near-normal levels of phosphorylated Akt (elevation caused by the carcinogen).42 No adverse effects were mentioned in the described study.43


Food Intake and Glycemic Effects


Animal studies summarized by Bergamaschi et al. showed inconclusive effects of CBD on food intake1: i.p. administration of 3–100 mg/kg b.w. had no effect on food intake in mice and rats. On the contrary, the induction of hyperphagia by CB1 and 5HT1A agonists in rats could be decreased with CBD (20 mg/kg b.w. i.p.). Chronic administration (14 days, 2.5 or 5 mg/kg i.p.) reduced the weight gain in rats. This effect could be inhibited by coadministration of a CB2R antagonist.1


The positive effects of CBD on hyperglycemia seem to be mainly mediated via CBD anti-inflammatory and antioxidant effects. For instance, in ob/ob mice (an animal model of obesity), 4-week treatment with 3 mg/kg (route of administration was not mentioned) increased the HDL-C concentration by 55% and reduced total cholesterol levels by more than 25%. In addition, treatment increased adiponectin and liver glycogen concentrations.44 and references therein.


Endocrine Effects


High CBD concentrations (1 mM) inhibited progesterone 17-hydroxylase, which creates precursors for sex steroid and glucocorticoid synthesis, whereas 100 μM CBD did not in an in vitro experiment with primary testis microsomes.45 Rats treated with 10 mg/kg i.p. b.w. CBD showed inhibition of testosterone oxidation in the liver.46


Genotoxicity and Mutagenicity


Jones et al. mention that 120 mg/kg CBD delivered intraperetonially to Wistar Kyoto rats showed no mutagenicity and genotoxicity based on personal communication with GW Pharmaceuticals47,48 These data are yet to be published. The 2012 study with an epilepsy mouse model could also show that CBD did not influence grip strength, which the study describes as a “putative test for functional neurotoxicity.”48


Motor function was also tested on a rotarod, which was also not affected by CBD administration. Static beam performance, as an indicator of sensorimotor coordination, showed more footslips in the CBD group, but CBD treatment did not interfere with the animals’ speed and ability to complete the test. Compared to other anticonvulsant drugs, this effect was minimal.48 Unfortunately, we could not find more studies solely focusing on genotoxicity by other research groups neither in animals nor in humans.



Dr. Alex Jimenez’s Insight

Clinical and scientific research has attempted to show the effects of cannabidiol, or CBD, for the treatment of a wide range of conditions, including arthritis, diabetes, multiple sclerosis, chronic pain, schizophrenia, PTSD, depression, anxiety, infections, epilepsy, and many other neurological disorders. Evidence has also found that cannabidiol has neuroprotective and neurogenic effects and its anti-cancer properties are currently being investigated in many research studies. Further evidence has suggested that CBD can also be safe and effective even in higher doses, as recommended by a healthcare professional.


Acute Clinical Data


Bergamaschi et al. list an impressive number of acute and chronic studies in humans, showing CBD safety for a wide array of side effects.1 They also conclude from their survey, that none of the studies reported tolerance to CBD. Already in the 1970s, it was shown that oral CBD (15–160 mg), iv injection (5–30 mg), and inhalation of 0.15 mg/kg b.w. CBD did not lead to adverse effects. In addition, psychomotor function and psychological functions were not disturbed. Treatment with up to 600 mg CBD neither influenced physiological parameters (blood pressure, heart rate) nor performance on a verbal paired-associate learning test.1


Fasinu et al. created a table with an overview of clinical studies currently underway, registered in Clinical Trials. gov.49 In the following chapter, we highlight recent, acute clinical studies with CBD.


CBD-Drug Interactions


CBD can inhibit CYP2D6, which is also targeted by omeprazole and risperidone.2,14 There are also indications that CBD inhibits the hepatic enzyme CYP2C9, reducing the metabolization of warfarin and diclofenac.2,14 More clinical studies are needed, to check whether this interaction warrants an adaption of the used doses of the coadministered drugs.


The antibiotic rifampicin induces CYP3A4, leading to reduced CBD peak plasma concentrations.14 In contrast, the CYP3A4 inhibitor ketoconazole, an antifungal drug, almost doubles CBD peak plasma concentration. Interestingly, the CYP2C19 inhibitor omeprazole, used to treat gastroesophageal reflux, could not significantly affect the pharmacokinetics of CBD.14


A study, where a regimen of 6×100 mg CBD daily was coadministered with hexobarbital in 10 subjects, found that CBD increased the bioavailability and elimination half-time of the latter. Unfortunately, it was not mentioned whether this effect was mediated via the cytochrome P450 complex.16


Another aspect, which has not been thoroughly looked at, to our knowledge, is that several cytochrome isozymes are not only expressed in the liver but also in the brain. It might be interesting to research organ-specific differences in the level of CBD inhibition of various isozymes. Apart from altering the bioavailability in the overall plasma of the patient, this interaction might alter therapeutic outcomes on another level. Dopamine and tyramine are metabolized by CYP2D6, and neurosteroid metabolism also occurs via the isozymes of the CYP3A subgroup.50,51 Studying CBD interaction with neurovascular cytochrome P450 enzymes might also offer new mechanisms of action. It could be possible that CBD-mediated CYP2D6 inhibition increases dopamine levels in the brain, which could help to explain the positive CBD effects in addiction/withdrawal scenarios and might support its 5HT (=serotonin) elevating effect in depression.


Also, CBD can be a substrate of UDP glucuronosyltransferase.14 Whether this enzyme is indeed involved in the glucuronidation of CBD and also causes clinically relevant drug interactions in humans is yet to be determined in clinical studies. Generally, more human studies, which monitor CBD-drug interactions, are needed.


Physiological Effects


In a double-blind, placebo-controlled crossover study, CBD was coadministered with intravenous fentanyl to a total of 17 subjects.10 Blood samples were obtained before and after 400 mg CBD (previously demonstrated to decrease blood flow to (para)limbic areas related to drug craving) or 800 mg CBD pretreatment. This was followed by a single 0.5 (Session 1) or 1.0μg/kg (Session 2, after 1 week of first administration to allow for sufficient drug washout) intravenous fentanyl dose. Adverse effects and safety were evaluated with both forms of the Systematic Assessment for Treatment Emergent Events (SAFTEE). This extensive tool tests, for example, 78 adverse effects divided into 23 categories corresponding to organ systems or body parts. The SAFTEE outcomes were similar between groups. No respiratory depression or cardiovascular complications were recorded during any test session.


The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows. Peak CBD plasma concentrations of the 400 and 800 mg group were measured after 4 h in the first session (CBD administration 2 h after light breakfast). Peak urinary CBD and its metabolite concentrations occurred after 6 h in the low CBD group and after 4 h in the high CBD group. No effect was evident for urinary CBD and metabolite excretion except at the higher fentanyl dose, in which CBD clearance was reduced. Importantly, fentanyl coadministration did not produce respiratory depression or cardiovascular complications during the test sessions and CBD did not potentiate fentanyl’s effects. No correlation was found between CBD dose and plasma cortisol levels.


Various vital signs were also measured (blood pressure, respiratory/heart rate, oxygen saturation, EKG, respiratory function): CBD did not worsen the adverse effects (e.g., cardiovascular compromise, respiratory depression) of iv fentanyl. Coadministration was safe and well tolerated, paving the way to use CBD as a potential treatment for opioid addiction. The validated subjective measures scales Anxiety (visual analog scale [VAS]), PANAS (positive and negative subscores), and OVAS (specific opiate VAS) were administered across eight time points for each session without any significant main effects for CBD for any of the subjective effects on mood.10


A Dutch study compared subjective adverse effects of three different strains of medicinal cannabis, distributed via pharmacies, using VAS. “Visual analog scale is one of the most frequently used psychometric instruments to measure the extent and nature of subjective effects and adverse effects. The 12 adjectives used for this study were as follows: alertness, tranquility, confidence, dejection, dizziness, confusion/disorientation, fatigue, anxiety, irritability, appetite, creative stimulation, and sociability.” The high CBD strain contained the following concentrations: 6% Δ9-THC/7.5% CBD (n=25). This strain showed significantly lower levels of anxiety and dejection. Moreover, appetite increased less in the high CBD strain. The biggest observed adverse effect was “fatigue” with a score of 7 (out of 10), which did not differ between the three strains.52


Neurological and Neurospychiatric Effects


Anxiety. Forty-eight participants received subanxiolytic levels (32 mg) of CBD, either before or after the extinction phase in a double-blind, placebo-controlled design of a Pavlovian fear-conditioning experiment (recall with conditioned stimulus and context after 48 h and exposure to unconditioned stimulus after reinstatement). Skin conductance (=autonomic response to conditioning) and shock expectancy measures (=explicit aspects) of conditioned responding were recorded throughout. Among other scales, the Mood Rating Scale (MRS) and the Bond and Bodily Symptoms Scale were used to assess anxiety, current mood, and physical symptoms. “CBD given postextinction (active after consolidation phase) enhanced consolidation of extinction learning as assessed by shock expectancy.” Apart from the extinction-enhancing effects of CBD in human aversive conditioned memory, CBD showed a trend toward some protection against reinstatement of contextual memory. No side/adverse effects were reported.53


Psychosis. The review by Bergamaschi et al. mentions three acute human studies that have demonstrated the CBD antipsychotic effect without any adverse effects being observed. This holds especially true for the extrapyramidal motor side effects elicited by classical antipsychotic medication.1


Fifteen male, healthy subjects with minimal prior Δ9-THC exposure (<15 times) were tested for CBD affecting Δ9-THC propsychotic effects using functional magnetic resonance imaging (fMRI) and various questionnaires on three occasions, at 1-month intervals, following administration of 10 mg delta-9-Δ9-THC, 600 mg CBD, or placebo. Order of drug administration was pseudorandomized across subjects, so that an equal number of subjects received any of the drugs during the first, second, or third session in a double-blind, repeated-measures, within-subject design.54 No CBD effect on psychotic symptoms as measured with PANSS positive symptoms subscale, anxiety as indexed by the State Trait Anxiety Inventory (STAI) state, and Visual Analogue Mood Scale (VAMS) tranquilization or calming subscale, compared to the placebo group, was observed. The same is true for a verbal learning task (=behavioral performance of the verbal memory).


Moreover, pretreatment with CBD and subsequent Δ9-THC administration could reduce the latter’s psychotic and anxiety symptoms, as measured using a standardized scale. This effect was caused by opposite neural activation of relevant brain areas. In addition, no effects on peripheral cardiovascular measures such as heart rate and blood pressure were measured.54


A randomized, double-blind, crossover, placebo-controlled trial was conducted in 16 healthy nonanxious subjects using a within-subject design. Oral Δ9-THC=10 mg, CBD=600 mg, or placebo was administered in three consecutive sessions at 1-month intervals. The doses were selected to only evoke neurocognitive effects without causing severe toxic, physical, or psychiatric reactions. The 600 mg CBD corresponded to mean (standard deviation) whole blood levels of 0.36 (0.64), 1.62 (2.98), and 3.4 (6.42) ng/mL, 1, 2, and 3 h after administration, respectively.


Physiological measures and symptomatic effects were assessed before, and at 1, 2, and 3 h postdrug administration using PANSS (a 30-item rating instrument used to assess psychotic symptoms, with ratings based on a semistructured clinical interview yielding subscores for positive, negative, and general psychopathology domains), the self-administered VAMS with 16 items (e.g., mental sedation or intellectual impairment, physical sedation or bodily impairments, anxiety effects and other types of feelings or attitudes), the ARCI (Addiction Research Center Inventory; containing empirically derived drug-induced euphoria; stimulant-like effects; intellectual efficiency and energy; sedation; dysphoria; and somatic effects) to assess drug effects and the STAI-T/S, where subjects were evaluated on their current mood and their feelings in general.


There were no significant differences between the effects of CBD and placebo on positive and negative psychotic symptoms, general psychopathology (PANSS), anxiety (STAI-S), dysphoria (ARCI), sedation (VAMS, ARCI), and the level of subjective intoxication (ASI, ARCI), where Δ9-THC did have a pronounced effect. The physiological parameters, heart rate and blood pressure, were also monitored and no significant difference between the placebo and the CBD group was observed.55


Addiction. A case study describes a patient treated for cannabis withdrawal according to the following CBD regimen: “treated with oral 300 mg on Day 1; CBD 600 mg on Days 2–10 (divided into two doses of 300 mg), and CBD 300 mg on Day 11.” CBD treatment resulted in a fast and progressive reduction in withdrawal, dissociative and anxiety symptoms, as measured with the Withdrawal Discomfort Score, the Marijuana Withdrawal Symptom Checklist, Beck Anxiety Inventory, and Beck Depression Inventory (BDI). Hepatic enzymes were also measured daily, but no effect was reported.56


Naturalistic studies with smokers inhaling cannabis with varying amounts of CBD showed that the CBD levels were not altering psychomimetic symptoms.1 Interestingly, CBD was able to reduce the “wanting/liking”=implicit attentional bias caused by exposure to cannabis and food-related stimuli. CBD might work to alleviate disorders of addiction, by altering the attentive salience of drug cues. The study did not further measure side effects.57


CBD can also reduce heroin-seeking behaviors (e.g., induced by a conditioned cue). This was shown in the preclinical data mentioned earlier and was also replicated in a small double-blind pilot study with individuals addicted to opioids, who have been abstinent for 7 days.52,53 They either received placebo or 400 or 800 mg oral CBD on three consecutive days. Craving was induced with a cue-induced reinstatement paradigm (1 h after CBD administration). One hour after the video session, subjective craving was already reduced after a single CBD administration. The effect persisted for 7 days after the last CBD treatment. Interestingly, anxiety measures were also reduced after treatment, whereas no adverse effects were described.23,58


A pilot study with 24 subjects was conducted in a randomized, double-blind, placebo-controlled design to evaluate the impact of the ad hoc use of CBD in smokers, who wished to stop smoking. Pre- and post-testing for mood and craving of the participants was executed. These tests included the Behaviour Impulsivity Scale, BDI, STAI, and the Severity of Dependence Scale. During the week of CBD inhalator use, subjects used a diary to log their craving (on a scale from 1 to 100=VAS measuring momentary subjective craving), the cigarettes smoked, and the number of times they used the inhaler. Craving was assessed using the Tiffany Craving Questionnaire (11). On day 1 and 7, exhaled CO was measured to test smoking status. Sedation, depression, and anxiety were evaluated with the MRS.


Over the course of 1 week, participants used the inhaler when they felt the urge to smoke and received a dose of 400 μg CBD via the inhaler (leading to >65% bioavailability); this significantly reduced the number of cigarettes smoked by ca. 40%, while craving was not significantly different in the groups post-test. At day 7, the anxiety levels for placebo and CBD group did not differ. CBD did not increase depression (in contract to the selective CB1 antagonist rimonabant). CBD might weaken the attentional bias to smoking cues or could have disrupted reconsolidation, thereby destabilizing drug-related memories.59


Cell Migration


According to our literature survey, there currently are no studies about CBD role in embryogenesis/cell migration in humans, even though cell migration does play a role in embryogenesis and CBD was shown to be able to at least influence migratory behavior in cancer.1


Endocrine Effects and Glycemic (Including Appetite) Effects


To the best of our knowledge, no acute studies were performed that solely concentrated on CBD glycemic effects. Moreover, the only acute study that also measured CBD effect on appetite was the study we described above, comparing different cannabis strains. In this study, the strain high in CBD elicited less appetite increase compared to the THC-only strain.52


Eleven healthy volunteers were treated with 300 mg (seven patients) and 600 mg (four patients) oral CBD in a double-blind, placebo-controlled study. Growth hormone and prolactin levels were unchanged. In contrast, the normal decrease of cortisol levels in the morning (basal measurement=11.0±3.7 μg/dl; 120 min after placebo=7.1±3.9 μg/dl) was inhibited by CBD treatment (basal measurement=10.5±4.9 μg/dl; 120 min after 300 mg CBD=9.9±6.2 μg/dl; 120 min after 600 mg CBD=11.6±11.6 μg/dl).60


A more recent study also used 600 mg oral CBD for a week and compared 24 healthy subjects to people at risk for psychosis (n=32; 16 received placebo and 16 CBD). Serum cortisol levels were taken before the TSST (Trier Social Stress Test), immediately after, as well as 10 and 20 min after the test. Compared to the healthy individuals, the cortisol levels increased less after TSST in the 32 at-risk individuals. The CBD group showed less reduced cortisol levels but differences were not significant.61 It has to be mentioned that these data were presented at a conference and are not yet published (to our knowledge) in a peer-reviewed journal.


Chronic CBD Studies in Humans


Truly chronic studies with CBD are still scarce. One can often argue that what the studies call “chronic” CBD administration only differs to acute treatment, because of repeated administration of CBD. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.


CBD-Drug Interactions


An 8-week-long clinical study, including 13 children who were treated for epilepsy with clobazam (initial average dose of 1 mg/kg b.w.) and CBD (oral; starting dose of 5 mg/kg b.w. raised to maximum of 25 mg/kg b.w.), showed the following. The CBD interaction with isozymes CYP3A4 and CYP2C19 caused increased clobazam bioavailability, making it possible to reduce the dose of the antiepileptic drug, which in turn reduced its side effects.62


These results are supported by another study described in the review by Grotenhermen et al.63 In this study, 33 children were treated with a daily dose of 5 mg/kg CBD, which was increased every week by 5 mg/kg increments, up to a maximum level of 25 mg/kg. CBD was administered on average with three other drugs, including clobazam (54.5%), valproic acid (36.4%), levetiracetam (30.3%), felbamate (21.2%), lamotrigine (18.2%), and zonisamide (18.2%). The coadministration led to an alteration of blood levels of several antiepileptic drugs. In the case of clobazam this led to sedation, and its levels were subsequently lowered in the course of the study.


Physiological Effects


A first pilot study in healthy volunteers in 1973 by Mincis et al. administering 10 mg oral CBD for 21 days did not find any neurological and clinical changes (EEG; EKG).64 The same holds true for psychiatry and blood and urine examinations. A similar testing battery was performed in 1980, at weekly intervals for 30 days with daily oral CBD administration of 3 mg/kg b.w., which had the same result.65


Neurological and Neuropsychiatric Effects


Anxiety. Clinical chronic (lasting longer than a couple of weeks) studies in humans are crucial here but were mostly still lacking at the time of writing this review. They hopefully will shed light on the inconsistencies observerd in animal studies. Chronic studies in humans may, for instance, help to test whether, for example, an anxiolytic effect always prevails after chronic CBD treatment or whether this was an artifact of using different animal models of anxiety or depression.2,18


Psychosis and bipolar disorder. In a 4-week open trial, CBD was tested on Parkinson’s patients with psychotic symptoms. Oral doses of 150–400 mg/day CBD (in the last week) were administered. This led to a reduction of their psychotic symptoms. Moreover, no serious side effects or cognitive and motor symptoms were reported.66


Bergamaschi et al. describe a chronic study, where a teenager with severe side effects of traditional antipsychotics was treated with up to 1500 mg/day of CBD for 4 weeks. No adverse effects were observed and her symptoms improved. The same positive outcome was registered in another study described by Bergamaschi et al., where three patients were treated with a starting dose of CBD of 40 mg, which was ramped up to 1280 mg/day for 4 weeks.1 A double-blind, randomized clinical trial of CBD versus amisulpride, a potent antipsychotic in acute schizophrenia, was performed on a total of 42 subjects, who were treated for 28 days starting with 200 mg CBD per day each.67 The dose was increased stepwise by 200 mg per day to 4×200 mg CBD daily (total 800 mg per day) within the first week. The respective treatment was maintained for three additional weeks. A reduction of each treatment to 600 mg per day was allowed for clinical reasons, such as unwanted side effects after week 2. This was the case for three patients in the CBD group and five patients in the amisulpride group. While both treatments were effective (no significant difference in PANSS total score), CBD showed the better side effect profile. Amisulpride, working as a dopamine D2/D3-receptor antagonist, is one of the most effective treatment options for schizophrenia. CBD treatment was accompanied by a substantial increase in serum anandamide levels, which was significantly associated with clinical improvement, suggesting inhibition of anandamide deactivation via reduced FAAH activity.


In addition, the FAAH substrates palmitoylethanolamide and linoleoyl-ethanolamide (both lipid mediators) were also elevated in the CBD group. CBD showed less serum prolactin increase (predictor of galactorrhoea and sexual dysfunction), fewer extrapyramidal symptoms measured with the Extrapyramidal Symptom Scale, and less weight gain. Moreover, electrocardiograms as well as routine blood parameters were other parameters whose effects were measured but not reported in the study. CBD better safety profile might improve acute compliance and long-term treatment adherence.67,68


A press release by GW Pharmaceuticals of September 15th, 2015, described 88 patients with treatment-resistant schizophrenic psychosis, treated either with CBD (in addition to their regular medication) or placebo. Important clinical parameters improved in the CBD group and the number of mild side effects was comparable to the placebo group.2 Table 2 shows an overview of studies with CBD for the treatment of psychotic symptoms and its positive effect on symptomatology and the absence of side effects.69


Table 2 Studies with CBD


Treatment of two patients for 24 days with 600–1200 mg/day CBD, who were suffering from BD, did not lead to side effects.70 Apart from the study with two patients mentioned above, CBD has not been tested systematically in acute or chronic administration scenarios in humans for BD according to our own literature search.71


Epilepsy. Epileptic patients were treated for 135 days with 200–300 mg oral CBD daily and evaluated every week for changes in urine and blood. Moreover, neurological and physiological examinations were performed, which neither showed signs of CBD toxicity nor severe side effects. The study also illustrated that CBD was well tolerated.65


A review by Grotenhermen and Müller-Vahl describes several clinical studies with CBD2: 23 patients with therapy-resistant epilepsy (e.g., Dravet syndrome) were treated for 3 months with increasing doses of up to 25 mg/kg b.w. CBD in addition to their regular epilepsy medication. Apart from reducing the seizure frequency in 39% of the patients, the side effects were only mild to moderate and included reduced/increased appetite, weight gain/loss, and tiredness.


Another clinical study lasting at least 3 months with 137 children and young adults with various forms of epilepsy, who were treated with the CBD drug Epidiolex, was presented at the American Academy for Neurology in 2015. The patients were suffering from Dravet syndrome (16%), Lennox–Gastaut syndrome (16%), and 10 other forms of epilepsy (some among them were very rare conditions). In this study, almost 50% of the patients experienced a reduction of seizure frequency. The reported side effects were 21% experienced tiredness, 17% diarrhea, and 16% reduced appetite. In a few cases, severe side effects occurred, but it is not clear, if these were caused by Epidiolex. These were status epilepticus (n=10), diarrhea (n=3), weight loss (n=2), and liver damage in one case.


The largest CBD study conducted thus far was an open-label study with Epidiolex in 261 patients (mainly children, the average age of the participants was 11) suffering from severe epilepsy, who could not be treated sufficiently with standard medication. After 3 months of treatment, where patients received CBD together with their regular medication, a median reduction of seizure frequency of 45% was observed. Ten percent of the patients reported side effects (tiredness, diarrhea, and exhaustion).2


After extensive literature study of the available trials performed until September 2016, CBD side effects were generally mild and infrequent. The only exception seems to be a multicenter open-label study with a total of 162 patients aged 1–30 years, with treatment-resistant epilepsy. Subjects were treated for 1 year with a maximum of 25 mg/kg (in some clinics 50 mg/kg) oral CBD, in addition to their standard medication.


This led to a reduction in seizure frequency. In this study, 79% of the cohort experienced side effects. The three most common adverse effects were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), and diarrhea (n=31 [19%]).72 It has to be pointed out that no control group existed in this study (e.g., placebo or another drug). It is therefore difficult to put the side effect frequency into perspective. Attributing the side effects to CBD is also not straightforward in severely sick patients. Thus, it is not possible to draw reliable conclusions on the causation of the observed side effects in this study.


Parkinson’s disease. In a study with a total of 21 Parkinson’s patients (without comorbid psychiatric conditions or dementia) who were treated with either placebo, 75 mg/day CBD or 300 mg/day CBD in an exploratory double-blind trial for 6 weeks, the higher CBD dose showed significant improvement of quality of life, as measured with PDQ-39. This rating instrument comprised the following factors: mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. For the factor, “activities of daily living,” a possible dose-dependent relationship could exist between the low and high CBD group—the two CBD groups scored significantly different here. Side effects were evaluated with the UKU (Udvalg for Kliniske Undersøgelser). This assessment instrument analyzes adverse medication effects, including psychic, neurologic, autonomic, and other manifestations. Using the UKU and verbal reports, no significant side effects were recognized in any of the CBD groups.73


Huntington’s disease. Fifteen neuroleptic-free patients with Huntington’s disease were treated with either placebo or oral CBD (10 mg/kg b.w. per day) for 6 weeks in a double-blind, randomized, crossover study design. Using various safety outcome variables, clinical tests, and the cannabis side effect inventory, it was shown that there were no differences between the placebo group and the CBD group in the observed side effects.6


Immune System


Forty-eight patients were treated with 300 mg/kg oral CBD, 7 days before and until 30 days after the transplantation of allogeneic hematopoietic cells from an unrelated donor to treat acute leukemia or myelodysplastic syndrome in combination with standard measures to avoid GVHD (graft vs. host disease; cyclosporine and short course of MTX). The occurrence of various degrees of GVHD was compared with historical data from 108 patients, who had only received the standard treatment. Patients treated with CBD did not develop acute GVHD. In the 16 months after transplantation, the incidence of GHVD was significantly reduced in the CBD group. Side effects were graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) classification, which did not detect severe adverse effects.74


Endocrine and Glycemic (Including Appetite, Weight Gain) Effects


In a placebo-controlled, randomized, double-blind study with 62 subjects with noninsulin-treated type 2 diabetes, 13 patients were treated with twice-daily oral doses of 100 mg CBD for 13 weeks. This resulted in lower resistin levels compared to baseline. The hormone resistin is associated with obesity and insulin resistance. Compared to baseline, glucose-dependent insulinotropic peptide levels were elevated after CBD treatment. This incretin hormone is produced in the proximal duodenum by K cells and has insulinotropic and pancreatic b cell preserving effects. CBD was well tolerated in the patients. However, with the comparatively low CBD concentrations used in this phase-2-trial, no overall improvement of glycemic control was observed.40


When weight and appetite were measured as part of a measurement battery for side effects, results were inconclusive. For instance, the study mentioned above, where 23 children with Dravet syndrome were treated, increases as well as decreases in appetite and weight were observed as side effects.2 An open-label trial with 214 patients suffering from treatment-resistant epilepsy showed decreased appetite in 32 cases. However, in the safety analysis group, consisting of 162 subjects, 10 showed decreased weight and 12 had gained weight.52 This could be either due to the fact that CBD only has a small effect on these factors, or appetite and weight are complex endpoints influenced by multiple factors such as diet and genetic predisposition. Both these factors were not controlled for in the reviewed studies.



Dr. Alex Jimenez’s Insight

One of the most crucially important qualities of cannabidiol, or CBD, is its lack of psychoactivity. When taken on its own, consumers can experience the many health benefits of CBD without experiencing the euphoric sensations commonly known to be caused by THC. Cannabidiol acts directly with the endocannabinoid system, an essential system in the human body which many individuals may not be particularly familiar with. When CBD binds to the endocannabinoid system’s receptors, it can stimulate all kinds of changes in the human body. Most of those changes are beneficial, and research studies keep uncovering real and potential medical uses for them.




This review could substantiate and expand the findings of Bergamaschi et al. about CBD favorable safety profile.1 Nonetheless, various areas of CBD research should be extended. First, more studies researching CBD side effects after real chronic administration need to be conducted. Many so-called chronic administration studies, cited here were only a couple of weeks long. Second, many trials were conducted with a small number of individuals only. To perform a throrough general safety evaluation, more individuals have to be recruited into future clinical trials. Third, several aspects of a toxicological evaluation of a compound such as genotoxicity studies and research evaluating CBD effect on hormones are still scarce. Especially, chronic studies on CBD effect on, for example, genotoxicity and the immune system are still missing. Last, studies that evaluate whether CBD-drug interactions occur in clinical trials have to be performed.


In conclusion, CBD safety profile is already established in a plethora of ways. However, some knowledge gaps detailed above should be closed by additional clinical trials to have a completely well-tested pharmaceutical compound.


Abbreviations Used


  • AD – Alzheimer’s disease
  • ARCI – Addiction Research Center Inventory
  • BD – bipolar disorder
  • BDI – Beck Depression Inventory
  • CBD – cannabidiol
  • HSP – heat shock protein
  • IL – interleukin
  • MRS – Mood Rating Scale
  • PPI – prepulse inhibition
  • ROS – reactive oxygen species
  • SAFTEE – Systematic Assessment for Treatment Emergent Events
  • STAI – State Trait Anxiety Inventory
  • TSST – Trier Social Stress Test
  • UKU – Udvalg for Kliniske Undersøgelser
  • VAMS – Visual Analogue Mood Scale
  • VAS – Visual Analog Scales




The study was commissioned by the European Industrial Hemp Association. The authors thank Michal Carus, Executive Director of the EIHA, for making this review possible, for his encouragement, and helpful hints.


Author Disclosure Statement


EIHA paid nova-Institute for the review. F.G. is Executive Director of IACM.


Chiropractic Care Guide to CBD


Chiropractors and health professionals everywhere have become increasingly curious about the health benefits of CBD, or cannabidiol. Below, we will summarize what CBD oil is and we will also discuss its benefits to help guide consumers regarding the use of CBD oil. Incorporating CBD oil into chiropractic care with patients who can benefit from it’s various advantages, may be an innovative approach to help effectively treat a variety of health issues.


What is CBD Oil?


Cannabidiol, or CBD, is one of the compounds available today with the most growing interest behind its use but it is also one of the most controversial, and consumers worldwide are discovering its own health benefits. CBD is a cannabinoid, a type of over 100 chemical compounds found in the cannabis plant, such as marijuana and hemp. Found in the cannabis plant’s flowers, seeds, and stalks, CBD could be extracted from the plant as part of its cannabis oil. This oil can then be processed into many CBD supplements which can be used to boost well-being and the human body’s ability to keep equilibrium. When CBD oil has been extracted from low-THC hemp, the resulting products are non-psychoactive and safe to use by anyone.


How is CBD Used on Patients?


These CBD oil products can be given to patients to assist them attain health and wellness by promoting proper sleep, appetite, metabolism, immune reaction, and much more.


When CBD petroleum goods are utilized, plant-based cannabinoids or phytocannabinoids such as CBD are consumed by the body in the place where they make their way to the bloodstream and are transported through the body to interact with specific cannabinoid receptors in both peripheral and central nervous systems.


The neural communication network that employs these cannabinoid neurotransmitters, known as the endocannabinoid system, plays a fundamental role in the nervous system’s normal functioning. Endocannabinoids, such as anandamide and 2-AG, function as neurotransmitters, delivering chemical messages between nerve cells throughout the nervous system.


Phytocannabinoids mimic the functions of the body’s endogenous, or naturally-occurring, cannabinoids like anandamide and 2-AG. CBD and THC’s chemical structures are similar to those of 2-AG and anandamide, letting us use them to control the endocannabinoid system to achieve beneficial effects in the body.


CBD oil products come in many different consumption forms, such as capsules, tinctures, topical salves, vaporizers, pure hemp oil oral applicators, and more. These daily use products supply all the benefits of CBD with none of the worry over THC from other medical marijuana solutions.


But is CBD Legal?


Hemp products, such as nutritional supplements, are lawful in the U.S. provided that they’re manufactured using imported hemp. Hemp is defined at the U.S. as any cannabis plant containing 0.3 percent THC per dry weight or less. At those levels, the THC in hemp-derived CBD petroleum merchandise is far too low to produce psychoactive effects in people. Because our products are derived from low-THC hemp, they’re legal from the U.S. and in over 40 countries globally. However, we suggest you check your regional laws to find out if CBD oil products possess some particular restrictions.



Dr. Alex Jimenez’s Insight

Cannabidiol, or CBD, is a phytocannabinoid which is devoid of psychoactive activity which is why it has been used to provide its many benefits to patients without the side effects commonly associated with THC, or marijuana. Many healthcare professionals, including chiropractors, have started utilizing CBD as a part of their treatment program. Numerous research studies have demonstrated the many health benefits of cannabidiol, or CBD. According to the article above, the favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. Cannabidiol, or CBD, is most often utilized as an adjunct therapy, therefore, it’s interaction with other drugs and/or medications requires further research.


Is CBD Safe to Use on Patients?


CBD is regarded as safe and nontoxic for humans, even at large quantities. Researchers have conducted numerous studies regarding the use of cannabidiol, or CBD, for its health benefits.


In conclusion, the use of cannabidiol, or CBD, has been a controversial topic for many years. However, due to it’s reported health benefits, more and more research studies regarding its advantages in the human body have been conducted in attempts to shine light on the safety and efficiency of this compound as well as thoroughly discussing its side effects. Furthermore, the use of CBD by healthcare professionals, including chiropractors, has become a new treatment approach for a variety of underlying health issues. Further research studies are still required to conclude the health benefits of cannabidiol, or CBD.Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


Curated by Dr. Alex Jimenez


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Additional Topics: Back Pain

Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment

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Mechanisms of Acute Pain vs Chronic Pain Thu, 12 Jul 2018 21:38:10 +0000

Pain is a very important function of the human body, including the involvement of nociceptors and the central nervous system, or CNS, to transmit messages from noxious stimulation to the brain. Nociceptors are adrenal glands which are responsible for detecting hazardous or harmful stimuli and transmitting electrical signals into the nervous system. The receptors are present in skin, viscera, muscles, joints and meninges to discover a range of stimulation, which might be mechanical, thermal or chemical.


There are two types of nociceptors:


  • C-fibres would be the most common type and are slow to conduct and respond to stimuli. As the proteins in the membrane of the receptor convert the stimulation into electrical impulses that can be taken through the nervous system.
  • A

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    Pain is a very important function of the human body, including the involvement of nociceptors and the central nervous system, or CNS, to transmit messages from noxious stimulation to the brain. Nociceptors are adrenal glands which are responsible for detecting hazardous or harmful stimuli and transmitting electrical signals into the nervous system. The receptors are present in skin, viscera, muscles, joints and meninges to discover a range of stimulation, which might be mechanical, thermal or chemical.


    There are two types of nociceptors:


    • C-fibres would be the most common type and are slow to conduct and respond to stimuli. As the proteins in the membrane of the receptor convert the stimulation into electrical impulses that can be taken through the nervous system.
    • A-delta fibers are known to conduct more rapidly and convey messages of sharp, momentary pain.


    Additionally, there are silent nociceptors which are usually restricted to stimuli but can be “awoken” with high-intensity mechanical stimulation in response to chemical mediators from the body. Nociceptors may have many different voltage-gated stations for transduction that cause a set of action potentials to commence the electric signaling to the nervous system. The excitability and behavior of the cell are based on the types of channels within the nociceptor.


    It is important to differentiate between nociception and pain when considering the mechanism of the pain. Nociception is the normal response of the body to noxious stimuli, including reflexes below the suprathreshold that protect the human body from injury. Pain is just perceived when superthreshold for those nociceptors to reach an action possible and initiate the pain pathway is attained, which is comparatively high. The purpose of the article below is to demonstrate the cellular and molecular mechanisms of pain, including acute pain and chronic pain, or persistent pain, as referred to below.


    Cellular and Molecular Mechanisms of Pain




    The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.


    Introduction: Acute Versus Persistent Pain


    The ability to detect noxious stimuli is essential to an organism’s survival and wellbeing. This is dramatically illustrated by examination of individuals who suffer from congenital abnormalities that render them incapable of detecting painful stimuli. These people cannot feel piercing pain from a sharp object, heat of an open flame, or even discomfort associated with internal injuries, such as a broken bone. As a result, they do not engage appropriate protective behaviors against these conditions, many of which can be life threatening.


    More commonly, alterations of the pain pathway lead to hypersensitivity, such that pain outlives its usefulness as an acute warning system and instead becomes chronic and debilitating. This may be seen, at some level, as an extension of the normal healing process, whereby tissue or nerve damage elicits hyperactivity to promote guarding of the injured area. For example, sunburn produces temporary sensitization of the affected area. As a result normally innocuous stimuli, such as light touch or warmth, are perceived as painful (a phenomenon referred to as allodynia), or normally painful stimuli elicit pain of greater intensity (referred to as hyperalgesia). At its extreme, the sensitization does not resolve. Indeed, individuals who suffer from arthritis, post-herpetic neuralgia (following a bout of shingles), or bone cancer, experience intense and often unremitting pain that is not only physiologically and psychologically debilitating, but may also hamper recovery. Chronic pain may even persist long after an acute injury, perhaps most commonly experienced as lower back pain or sciatica.


    Persistent or chronic pain syndromes can be initiated or maintained at peripheral and/or central loci. In either case, the elucidation of molecules and cell types that underlie normal (acute) pain sensation is key to understanding the mechanisms underlying pain hypersensitivity. In the present review we highlight the molecular complexity of the primary afferent nerve fibers that detect noxious stimuli. We not only summarize the processing of acute pain, but also describe how changes in pain processing occur in the setting of tissue or nerve injury.


    The profound differences between acute and chronic pain emphasize the fact that pain is not generated by an immutable, hard-wired system, but rather results from the engagement of highly plastic molecules and circuits, the molecular biochemical and neuroanatomical basis of which are the focus of current studies. Importantly, this new information has identified a host of potential therapeutic targets for the treatment of pain. We focus here on the peripheral and second order neurons in the spinal cord; the reader is referred to some excellent reviews of supraspinal pain processing mechanisms, which include remarkable insights that imaging studies have brought to the field (Apkarian et al., 2005).


    Anatomical Overview


    Nociception is the process by which intense thermal, mechanical or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors (Basbaum and Jessell, 2000). The cell bodies of nociceptors are located in the dorsal root ganglia (DRG) for the body and the trigeminal ganglion for the face, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach the noxious range, suggesting that they possess biophysical and molecular properties that enable them to selectively detect and respond to potentially injurious stimuli. There are two major classes of nociceptors. The first includes medium diameter myelinated (Aδ) afferents that mediate acute, well-localized “first” or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e. light touch). The second class of nociceptor includes small diameter unmyelinated “C” fibers that convey poorly localized, “second” or slow pain.


    Electrophysiological studies have further subdivided Aδ nociceptors into two main classes. Type I (HTM: high threshold mechanical nociceptors) respond to both mechanical and chemical stimuli, but have relatively high heat thresholds (>50C). If, however, the heat stimulus is maintained, these afferents will respond at lower temperatures. And most importantly, they will sensitize (i.e. the heat or mechanical threshold will drop) in the setting of tissue injury. Type II Aδ nociceptors have a much lower heat threshold, but a very high mechanical threshold. Activity of this afferent almost certainly mediates the “first” acute pain response to noxious heat. Indeed, compression block of myelinated peripheral nerve fibers eliminates first, but not second, pain. By contrast, the Type I fiber likely mediates the first pain provoked by pinprick and other intense mechanical stimuli.


    The unmyelinated C fibers are also heterogeneous. Like the myelinated afferents, most C fibers are polymodal, that is, they include a population that is both heat and mechanically sensitive (CMHs) (Perl, 2007). Of particular interest are the heat responsive, but mechanically insensitive unmyelinated afferents (so-called silent nociceptors) that develop mechanical sensitivity only in the setting of injury (Schmidt et al., 1995). These afferents are more responsive to chemical stimuli (capsaicin or histamine) compared to the CMHs, and likely come into play when the chemical milieu of inflammation alters their properties. Subsets of these afferents are also responsive to a variety of itch-producing pruritogens. It is worth noting that not all C fibers are nociceptors. Some respond to cooling, and a particularly interesting population of unmyelinated afferents responds to innocuous stroking of the hairy skin, but not to heat or chemical stimulation. These latter fibers appear to mediate pleasant touch (Olausson et al., 2008).


    Neuroanatomical and molecular characterization of nociceptors has further demonstrated their heterogeneity, particularly for the C fibers (Snider and McMahon, 1998). For example, the so-called ‘peptidergic’ population of C nociceptors releases the neuropeptides, substance P, and calcitonin-gene related peptide (CGRP); they also express the TrkA neurotrophin receptor, which responds to nerve growth factor (NGF). The non-peptidergic population of C nociceptors expresses the c-Ret neurotrophin receptor that is targeted by glial-derived neurotrophic factor (GDNF), as well as neurturin and artemin. A large percentage of the c-Ret-positive population also binds the IB4 isolectin, and expresses G protein-coupled receptors of the Mrg family (Dong et al., 2001), as well as specific purinergic receptor subtypes, notably P2X3. Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (TRPV1), cold (TRPM8), acidic milieu (ASICs), and a host of chemical irritants (TRPA1) (Julius and Basbaum, 2001). As noted below, these functionally and molecularly heterogeneous classes of nociceptors associate with specific function in the detection of distinct pain modalities.


    The Nociceptor: a Bidirectional Signaling Machine


    One generally thinks of the nociceptor as carrying information in one direction, transmitting noxious stimuli from the periphery to the spinal cord. However, primary afferent fibers have a unique morphology, called pseudo-unipolar, wherein both central and peripheral terminals emanate from a common axonal stalk. The majority of proteins synthesized by the DRG or trigeminal ganglion cell are distributed to both central and peripheral terminals. This distinguishes the primary afferent neuron from the prototypical neuron, where the recipient branch of the neuron (the dendrite) is biochemically distinct from the transmission branch (the axon). The biochemical equivalency of central and peripheral terminals means that the nociceptor can send and receive messages from either end. For example, just as the central terminal is the locus of Ca2+-dependent neurotransmitter release, so the peripheral terminal releases a variety of molecules that influence the local tissue environment. Neurogenic inflammation, in fact, refers to the process whereby peripheral release of the neuropeptides, CGRP and substance P, induces vasodilation and extravasation of plasma proteins, respectively (Basbaum and Jessell, 2000). Furthermore, whereas only the peripheral terminal of the nociceptor will respond to environmental stimuli (painful heat, cold and mechanical stimulation), both the peripheral and central terminals can be targeted by a host of endogenous molecules (such as pH, lipids, and neurotransmitters) that regulate its sensitivity. It follows that therapeutics directed at both terminals can be developed to influence the transmission of pain messages. For example, spinal (intrathecal) delivery of morphine targets opioid receptors expressed by the central terminal of nociceptors, whereas topically applied drugs (such as local anesthetics or capsaicin) regulate pain via an action at the peripheral terminal.


    Central Projections of the Nociceptor


    Primary afferent nerve fibers project to the dorsal horn of the spinal cord, which is organized into anatomically and electrophysiological distinct laminae (Basbaum and Jessell, 2000) (Figure 1). For example, Aδ nociceptors project to lamina I as well as to deeper dorsal horn (lamina V). The low threshold, rapidly conducting Aβ afferents, which respond to light touch, project to deep laminae (III, IV, and V). By contrast, C nociceptors project more superficially to laminae I and II.


    Figure 1 Anatomy of the Pain Pathway


    This remarkable stratification of afferent subtypes within the superficial dorsal horn is further highlighted by the distinct projection patterns of C nociceptors (Snider and McMahon, 1998). For example, most peptidergic C fibers terminate within lamina I and the most dorsal part of lamina II. By contrast, the nonpeptidergic afferents, including the Mrg-expressing subset, terminate in the mid-region of lamina II. The most ventral part of lamina II is characterized by the presence of excitatory interneurons that express the gamma isoform of protein kinase C (PKC), which has been implicated in injury-induced persistent pain (Malmberg et al., 1997). Recent studies indicate that this PKCγ layer is targeted predominantly by myelinated non-nociceptive afferents (Neumann et al., 2008). Consistent with these anatomical studies, electrophysiological analyses demonstrate that spinal cord neurons within lamina I are generally responsive to noxious stimulation (via Aδ and C fibers), neurons in laminae III and IV are primarily responsive to innocuous stimulation (via Aβ), and neurons in lamina V receive a convergent non-noxious and noxious input via direct (monosynaptic) Aδ and Aβ inputs and indirect (polysynaptic) C fiber inputs. The latter are called wide dynamic range (WDR) neurons, in that they respond to a broad range of stimulus intensities. There is also commonly a visceral input to these WDR neurons, such that the resultant convergence of somatic and visceral likely contributes to the phenomenon of referred pain, whereby pain secondary to an injury affecting a visceral tissue (for example, the heart in angina) is referred to a somatic structure (for example, the shoulder).


    Ascending Pathways and the Supraspinal Processing of Pain


    Projection neurons within laminae I and V constitute the major output from the dorsal horn to the brain (Basbaum and Jessell, 2000). These neurons are at the origin of multiple ascending pathways, including the spinothalamic and spinoreticulothalamic tracts, which carry pain messages to the thalamus and brainstem, respectively (Figure 2). The former is particularly relevant to the sensory-discriminative aspects of the pain experience (that is, where is the stimulus and how intense is it?), whereas the latter may be more relevant to poorly localized pains. More recently, attention has focused on spinal cord projections to the parabrachial region of the dorsolateral pons, because the output of this region provides for a very rapid connection with the amygdala, a region generally considered to process information relevant to the aversive properties of the pain experience.


    Figure 2 Primary Afferent Fibers and Spinal Cord


    From these brainstem and thalamic loci, information reaches cortical structures. There is no single brain area essential for pain (Apkarian et al., 2005). Rather, pain results from activation of a distributed group of structures, some of which are more associated with the sensory-discriminative properties (such as the somatosensory cortex) and others with the emotional aspects (such as the anterior cingulate gyrus and insular cortex). More recently, imaging studies demonstrate activation of prefrontal cortical areas, as well as regions not generally associated with pain processing (such as the basal ganglia and cerebellum). Whether and to what extent activation of these regions is more related to the response of the individual to the stimulus, or to the perception of the pain is not clear. Finally, Figure 2 illustrates the powerful descending controls that influence (both positive and negatively) the transmission of pain messages at the level of the spinal cord.


    Acute Pain


    The primary afferent nerve fiber detects environmental stimuli (of a thermal, mechanical, or chemical nature) and transduces this information into the language of the nervous system, namely electrical current. First, we review progress in understanding the molecular basis of signal detection, and follow this with a brief overview of recent genetic studies that highlight the contribution of voltage-gated channels to pain transmission (Figure 3).


    Figure 3 Nociceptor Diversity


    Activating the Nociceptor: Heat


    Human psychophysical studies have shown that there is a clear and reproducible demarcation between the perception of innocuous warmth and noxious heat, which enables us to recognize and avoid temperatures capable of causing tissue damage. This pain threshold, which typically rests around 43°C, parallels the heat sensitivity of C and Type II Aδ nociceptors described earlier. Indeed, cultured neurons from dissociated dorsal root ganglia show similar heat sensitivity. The majority display a threshold of 43°C, with a smaller cohort activated by more intense heat (threshold >50°C) (Cesare and McNaughton, 1996; Kirschstein et al., 1997; Leffler et al., 2007; Nagy and Rang, 1999). Molecular insights into the process of heat sensation came from the cloning and functional characterization of the receptor for capsaicin, the main pungent ingredient in ‘hot’ chili peppers. Capsaicin and related vanilloid compounds produce burning pain by depolarizing specific subsets of C and Aδ nociceptors through activation of the capsaicin (or vanilloid) receptor, TRPV1, one of approximately 30 members of the greater transient receptor potential (TRP) ion channel family (Caterina et al., 1997). The cloned TRPV1 channel is also gated by increases in ambient temperature, with a thermal activation threshold (∼43°C).


    Several lines of evidence support the hypothesis that TRPV1 an endogenous transducer of noxious heat. First, TRPV1 is expressed in the majority of heat-sensitive nociceptors (Caterina et al., 1997). Second, capsaicin- and heat-evoked currents are similar, if not identical, in regard to their pharmacological and biophysical properties, as are those of heterologously expressed TRPV1 channels. Third, and as described in greater detail below, TRPV1-evoked responses are markedly enhanced by pro-algesic or pro-inflammatory agents (such as extracellular protons, neurotrophins, or bradykinin), all of which produce hypersensitivity to heat in vivo (Tominaga et al., 1998)). Fourth, analysis of mice lacking this ion channel not only revealed a complete loss of capsaicin sensitivity, but these animals also exhibit significant impairment in their ability to detect and respond to noxious heat (Caterina et al., 2000; Davis et al., 2000). These studies also demonstrated an essential role for this channel in the process whereby tissue injury and inflammation leads to heat hypersensitivity, reflecting the ability of TRPV1 to serve as a molecular integrator of thermal and chemical stimuli (Caterina et al., 2000; Davis et al., 2000).


    The contribution of TRPV1 to acute heat sensation, however, has been challenged by data collected from an ex vivo preparation in which recordings are obtained from the soma of DRG neurons with intact central and peripheral fibers. In one study, no differences were observed in heat-evoked responses from wild type and TRPV1-deficient animals (Woodbury et al., 2004), but a more recent analysis from this group found that TRPV1-deficient mice do, indeed, lack a cohort of neurons robustly activated by noxious heat (Lawson et al., 2008). Taken together with the results described above we conclude that TRPV1 unquestionably contributes to acute heat sensation, but agree that TRPV1 is not solely responsible for heat transduction.


    In this regard, whereas TRPV1-deficient mice lack a component of behavioral heat sensitivity, the use of high dose capsaicin to ablate the central terminals of TRPV1-expressing primary afferent fibers results in a more profound, if not complete loss of acute heat pain sensitivity (Cavanaugh et al., 2009). As for the TRPV1 mutant, there is also a loss of tissue injury-evoked heat hyperalgesia. Taken together these results indicate that both the TRPV1-dependent and TRPV1-independent component of noxious heat sensitivity is mediated via TRPV1-expressing nociceptors.


    What accounts for the TRPV1-independent component of heat sensation? A number of other TRPV channel subtypes, including TRPV2, 3 and 4, have emerged as candidate heat transducers that could potentially cover detection of stimulus intensities flanking that of TRPV1, including both very hot (>50°C) and warm (mid-30°Cs) temperatures (Lumpkin and Caterina, 2007). Heterologously expressed TRPV2 channels display a temperature activation threshold of ∼52°C, whereas TRPV3 and TRPV4 are activated between 25 – 35°C. TRPV2 is expressed in a subpopulation of Aδ neurons that respond to high threshold noxious heat and its biophysical properties resemble those of native high threshold heat-evoked currents (Leffler et al., 2007; Rau et al., 2007). As yet, there are no published reports describing either physiological or behavioral tests of TRPV2 knockout mice. On the other hand, TRPV3- and TRPV4-deficient mice do display altered thermal preference when placed on a surface of graded temperatures, suggesting that these channels contribute in some way to temperature detection in vivo (Guler et al., 2002). Interestingly, both TRPV3 and TRPV4 show substantially greater expression in keratinocytes and epithelial cells compared to sensory neurons, raising the possibility that detection of innocuous heat stimuli involves a functional interplay between skin and the underlying primary afferent fibers (Chung et al., 2003; Peier et al., 2002b).


    Activating the Nociceptor: Cold


    As for capsaicin and TRPV1, natural cooling agents, such as menthol and eucalyptol, have been exploited as pharmacological probes to identify and characterize cold-sensitive fibers and cells (Hensel and Zotterman, 1951; Reid and Flonta, 2001) and the molecules that underlie their behavior. Indeed, most cold-sensitive neurons respond to menthol and display a thermal activation threshold of ∼25°C. TRPM8 is a cold and menthol-sen sitive channel whose physiological characteristics match those of native cold currents and TRPM8-deficient mice show a very substantial loss of menthol and cold-evoked responses at the cellular or nerve fiber level. Likewise, these animals display severe deficits in cold-evoked behavioral responses (Bautista et al., 2007; Colburn et al., 2007; Dhaka et al., 2007) over a wide range of temperatures spanning 30 to 10°C. As in the case of TRPV1 and he at, TRPM8-deficient mice are not completely insensitive to cold. For example, there remains a small (∼4%) cohort of cold-sensitive, menthol-insensitive neurons that have a low threshold of activation, of approximately 12°C. These may account for the residual cold sensitivity seen in behavioral tests, wherein TRPM8-deficient animals can still avoid extremely cold surfaces below 10°C. Importantly, TRPM8-deficient mice show normal sensitivity to noxious heat. Indeed, TRPV1 and TRPM8 are expressed in largely non-overlapping neuronal populations, consistent with the notion that hot and cold detection mechanisms are organized into anatomically and functionally distinct ‘labeled lines.’


    Based on heterologous expression systems, TRPA1 has also been suggested to detect cold, specifically within the noxious (<15°C) range. Moreover TRPA1 is activated by the cooling compounds icilin and menthol (Bandell et al., 2004; Karashima et al., 2007; Story et al., 2003), albeit at relatively high concentrations compared to their actions at TRPM8. However, there continues to be disagreement as to whether native or recombinant TRPA1 are intrinsically cold sensitive (Bandell et al., 2004; Jordt et al., 2004; Karashima et al., 2009; Nagata et al., 2005; Zurborg et al., 2007). This controversy has not been resolved by the analysis of two independent TRPA1-deficient mouse lines. At the cellular level, one study showed normal cold-evoked responses in TRPA1-deficient neurons following a 30 second drop in temperature from 22°C to 4 °C (Bautista et al., 2006); a more recent study has shown a decrease in cold sensitive neurons from 26% (WT) to 10% (TRPA1-/-), when tested after a 200 sec drop in temperature, from 30°C to 10°C (Karashima et al., 2009). In behavioral studies, TRPA1-deficient mice display responses similar to wild-type littermates in the cold-plate and acetone-evoked evaporative cooling assays (Bautista et al., 2006). A second study using the same assays showed that female, but not male, TRPA1 knockout animals displayed attenuated cold sensitivity compared to wild type littermates (Kwan et al., 2006). Karashima et al found no difference in shivering or paw withdrawal latencies in male or female TRPA1-deficient mice on the cold plate test, but observed that prolonged exposure to the cold surface elicited jumping in wild type, but not TRPA1-deficient animals (Karashima et al., 2009). Conceivably, the latter phenotype reflects a contribution of TRPA1 to cold sensitivity in the setting of tissue injury, but not to acute cold pain. Consistent with the latter hypothesis, single nerve fiber recordings show no decrement in acute cold sensitivity in TRPA1-deficient mice (Cavanaugh et al., 2009; Kwan et al., 2009). Finally, it is noteworthy that capsaicin-treated mice lacking the central terminals of TRPV1-expressing fibers show intact behavioral responses to cool and noxious cold stimuli (Cavanaugh et al., 2009). Because TRPA1 is expressed in a subset of TRPV1-positive neurons, it follows that TRPA1 is not required for normal acute cold sensitivity. Future studies using mice deficient for both TRPM8 and TRPA1 will help to resolve these issues and to identify the molecules and cell types that underlie the residual TRPM8-independent component of cold sensitivity.


    Additional molecules, including voltage-gated sodium channels (discussed below), voltage-gated potassium channels, and two-pore background KCNK potassium channels, coordinate with TRPM8 to fine tune cold thresholds or to propagate cold-evoked action potentials (Viana et al., 2002; Zimmermann et al., 2007; Noel et al., 2009). For example, specific Kv1 inhibitors increase the temperature threshold of cold-sensitive neurons and injection of these inhibitors into the rodent hindpaw reduces behavioral responses to cold, but not to heat or mechanical stimuli (Madrid et al., 2009). Two members of the KCNK channel family, KCNK2 (TREK-1) and KCNK4 (TRAAK) are expressed in a subset of C-fiber nociceptors (Noel et al., 2009) and can be modulated by numerous physiological and pharmacological stimuli, including pressure and temperature. Furthermore, mice lacking these channels display abnormalities in sensitivity to pressure, heat, and cold (Noel et al., 2009). Although these findings suggest that TREK-1 and TRAAK channels modulate nociceptor excitability, it remains unclear how their intrinsic sensitivity to physical stimuli relates to their in vivo contribution to thermal or mechanical transduction.


    Activating the Nociceptor: Mechanical


    The somatosensory system detects quantitatively and qualitatively diverse mechanical stimuli, ranging from light brush of the skin to distension of the bladder wall. A variety of mechanosensitive neuronal subtypes are specialized to detect this diverse array of mechanical stimuli and can be categorized according to threshold sensitivity. High threshold mechanoreceptors include C fibers and slowly adapting Aδ mechanoreceptor (AM) fibers, both of which terminate as free nerve endings in the skin. Low threshold mechanoreceptors include Aδ D-hair fibers that terminate on down hairs in the skin and detect light touch. Finally, Aβ fibers that innervate Merkel cells, Pacinian corpuscles and hair follicles detect texture, vibration, and light pressure.


    As in the case of thermal stimuli, mechanical sensitivity has been probed at a number of levels, including dissociated sensory neurons in culture, ex-vivo fiber recordings, as well as recordings from central (i.e. dorsal horn neurons) and measurements of behavioral output. Ex-vivo skin-nerve recordings have been most informative in matching stimulus properties (such as intensity, frequency, speed, and adaptation) to specific fiber subtypes. For example, Aβ fibers are primarily associated with sensitivity to light touch, whereas C and Aδ fibers are primarily responsive to noxious mechanical insults. At the behavioral level, mechanical sensitivity is typically assessed using two techniques. The most common involves measuring reflex responses to constant force applied to the rodent hind paw by calibrated filaments (Von Frey hairs). The second applies increasing pressure to the paw or tail via a clamp system. In either case, information about mechanical thresholds is obtained under normal (acute) or injury (hypersensitivity) situations. One of the challenges in this area has been to develop additional behavioral assays that measure different aspects of mechanosensation, such as texture discrimination and vibration, which will facilitate the study of both noxious and non-noxious touch (Wetzel et al., 2007).


    At the cellular level, pressure can be applied to the cell bodies of cultured somatosensory neurons (or to their neurites) using a glass probe, changes in osmotic strength, or stretch via distension of an elastic culture surface, though it is unclear which stimulus best mimics physiological pressure (Bhattacharya et al., 2008; Cho et al., 2006; Cho et al., 2002; Drew et al., 2002; Hu and Lewin, 2006; Lin et al., 2009; Takahashi and Gotoh, 2000). Responses can be assessed using electrophysiological or live cell imaging methods. The consensus from such studies is that that pressure opens a mechanosensitive cation channel to elicit rapid depolarization. However, a dearth of specific pharmacological probes and molecular markers with which to characterize these responses or to label relevant neuronal subtypes has hampered attempts to match cellular activities with anatomically or functionally defined nerve fiber subclasses. These limitations have also impeded the molecular analysis of mechansosensation and the identification of molecules that constitute the mechanotransduction machinery. Nonetheless, a number of candidates have emerged, based largely on studies of mechanosensation in model genetic organisms. Mammalian orthologues of these proteins have been examined using gene targeting approaches in mice, in which the techniques mentioned above can be used to assess deficits in mechanosensation at all levels. Below we briefly summarize some of the candidates revealed in these studies.


    Candidate Mechanotransducers: DEG/ENaC Channels


    Studies in the nematode Caenorhabditis elegans (C. elegans) have identified mec-4 and mec-10, members of the degenerin/epithelial Na+ channel (DEG/ENaC) families, as mechanotransducers in body touch neurons (Chalfie, 2009). Based on these studies, the mammalian orthologues ASIC 1, 2 and 3 have been proposed as mechanotransduction channels. ASICs are acid-sensitive ion channels that serve as receptors for extracellular protons (tissue acidosis) produced during ischemia (see below). Although these channels are expressed by both low and high threshold mechanosensitive neurons, genetic studies do not uniformly support an essential role in mechanotransduction. Mice lacking functional ASIC1 channels display normal behavioral responses to cutaneous touch, and little or no change in mechanical sensitivity when assessed by single fiber recording (Page et al., 2004; Price et al., 2000). Likewise, peripheral nerve fibers from ASIC2-deficient mice display only a slight decrease in action potential firing to mechanical stimuli, whereas ASIC3-deficient fibers display a slight increase (no change in mechanical thresholds or baseline behavioral mechanical sensitivity was observed in these animals) (Price et al., 2001; Roza et al., 2004). Analysis of mice deficient for both ASIC2 and ASIC3 also fails to support a role for these channels in cutaneous mechanotransduction (Drew et al., 2004). Thus, although these channels appear to play a role in musculoskeletal and ischemic pain (see below), their contribution to mechanosensation remains unresolved.


    Genetic studies suggest that C. elegans mec-4/mec-10 channels exist in a complex with the stomatin-like protein MEC-2 (Chalfie, 2009). Mice lacking the MEC-2 orthologue, SLP3, display a loss of mechanosensitivity in low-threshold Aβ and Aδ fibers, but not in C fibers (Wetzel et al., 2007). These mice exhibit altered tactile acuity, but display normal responses to noxious pressure, suggesting that SLP3 contributes to the detection of innocuous, but not noxious mechanical stimuli. Whether SLP3 functions in a mechanotransduction complex or interacts with ASICs in mammalian sensory neurons is unknown.


    Candidate Mechanotransducers: TRP Channels


    As noted above, when expressed heterologously, TRPV2 not only responds to noxious heat, but also to osmotic stretch. Additionally, native TRPV2 channels in vascular smooth muscle cells are activated by direct suction and osmotic stimuli (Muraki et al., 2003). A role for TRPV2 for somatosensory mechanotransduction in vivo has not yet been tested.


    TRPV2 is robustly expressed in medium and large diameter, Aδ fibers that respond to both mechanical and thermal stimuli (Caterina et al., 1999; Muraki et al., 2003). TRPV4 shows modest expression in sensory ganglia, but is more abundantly expressed in the kidney and stretch-sensitive urothelial cells of the bladder (Gevaert et al., 2007; Mochizuki et al., 2009). When heterologously expressed, both TRPV2 and TRPV4 have been shown to respond to changes in osmotic pressure (Guler et al., 2002; Liedtke et al., 2000; Mochizuki et al., 2009; Strotmann et al., 2000). Analysis of TRPV4-deficient animals suggests a role in osmosensation as knockout animals display defects in blood pressure, water balance, and bladder voiding (Gevaert et al., 2007; Liedtke and Friedman, 2003). These animals exhibit normal acute cutaneous mechanosensation, but show deficits in models of mechanical and thermal hyperalgesia (Alessandri-Haber et al., 2006; Chen et al., 2007; Grant et al., 2007; Suzuki et al., 2003). Thus, TRPV4 is unlikely to serve as a primary mechanotransducer in sensory neurons, but may contribute to injury-evoked pain hypersensitivity.


    TRPA1 has also been proposed to serve as a detector of mechanical stimuli. Heterologously expressed mammalian TRPA1 is activated by membrane crenators (Hill and Schaefer, 2007) and the worm orthologue is sensitive to mechanical pressure applied via a suction pipette (Kindt et al., 2007). However, TRPA1-deficient mice display only weak defects in mechanosensory behavior and the results are inconsistent. Two studies reported no change in mechanical thresholds in TRPA1-deficient animals (Bautista et al., 2006; Petrus et al., 2007), whereas a third study reported deficits (Kwan et al., 2006). A more recent study shows that C and Aβ mechanosensitive fibers in TRPA1 knockout animals have altered responses to mechanical stimulation (some increased and others decreased) (Kwan et al., 2009). Whether and how these differential physiological effects are manifest at the level of behavior is unclear. Taken together, TRPA1 does not appear to function as a primary detector of acute mechanical stimuli, but perhaps modulates excitability of mechanosensitive afferents.


    Candidate Mechanotransducers: KCNK Channels


    In addition to the potential mechanotransducer role of KCNK2 and 4 (see above), KCNK18 has been discussed for its possible contribution to mechanosensation. Thus, KCNK18 is targeted by hydroxy-a-sanshool, the pungent ingredient in Szechuan peppercorns that produces tingling and numbing sensations, suggestive of an interaction with touch-sensitive neurons (Bautista et al., 2008; Bryant and Mezine, 1999; Sugai et al., 2005). KCNK18 is expressed in a subset of presumptive peptidergic C fibers and low threshold (Aβ) mechanoreceptors, where it serves as a major regulator of action potential duration and excitability (Bautista et al., 2008; Dobler et al., 2007). Moreover, sanshool depolarizes osmo- and mechanosensitive large diameter sensory neurons, as well as a subset of nociceptors (Bautista et al., 2008; Bhattacharya et al., 2008). Although it is not known if KCNK18 is directly sensitive to mechanical stimulation, it may be a critical regulator of the excitability of neurons involved in innocuous or noxious touch sensation.


    In summary, the molecular basis of mammalian mechanotransduction is far from clarified. Mechanical hypersensitivity in response to tissue or nerve injury represents a major clinical problem and thus elucidating the biological basis of touch under normal and pathophysiological conditions remains one of the main challenges in somatosensory and pain research.


    Activating the Nociceptor: Chemical


    Chemo-nociception is the process by which primary afferent neurons detect environmental irritants and endogenous factors produced by physiological stress. In the context of acute pain, chemo-nociceptive mechanisms trigger aversive responses to a variety of environmental irritants. Here, again, TRP channels have prominent roles, which is perhaps not surprising given that they function as receptors for plant-derived irritants, including capsaicin (TRPV1), menthol (TRPM8), as well as the pungent ingredients in mustard and garlic plants, isothiocyanates and thiosulfinates (TRPA1) (Bandell et al., 2004; Caterina et al., 1997; Jordt et al., 2004; McKemy et al., 2002; Peier et al., 2002a).


    With respect to environmental irritants, TRPA1 has emerged as a particularly interesting member of this group. This is because TRPA1 responds to compounds that are structurally diverse but unified in their ability to form covalent adducts with thiol groups. For example, allyl isothiocyanate (from wasabi) or allicin (from garlic) are membrane permeable electrophiles that activate TRPA1 by covalently modifying cysteine residues within the amino-terminal cytoplasmic domain of the channel (Hinman et al., 2006; Macpherson et al., 2007). How this promotes channel gating is currently unknown. Nevertheless, simply establishing the importance of thiol reactivity in this process has implicated TRPA1 as a key physiological target for a wide and chemically diverse group of environmental toxicants. One notable example is acrolein (2-propenal), a highly reactive α,β-unsaturated aldehyde present in tear gas, vehicle exhaust, or smoke from burning vegetation (i.e. forest fires and cigarettes). Acrolein and other volatile irritants (such as hypochlorite, hydrogen peroxide, formalin, and isocyanates) activate sensory neurons that innervate the eyes and airways, producing pain and inflammation (Bautista et al., 2006; Bessac and Jordt, 2008; Caceres et al., 2009). This action can have especially dire consequences for those suffering from asthma, chronic cough, or other pulmonary disorders. Mice lacking TRPA1 show greatly reduced sensitivity to such agents, underscoring the critical nature of this channel as a sensory detector of reactive environmental irritants (Caceres et al., 2009). In addition to these environmental toxins, TRPA1 is targeted by some general anesthetics (such as isofluorane) or metabolic byproducts of chemotherapeutic agents (such as cyclophosphamide), which likely underlies some of the adverse side effects of these drugs, including acute pain and robust neuroinflammation (Bautista et al., 2006; Matta et al., 2008).


    Finally, chemical irritants and other pro-algesic agents are also produced endogenously in response to tissue damage or physiological stress, including oxidative stress. Such factors can act alone, or in combination, to sensitize nociceptors to thermal and/or mechanical stimuli, thereby lowering pain thresholds. The result of this action is to enhance guarding and protective reflexes in the aftermath of injury. Thus, chemo-nociception represents an important interface between acute and persistent pain, especially in the context of peripheral tissue injury and inflammation, as discussed in greater detail below.


    Acute Pain: Conducting the Pain Signal


    Once thermal and mechanical signals are transduced by the primary afferent terminal, the receptor potential activates a variety of voltage-gated ion channels. Voltage-gated sodium and potassium channels are critical to the generation of action potentials that convey nociceptor signals to synapses in the dorsal horn. Voltage-gated calcium channels play a key role in neurotransmitter release from central or peripheral nociceptor terminals to generate pain or neurogenic inflammation, respectively. We restrict our discussion to members of the sodium and calcium channel families that serve as targets of currently used analgesic drugs, or for which human genetics support a role in pain transmission. A recent review has discussed the important contribution of KCNQ potassium channels, including the therapeutic benefit of increasing K+ channel activity for the treatment of persistent pain (Brown and Passmore, 2009).


    Voltage-Gated Sodium Channels


    A variety of sodium channels are expressed in somatosensory neurons, including the tetrodotoxin (TTX)-sensitive channels Nav1.1, 1.6 and 1.7, and the TTX-insensitive channels, Nav1.8 and 1.9. In recent years, the contribution of Nav1.7 has received much attention, as altered activity of this channel leads to a variety of human pain disorders (Cox et al., 2006; Dib-Hajj et al., 2008). Patients with loss-of-function mutations within this gene are unable to detect noxious stimuli, and as a result suffer injuries due to lack of protective reflexes. In contrast, a number of gain-of-function mutations in Nav1.7 leads to hyperexcitability of the channel and are associated with two distinct pain disorders in humans, erythromelalgia, and paroxysmal extreme pain disorder, both of which cause intense burning sensations (Estacion et al., 2008; Fertleman et al., 2006; Yang et al., 2004). Animal studies have demonstrated that Nav1.7 is highly upregulated in a variety of inflammatory pain models. Indeed, analysis of mice lacking Nav1.7 in C nociceptors supports a key role for this channel in mechanical and thermal hypersensitivity following inflammation, and in acute responses to noxious mechanical stimuli (Nassar et al., 2004). Somewhat surprisingly, pain induced by nerve injury is unaltered, suggesting that distinct sodium channel subtypes, or another population of Nav1.7-expressing afferents, contribute to neuropathic pain (Nassar et al., 2005).


    The Nav1.8 sodium channel is also highly expressed by most C nociceptors. As with Nav1.7 knockout animals, those lacking Nav1.8 display modest deficits in sensitivity to innocuous or noxious heat, or innocuous pressure; however, they display attenuated responses to noxious mechanical stimuli (Akopian et al., 1999). Nav1.8 is also required for the transmission of cold stimuli, as mice lacking this channel are insensitive to cold over a wide range of temperatures (Zimmermann et al., 2007). This is because Nav1.8 is unique among voltage-sensitive sodium channels in that it does not inactivate at low temperature, making it the predominant action potential generator under cold conditions.


    Interestingly, transgenic mice lacking the Nav1.8 expressing subset of sensory neurons, which were deleted by targeted expression of diphtheria toxin A (Abrahamsen et al., 2008), display attenuated responses to both low and high threshold mechanical stimuli and cold. In addition, mechanical and thermal hypersensitivity in inflammatory pain models is severely attenuated. The differential phenotypes of mice lacking Nav1.8 channels versus deletion of the Nav1.8-expressing neurons presumably reflects the contribution of multiple voltage-gated sodium channel subtypes to transmission of pain messages.


    Voltage-gated sodium channels are targets of local anesthetic drugs, highlighting the potential for the development of subtype-specific analgesics. Nav1.7 is a particularly interesting target for treating inflammatory pain syndromes, in part, because the human genetic studies suggest that Nav1.7 inhibitors should reduce pain without altering other essential physiological processes (see above). Another potential application of sodium channel blockers may be to treat extreme hypersensitivity to cold, a particularly troublesome adverse side effect of platinum-based chemotherapeutics, such as oxaliplatin (Attal et al., 2009). Nav1.8 (or TRPM8) antagonists may alleviate this, or other forms of cold allodynia. Finally, the great utility of the antidepressant serotonin and norepinephrine reuptake inhibitors for the treatment of neuropathic pain may, in fact, result from their ability to block voltage gated sodium channels (Dick et al., 2007).


    Voltage-Gated Calcium Channels


    A variety of voltage-gated calcium channels are expressed in nociceptors. N-, P/Q- and T-type calcium channels have received the most attention. P/Q-type channels are expressed at synaptic terminals in laminae II-IV of the dorsal horn. Their exact role in nociception is not completely resolved. However, mutations in these channels have been linked to familial hemiplegic migraine (de Vries et al., 2009). N- and T-type calcium channels are also expressed by C-fibers and are upregulated under pathophysiological states, as in models of diabetic neuropathy or after other forms of nerve injury. Animals lacking Cav2.2 or 3.2 show reduced sensitization to mechanical or thermal stimuli following inflammation or nerve injury, respectively (Cao, 2006; Swayne and Bourinet, 2008; Zamponi et al., 2009; Messinger et al., 2009). Moreover, ω-conotoxin GVIA, which blocks N-type channels, is administered intrathecally (as ziconotide) to provide relief for intractable cancer pain (Rauck et al., 2009).


    All calcium channels are heteromeric proteins composed of α1 pore forming subunits and the modulatory subunits α2δ, α2β or α2γ. The α2δ subunit regulates current density and kinetics of activation and inactivation. In C nociceptors, the α2δ subunit is dramatically upregulated following nerve injury and plays a key role in injury-evoked hypersensitivity and allodynia (Luo et al., 2001). Indeed, this subunit is the target of gabapentinoid class of anticonvulsants, which are now widely used to treat neuropathic pain (Davies et al., 2007).


    Persistent Pain: Peripheral Mechanisms


    Persistent pain associated with injury or diseases (such as diabetes, arthritis, or tumor growth) can result from alterations in the properties of peripheral nerves. This can occur as a consequence of damage to nerve fibers, leading to increased spontaneous firing or alterations in their conduction or neurotransmitter properties. In fact, the utility of topical and even systemic local anesthetics for the treatment of different neuropathic pain conditions (such as postherpetic neuralgia) likely reflects their action on sodium channels that accumulate in injured nerve fibers.


    The Chemical Milieu of Inflammation


    Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively. these factors, referred to as the ‘inflammatory soup’, represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell surface receptors capable of recognizing and responding to each of these pro-inflammatory or pro-algesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.


    Figure 4 Peripheral Mediators of Inflammation


    Unquestionably the most common approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization, or which form the basis of new therapeutic strategies for treating inflammatory pain.


    NGF is perhaps best known for its role as a neurotrophic factor required for survival and development of sensory neurons during embryogenesis, but in the adult, NGF is also produced in the setting of tissue injury and constitutes an important component of the inflammatory soup (Ritner et al., 2009). Among its many cellular targets, NGF acts directly on peptidergic C fiber nociceptors, which express the high affinity NGF receptor tyrosine kinase, TrkA, as well as the low affinity neurotrophin receptor, p75 (Chao, 2003; Snider and McMahon, 1998). NGF produces profound hypersensitivity to heat and mechanical stimuli through two temporally distinct mechanisms. At first, a NGF-TrkA interaction activates downstream signaling pathways, including phospholipase C (PLC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K). This results in functional potentiation of target proteins at the peripheral nociceptor terminal, most notably TRPV1, leading to a rapid change in cellular and behavioral heat sensitivity (Chuang et al., 2001). In addition to these rapid actions, NGF is also retrogradely transported to the nucleus of the nociceptor, where it promotes increased expression of pro-nociceptive proteins, including substance P, TRPV1, and the Nav1.8 voltage-gated sodium channel subunit (Chao, 2003; Ji et al., 2002). Together, these changes in gene expression enhance excitability of the nociceptor and amplify the neurogenic inflammatory response.


    In addition to neurotrophins, injury promotes the release of numerous cytokines, chief among them interleukin 1β (IL-1β) and IL-6, and tumor necrosis factor α (TNF-α) (Ritner et al., 2009). Although there is evidence to support a direct action of these cytokines on nociceptors, their primary contribution to pain hypersensitivity results from potentiation of the inflammatory response and increased production of pro-algesic agents (such as prostaglandins, NGF, bradykinin, and extracellular protons).


    Irrespective of their pro-nociceptive mechanisms, interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease or resulting pain. The main approach involves blocking NGF or TNF-α action with a neutralizing antibody. In the case of TNF-α, this has been remarkably effective in the treatment of numerous autoimmune diseases, including rheumatoid arthritis, leading to dramatic reduction in both tissue destruction and accompanying hyperalgesia (Atzeni et al., 2005). Because the main actions of NGF on the adult nociceptor occur in the setting of inflammation, the advantage of this approach is that hyperalgesia will decrease without affecting normal pain perception. Indeed, anti-NGF antibodies are currently in clinical trials for treatment of inflammatory pain syndromes (Hefti et al., 2006).


    Targets of the Inflammatory Soup


    TRPV1. Robust hypersensitivity to heat can develop with inflammation or after injection of specific components of the inflammatory soup (such as bradykinin or NGF). Lack of such sensitization in TRPV1-deficient mice provides genetic support for the idea that TRPV1 is a key component of the mechanism through which inflammation produces thermal hyperalgesia (Caterina et al., 2000; Davis et al., 2000). Indeed, in vitro studies have shown that TRPV1 functions as a polymodal signal integrator whose thermal sensitivity can be profoundly modulated by components of the inflammatory soup (Tominaga et al., 1998). Some of these inflammatory agents (for example, extracellular protons and lipids) function as direct positive allosteric modulators of the channel, whereas others (bradykinin, ATP, and NGF) bind to their own receptors on primary afferents and modulate TRPV1 through activation of downstream intracellular signaling pathways. In either case, these interactions result in a profound decrease in the channel’s thermal activation threshold, as well as an increase in the magnitude of responses at supra-threshold temperatures—the biophysical equivalents of allodynia and hyperalgesia, respectively.


    However, there remains controversy concerning the intracellular signaling mechanisms most responsible for TRPV1 modulation (Lumpkin and Caterina, 2007). Reminiscent of ancestral TRP channels in the fly eye, many mammalian TRP channels are activated or positively modulated by phospholipase C-mediated cleavage of plasma membrane phosphatidyl inositol 4,5 bisphosphate (PIP2). Of course, there are many downstream consequences of this action, including a decrease in membrane PIP2, increase levels of diacylglycerol and its metabolites, increased cytoplasmic calcium, as well as consequent activation of protein kinases. In the case of TRPV1, most, if not all, of these pathways have been implicated in the sensitization process and it remains to be seen which are most relevant to behavioral thermal hypersensitivity. Nevertheless, there is broad agreement that TRPV1 modulation is relevant to tissue injury-evoked pain hypersensitivity, particularly in the setting of inflammation. This would include conditions such as sunburn, infection, rheumatoid or osteoarthritis, and inflammatory bowl disease. Another interesting example includes pain from bone cancer (Honore et al., 2009), where tumor growth and bone destruction are accompanied by extremely robust tissue acidosis, as well as production of cytokines, neurotrophins, and prostaglandins.


    TRPA1. As described above, TRPA1 is activated by compounds that form covalent adducts with cysteine residues. In addition to environmental toxins, this includes endogenous thiol reactive electrophiles that are produced during tissue injury and inflammation, or as a consequence of oxidative or nitrative stress. Chief among such agents are 4-hydroxy-2-nonenal and 15-deoxy-Δ12,14-prostaglandin J2, which are both α,β unsaturated aldehydes generated through peroxidation or spontaneous dehydration of lipid second messengers (Andersson et al., 2008; Cruz-Orengo et al., 2008; Materazzi et al., 2008; Trevisani et al., 2007). Other endogenous TRPA1 agonists include nitrooleic acid, hydrogen peroxide, and hydrogen sulfide. In addition to these directly acting agents, TRPA1 is also modulated indirectly by pro-algesic agents, such as bradykinin, which act via PLC-coupled receptors. Indeed, TRPA1-deficient mice show dramatically reduced cellular and behavioral responses to all of these agents, as well as a reduction in tissue injury-evoked thermal and mechanical hypersensitivity (Bautista et al., 2006; Kwan et al., 2006). Finally, because TRPA1 plays a key role in neurogenic and other inflammatory responses to both endogenous agents and volatile environmental toxins, its contribution to airway inflammation, such as occurs in asthma, is of particular interest. Indeed, genetic or pharmacological blockade of TRPA1 reduces airway inflammation in a rodent model of allergen-evoked asthma (Caceres et al., 2009).


    ASICs. As noted above, ASIC channels are members of the DEG/ENaC family that are activated by acidification, and thus represent another important site for the action of extracellular protons produced as a consequence of tissue injury or metabolic stress. ASIC subtypes can form a variety of homomeric or heteromeric channels, each having distinct pH sensitivity and expression profile. Channels containing the ASIC3 subtype are specifically expressed by nociceptors and especially well represented in fibers that innervate skeletal and cardiac muscle. In these tissues, anaerobic metabolism leads to buildup of lactic acid and protons, which activate nociceptors to generate musculoskeletal or cardiac pain (Immke and McCleskey, 2001). Interestingly, ASIC3-containing channels open in response to the modest decrease in pH (e.g. 7.4 to 7.0) that occurs with cardiac ischemia (Yagi et al., 2006). Lactic acid also significantly potentiates proton-evoked gating through a mechanism involving calcium chelation (Immke and McCleskey, 2003). Thus, ASIC3-containing channels detect and integrate signals specifically associated with muscle ischemia and, in this way, are functionally distinct from other acid sensors on the primary afferent, such as TRPV1 or other ASIC channel subtypes.


    Persistent Pain: Central Mechanisms


    Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system, leading to enhanced processing of nociceptive (pain) messages (Woolf, 1983). Although numerous mechanisms have been implicated in central sensitization here we focus on three: alteration in glutamatergic neurotransmission/NMDA receptor-mediated hypersensitivity, loss of tonic inhibitory controls (disinhibition) and glial-neuronal interactions (Figure 5).


    Figure 5 Spinal Cord Central Sensitization


    Glutamate/NMDA Receptor-Mediated Sensitization


    Acute pain is signaled by the release of glutamate from the central terminals of nociceptors, generating excitatory post-synaptic currents (EPSCs) in second order dorsal horn neurons. This occurs primarily through activation of postsynaptic AMPA and kainate subtypes of ionotropic glutamate receptors. Summation of sub-threshold EPSCs in the postsynaptic neuron will eventually result in action potential firing and transmission of the pain message to higher order neurons. Under these conditions, the NMDA subtype of glutamate channel is silent, but in the setting of injury, increased release of neurotransmitters from nociceptors will sufficiently depolarize postsynaptic neurons to activate quiescent NMDA receptors. The consequent increase in calcium influx can strengthen synaptic connections between nociceptors and dorsal horn pain transmission neurons, which in turn will exacerbate responses to noxious stimuli (that is, generate hyperalgesia).


    In many ways, this processes is comparable to that implicated in the plastic changes associated with hippocampal long-term potentiation (LTP) (for a review on LTP in the pain pathway, see Drdla and Sandkuhler, 2008). Indeed, drugs that block spinal LTP reduce tissue injury-induced hyperalgesia. As in the case of hippocampal LTP, spinal cord central sensitization is dependent on NMDA-mediated elevations of cytosolic Ca2+ in the postsynaptic neuron. Concurrent activation of metabotropic glutamate and substance P receptors on the postsynaptic neuron may also contribute to sensitization by augmenting cytosolic calcium. Downstream activation of a host of signaling pathways and second messenger systems, notably kinases (such as MAPK, PKA, PKC, PI3K, Src), further increases excitability of these neurons, in part by modulating NMDA receptor function (Latremoliere and Woolf, 2009). Illustrative of this model is the demonstration that spinal injections of a nine amino acid peptide fragment of Src not only disrupts an NMDA receptor–Src interaction but also markedly decreases the hypersensitivity produced by peripheral injury, without changing acute pain. Src null mutant mice also display reduced mechanical allodynia after nerve injury (Liu et al., 2008).


    In addition to enhancing inputs from the site of injury (primary hyperalgesia), central sensitization contributes to the condition in which innocuous stimulation of areas surrounding the injury site can produce pain. This secondary hyperalgesia involves heterosynaptic facilitation, wherein inputs from Aβ afferents, which normally respond to light touch, now engage pain transmission circuits, resulting in profound mechanical allodynia. The fact that compression block of peripheral nerve fibers concurrently interrupts conduction in Aβ afferents and eliminates secondary hyperalgesia indicates that these abnormal circuits are established in clinical settings as well as in animal models (Campbell et al., 1988).


    Loss of GABAergic and Glycinergic Controls: Disinhibition


    GABAergic or glycinergic inhibitory interneurons are densely distributed in the superficial dorsal horn and are at the basis of the longstanding gate control theory of pain, which postulates that loss of function of these inhibitory interneurons (disinhibition) would result in increased pain (Melzack and Wall, 1965). Indeed, in rodents, spinal administration of GABA (bicuculline) or glycine (strychnine) receptor antagonists (Malan et al., 2002; Sivilotti and Woolf, 1994; Yaksh, 1989) produces behavioral hypersensitivity resembling that observed after peripheral injury. Consistent with these observations, peripheral injury leads to a decrease in inhibitory postsynaptic currents in superficial dorsal horn neurons. Although Moore et al. (2002) suggested that the disinhibition results from peripheral nerve injury-induced death of GABAergic interneurons, this claim has been contested (Polgar et al., 2005). Regardless of the etiology, the resulting decreased tonic inhibition enhances depolarization and excitation of projection neurons. As for NMDA-mediated central sensitization, disinhibition enhances spinal cord output in response to painful and non-painful stimulation, contributing to mechanical allodynia (Keller et al., 2007; Torsney and MacDermott, 2006).


    Following upon an earlier report that deletion of the gene encoding PKCγ in the mouse leads to a marked decrease in nerve injury-evoked mechanical hypersensitivity (Malmberg et al., 1997), recent studies address the involvement of these neurons in the disinhibitory process. Thus, after blockade of glycinergic inhibition with strychnine, innocuous brushing of the hindpaw activates PKCγ-positive interneurons in lamina II (Miraucourt et al., 2007), as well as projection neurons in lamina I. Because PKCγ-positive neurons in the spinal cord are located only in the innermost part of lamina II (Figure 1), it follows that these neurons are essential for the expression of nerve injury-evoked persistent pain, and that disinhibitory mechanisms lead to their hyperactivation.


    Other studies indicate that changes in the projection neuron, itself, contribute to the dis-inhibitory process. For example, peripheral nerve injury profoundly down-regulates the K+-Cl- co-transporter KCC2, which is essential for maintaining normal K+ and Cl- gradients across the plasma membrane (Coull et al., 2003). Downregulating KCC2, which is expressed in lamina I projection neurons, results in a shift in the Cl- gradient, such that activation of GABA-A receptors depolarize, rather than hyperpolarize the lamina I projection neurons. This would, in turn, enhance excitability and increase pain transmission. Indeed, pharmacological blockade or siRNA-mediated downregulation of KCC2 in the rat induces mechanical allodynia. Nonetheless, Zeilhofer and colleagues suggest that, even after injury, sufficient inhibitory tone remains such that enhancement of spinal GABAergic neurotransmission might be a valuable approach to reduce pain hypersensitivity induced by peripheral nerve injury (Knabl et al., 2008). In fact, studies in mice suggest that drugs specifically targeting GABAA complexes containing α2 and/or α3 subunits reduce inflammatory and neuropathic pain without producing sedative-hypnotic side effects typically associated with benzodiazepines, which enhance activity of α1-containing channels.


    Disinhibition can also occur through modulation of glycinergic signaling. In this case the mechanism involves a spinal cord action of prostaglandins (Harvey et al., 2004). Specifically, tissue injury induces spinal release of the prostaglandin, PGE2, which acts on EP2 receptors expressed by excitatory interneurons and projection neurons in the superficial dorsal horn. Resultant stimulation of the cAMP-PKA pathway phosphorylates GlyRa3 glycine receptor subunits, rendering the neurons unresponsive to the inhibitory effects of glycine. Accordingly, mice lacking the GlyRa3 gene have decreased heat and mechanical hypersensitivity in models of tissue injury.


    Glial-Neuronal Interactions


    Finally, glial cells, notably microglia and astrocytes, also contribute to the central sensitization process that occurs in the setting of injury. Under normal conditions, microglia function as resident macrophages of the central nervous system. They are homogeneously distributed within the grey matter of the spinal cord and are presumed to function as sentinels of injury or infection. Within hours of peripheral nerve injury, however, microglia accumulate in the superficial dorsal horn within the termination zone of injured peripheral nerve fibers. Microglia also surround the cell bodies of ventral horn motoneurons, whose peripheral axons are concurrently damaged. The activated microglia release a panoply of signaling molecules, including cytokines (such as TNF-α, interleukin-1β and 6), which enhance neuronal central sensitization and nerve injury-induced persistent pain (DeLeo et al., 2007). Indeed, injection of activated brain microglia into the cerebral spinal fluid at the level of the spinal cord can reproduce the behavioral changes observed after nerve injury (Coull et al., 2005). Thus, it appears that microglial activation is sufficient to trigger the persistent pain condition (Tsuda et al., 2003).


    As microglia are activated following nerve, but not inflammatory tissue injury, it follows that activation of the afferent fiber, which occurs under both injury conditions, is not the critical trigger for microglial activation. Rather, physical damage of the peripheral afferent must induce the release of specific signals that are detected by microglia. Chief among these is ATP, which targets microglial P2-type purinergic receptors. Of particular interest are P2X4 (Tsuda et al., 2003), P2X7 (Chessell et al., 2005) and P2Y12 (Haynes et al., 2006; Kobayashi et al., 2008) receptor subtypes. Indeed, ATP was used to activate brain microglia in the spinal cord transplant studies referred to above (Tsuda et al., 2003). Furthermore, genetic or pharmacological blockade of purinergic receptor function (Chessell et al., 2005; Tozaki-Saitoh et al., 2008; Ulmann et al., 2008) prevents or reverses nerve injury-induced mechanical allodynia (Honore et al., 2006; Kobayashi et al., 2008; Tozaki-Saitoh et al., 2008; Tsuda et al., 2003).


    Coull and colleagues proposed a model in which ATP/P2X4-mediated activation of microglia triggers a mechanism of disinhibition (Coull et al., 2005). Specifically, they demonstrated that ATP-evoked activation of P2X4 receptors induces release of the brain-derived neurotrophic factor (BDNF) from microglia. The BDNF, in turn, acts upon TrkB receptors on lamina I projection neurons, to generate a change in the Cl- gradient, which as described above, would shift the action of GABA from hyperpolarization to depolarization. Whether the BDNF-induced effect involves KCC2 expression, as occurs after nerve injury, is not known. Regardless of the mechanism, the net result is that activation of microglia will sensitize lamina I neurons such that their response to monosynaptic inputs from nociceptors, or indirect inputs from Aβ afferents, is enhanced.


    In addition to BDNF, activated microglia, like peripheral macrophages, release and respond to numerous chemokines and cytokines, and these also contribute to central sensitization. For example, in the uninjured (normal) animal, the chemokine fractalkine (CXCL1) is expressed by both primary afferents and spinal cord neurons (Lindia et al., 2005; Verge et al., 2004; Zhuang et al., 2007). In contrast, the fractalkine receptor (CX3CR1) is expressed on microglial cells and importantly, is upregulated after peripheral nerve injury (Lindia et al., 2005; Zhuang et al., 2007). Because spinal delivery of fractalkine can activate microglia, it appears that nerve injury-induced release of fractalkine provides yet another route through which microglia can be engaged in the process of central sensitization. Indeed blockade of CX3CR1 with a neutralizing antibody prevents both the development and maintenance of injury-induced persistent pain (Milligan et al., 2004; Zhuang et al., 2007). This pathway may also be part of a positive feedback loop through which injured nerve fibers and microglial cells interact in a reciprocal and recurrent fashion to amplify pain signals. This point is underscored by the fact that fractalkine must be cleaved from the neuronal surface prior to signaling, an action that is carried out by the microglial-derived protease, cathepsin S, inhibitors of which reduce nerve injury-induced allodynia and hyperalgesia (Clark et al., 2007). Importantly, spinal administration of cathepsin S generates behavioral hypersensitivity in wild type, but not in CX3CX1 knockout mice, linking cathepsin S to fractalkine signaling (Clark et al., 2007; Zhuang et al., 2007). Although the factor(s) that initiates release of cathepsin S from microglia remains to be determined,. ATP seems a reasonable possibility.


    Very recently, several members of the Toll-like receptors (TLRs) family have also been implicated in the activation of microglia following nerve injury. TLRs are transmembrane signaling proteins expressed in peripheral immune cells and glia. As part of the innate immune system, they recognize molecules that are broadly shared by pathogens. Genetic or pharmacological inhibition of TLR2, TLR3 or TLR4 function in mice results not only in decreased microglial activation, but also reduces the hypersensitivity triggered by peripheral nerve injury (Kim et al., 2007; Obata et al., 2008; Tanga et al., 2005). Unknown are the endogenous ligands that activate TLR2-4 after nerve-injury. Among the candidates are mRNAs or heat shock proteins that could leak from the damaged primary afferent neurons and diffuse into the extracellular milieu of the spinal cord.


    The contribution of astrocytes to central sensitization is less clear. Astrocytes are unquestionably induced in the spinal cord after injury to either tissue or nerve (for a review, see Ren and Dubner, 2008). But, in contrast to microglia, astrocyte activation is generally delayed and persists much longer, up to several months. One interesting possibility is that astrocytes are more critical to the maintenance, rather than to the induction of central sensitization and persistent pain.


    Finally, it is worth noting that peripheral injury not only activates glia in the spinal cord, but also in the brainstem, where glia contribute to supraspinal facilitatory influences on the processing of pain messages in the spinal cord (see Figure 2), a phenomenon named descending facilitation (for a review, see Ren and Dubner, 2008). Such facilitation is especially prominent in the setting of injury, and appears to counteract the feedback inhibitory controls that concurrently arise from various brainstem loci (Porreca et al., 2002).



    Dr. Alex Jimenez’s Insight

    As established by the International Association for the Study of Pain, or the IASP, pain is “an unpleasant sensory and emotional experience associated with acutal or potential tissue damage, or described in terms of tissue damage or both. Numerous research studies have been proposed to demonstrate the physiological basis of pain, however, none has been able to include the entire aspects associated with pain perception. Understanding the pain mechanisms of acute pain versus chronic pain is fundamental during clinical evaluations as this can help determine the best treatment approach for patients with underlying health issues.


    Specificity in the Transmission and Control of Pain Messages


    Understanding how stimuli are encoded by the nervous system to elicit appropriate behaviors is of fundamental importance to the study of all sensory systems. In the simplest form, a sensory system uses labeled lines to transduce stimuli and elicit behaviors through strictly segregated circuits. This is perhaps best exemplified by the taste system, where exchanging a sweet receptor for a bitter one in a population of “sweet taste afferents” does not alter the behavior provoked by activity in that labeled line; under these conditions, a bitter tastant stimulates these afferents to elicit a perception of sweetness (Mueller et al., 2005).


    In the pain pathway, there is also evidence to support the existence of labeled lines. As mentioned above, heat and cold are detected by largely distinct subsets of primary afferent fibers. Moreover, elimination of subsets of nociceptors can produce selective deficits in the behavioral response to a particular noxious modality. For example, destruction of TRPV1-expressing nociceptors produces a profound loss of heat pain (including heat hyperalgesia), with no change in sensitivity to painful mechanical or cold stimuli. Conversely, deletion of the MrgprD subset of nociceptors results in a highly selective deficit in mechanical responsiveness, with no change in heat sensitivity (Cavanaugh et al., 2009). Further evidence for functional segregation at the level of the nociceptor comes from the analysis of two different opioid receptor subtypes (Scherrer et al., 2009). Specifically, the mu opioid receptor (MOR) predominates in the peptidergic population, whereas the delta opioid receptor (DOR) is expressed in non-peptidergic nociceptors. MOR-selective agonists block heat pain, whereas DOR selective agonists block mechanical pain, again illustrating functional separation of molecularly distinct nociceptor populations.


    These observations argue for behaviorally-relevant specificity at the level of the nociceptor. However, this is likely to be an oversimplification for at least two reasons. First, many nociceptors are polymodal and can therefore be activated by thermal, mechanical, or chemical stimuli, leaving one to wonder how elimination of large cohorts of nociceptors can have modality-specific effects. This argues for a substantial contribution of spinal circuits to the process whereby nociceptive signals are encoded into distinct pain modalities. Indeed, an important future goal is to better delineate neuronal subtypes within the dorsal horn and characterize their synaptic interactions with functionally or molecularly defined subpopulations of nociceptors. Second, the pain system shows a tremendous capacity for change, particularly in the setting of injury, raising questions about whether and how a labeled line system might accommodate such plasticity, and how alterations in such mechanisms underlie maladaptive changes that produce chronic pain. Indeed, we know that substance P-saporin-mediated deletion of a discrete population of lamina I dorsal horn neurons, which express the substance P receptor, can reduce both the thermal and mechanical pain hypersensitivity that occurs after tissue or nerve injury (Nichols et al., 1999). Such observations suggest that in the setting of injury specificity of the labeled line is not strictly maintained as information is transmitted to higher levels of the neuraxis.


    Clearly, answers to these questions will require the combined use of anatomical, electrophysiological, and behavioral methods to map the physical and functional circuitry that underlies nociception and pain. The ongoing identification of molecules and genes that mark specific neuronal cell types (both peripheral and central) provides essential tools with which to manipulate genetically or pharmacologically these neurons and to link their activities to specific components of pain behavior under normal and pathophysiological circumstances. Doing so should bring us closer to understanding how acute pain gives way to the maladaptive changes that produce chronic pain, and how this switch can be prevented or reversed.


    Hemp vs Marijuana - What's the Difference? | El Paso, TX Chiropractor


    Hemp vs Marijuana: What’s the Difference?


    With approximately half of U.S. states now permitting the sale of medical marijuana, and a few even allowing the sale of marijuana for recreational use, more and more people are becoming interested in the possible health benefits of this controversial plant.


    Whilst science on its medical use continues to advance, many people these days are considering how they could access the plant’s health benefits without experiencing its well-known unwanted psychoactive effect. This is completely possible with marijuana’s close relative, hemp but it is essential that you be aware of the difference so that you may be a smart consumer.


    One Cultivars of the Exact Same Plant


    Fundamentally, both hemp and marijuana are the exact same plant: Cannabis sativa. There is evidence that Cannabis sativa L has been grown in Asia thousands of years back for its fiber as well as a food supply. Humans eventually realized that the flowering tops of the plant had psychoactive properties. With time, as humans have done so with many other plants, Cannabis farmers began cultivating specific plants to enhance specific properties.


    Nowadays, though some might argue the true number of plant types, there are really two simple distinctions,


    Hemp – A plant primarily cultivated outside the United States, although a few U.S. countries let it be grown for study purposes) for use in clothes, paper, biofuels, bioplastics, dietary supplements, cosmetics, and foods. Hemp is cultivated outdoors as a large crop with both male and female plants being present to boost pollination and improve seed production. Legally imported industrial hemp contains less than 0.3 percent of its carcinogenic chemical tetrahydrocannabinol, or THC, content. In reality, legally imported hemp will usually specifically eliminate any extracts in the plant’s dried flowering tops.


    Marijuana (Marihuana) – Cannabis sativa especially cultivated to enhance its THC content to be used for medicinal or recreational purposes. Marijuana plants are typically grown indoors, under controlled conditions, and growers eliminate all of the male plants from the harvest to prevent fertilization because fertilization lowers the plant’s THC degree.


    Legality of Medical Marijuana


    The medical use of marijuana is an increased area of controversy for researchers and consumers alike. Although maybe not quite half of U.S. states have legalized the medical use of this plant, it remains illegal under federal law, and consequently its use remains controversial regardless of the fact that there does seem to be real health benefits for various serious health issues.


    Those that are looking to use marijuana for medical use should talk about its benefits versus its dangers with a skilled health-care professional before using it. In addition, many consumers who have an interest in its health benefits do not need the psychoactive side effects of THC or the danger of a positive drug test.


    Hemp: Health Benefits without the Risks


    Imported hemp, that has a very low, almost absent, level of THC, can be a solution for consumers that are looking for the plant’s health benefits minus the effects of THC.


    Though THC has some health benefits, hemp comprises more than 80 bioactive compounds that could provide excellent support for a range of health issues, such as stress response, positive mood, and physical discomfort or pain. Hemp can also benefit gastrointestinal health, help keep a healthy inflammatory response throughout the entire body, and support normal immune function.


    If you are considering the use of a nutritional supplement product which includes hemp, then it’s ideal to buy a product from a trusted source.


    In conclusion, both the peripheral and central nervous system detect, interpret and regulate a wide range of thermal and mechanical stimulation as well as environmental and endogenous chemical irritants. If the stimuli is too intense, it can generate acute pain where in the instance of persistent or chronic pain, pain transmission can be tremendously affected. The article above describes the cellular and molecular mechanisms of pain for guidance in clinical assessments. Furthermore, the use of hemp can have many health benefits in comparison to the controversial effects of marijuana. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain

    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



    The post Mechanisms of Acute Pain vs Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 Figure 1 Anatomy of the Pain Pathway Figure 2 Primary Afferent Fibers and Spinal Cord Figure 3 Nociceptor Diversity Figure 4 Peripheral Mediators of Inflammation Figure 5 Spinal Cord Central Sensitization Dr-Jimenez_White-Coat_01.png Hemp vs Marijuana - What's the Difference? | El Paso, TX Chiropractor Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17751 Brain Changes Associated with Chronic Pain Wed, 11 Jul 2018 21:10:22 +0000

    Pain is the human body's natural response to injury or illness, and it is often a warning that something is wrong. Once the problem is healed, we generally stop experiencing this painful symptoms, however, what happens when the pain continues long after the cause is gone? Chronic pain is medically defined as persistent pain that lasts 3 to 6 months or more. Chronic pain is certainly a challenging condition to live with, affecting everything from the individual's activity levels and their ability to work as well as their personal relationships and psychological conditions. But, are you aware that chronic pain may also be affecting the structure and function of your brain? It turns out these brain changes may lead to both cognitive and psychological impairment.


    Chronic pain doesn't just influence a singular re

    The post Brain Changes Associated with Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Pain is the human body’s natural response to injury or illness, and it is often a warning that something is wrong. Once the problem is healed, we generally stop experiencing this painful symptoms, however, what happens when the pain continues long after the cause is gone? Chronic pain is medically defined as persistent pain that lasts 3 to 6 months or more. Chronic pain is certainly a challenging condition to live with, affecting everything from the individual’s activity levels and their ability to work as well as their personal relationships and psychological conditions. But, are you aware that chronic pain may also be affecting the structure and function of your brain? It turns out these brain changes may lead to both cognitive and psychological impairment.


    Chronic pain doesn’t just influence a singular region of the mind, as a matter of fact, it can result in changes to numerous essential areas of the brain, most of which are involved in many fundamental processes and functions. Various research studies over the years have found alterations to the hippocampus, along with reduction in grey matter from the dorsolateral prefrontal cortex, amygdala, brainstem and right insular cortex, to name a few, associated with chronic pain. A breakdown of a few of the structure of these regions and their related functions might help to put these brain changes into context, for a lot of individuals with chronic pain. The purpose of the following article is to demonstrate as well as discuss the structural and functional brain changes associated with chronic pain, particularly in the case where those reflect probably neither damage nor atrophy.


    Structural Brain Changes in Chronic Pain Reflect Probably Neither Damage Nor Atrophy




    Chronic pain appears to be associated with brain gray matter reduction in areas ascribable to the transmission of pain. The morphological processes underlying these structural changes, probably following functional reorganisation and central plasticity in the brain, remain unclear. The pain in hip osteoarthritis is one of the few chronic pain syndromes which are principally curable. We investigated 20 patients with chronic pain due to unilateral coxarthrosis (mean age 63.25±9.46 (SD) years, 10 female) before hip joint endoprosthetic surgery (pain state) and monitored brain structural changes up to 1 year after surgery: 6–8 weeks, 12–18 weeks and 10–14 month when completely pain free. Patients with chronic pain due to unilateral coxarthrosis had significantly less gray matter compared to controls in the anterior cingulate cortex (ACC), insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex. These regions function as multi-integrative structures during the experience and the anticipation of pain. When the patients were pain free after recovery from endoprosthetic surgery, a gray matter increase in nearly the same areas was found. We also found a progressive increase of brain gray matter in the premotor cortex and the supplementary motor area (SMA). We conclude that gray matter abnormalities in chronic pain are not the cause, but secondary to the disease and are at least in part due to changes in motor function and bodily integration.




    Evidence of functional and structural reorganization in chronic pain patients support the idea that chronic pain should not only be conceptualized as an altered functional state, but also as a consequence of functional and structural brain plasticity [1], [2], [3], [4], [5], [6]. In the last six years, more than 20 studies were published demonstrating structural brain changes in 14 chronic pain syndromes. A striking feature of all of these studies is the fact that the gray matter changes were not randomly distributed, but occur in defined and functionally highly specific brain areas – namely, involvement in supraspinal nociceptive processing. The most prominent findings were different for each pain syndrome, but overlapped in the cingulate cortex, the orbitofrontal cortex, the insula and dorsal pons [4]. Further structures comprise the thalamus, dorsolateral prefrontal cortex, basal ganglia and hippocampal area. These findings are often discussed as cellular atrophy, reinforcing the idea of damage or loss of brain gray matter [7], [8], [9]. In fact, researchers found a correlation between brain gray matter decreases and duration of pain [6], [10]. But the duration of pain is also linked to the patient’s age, and the age dependent global, but also regionally specific decline of gray matter is well documented [11]. On the other hand, these structural changes could also be a decrease in cell size, extracellular fluids, synaptogenesis, angiogenesis or even due to blood volume changes [4], [12], [13]. Whatever the source is, for our interpretation of such findings it is important to see these morphometric findings in the light of a wealth of morphometric studies in exercise dependant plasticity, given that regionally specific structural brain changes have been repeatedly shown following cognitive and physical exercise [14].


    It is not understood why only a relatively small proportion of humans develop a chronic pain syndrome, considering that pain is a universal experience. The question arises whether in some humans a structural difference in central pain transmitting systems may act as a diathesis for chronic pain. Gray matter changes in phantom pain due to amputation [15] and spinal cord injury [3] indicate that the morphological changes of the brain are, at least in part, a consequence of chronic pain. However, the pain in hip osteoarthritis (OA) is one of the few chronic pain syndrome which is principally curable, as 88% of these patients are regularly free of pain following total hip replacement (THR) surgery [16]. In a pilot study we have analysed ten patients with hip OA before and shortly after surgery. We found decreases of gray matter in the anterior cingulated cortex (ACC) and insula during chronic pain before THR surgery and found increases of gray matter in the corresponding brain areas in the pain free condition after surgery [17]. Focussing on this result, we now expanded our studies investigating more patients (n = 20) after successful THR and monitored structural brain changes in four time intervals, up to one year following surgery. To control for gray matter changes due to motor improvement or depression we also administered questionnaires targeting improvement of motor function and mental health.


    Materials and Methods




    The patients reported here are a subgroup of 20 patients out of 32 patients published recently who were compared to an age- and gender-matched healthy control group [17] but participated in an additional one year follow-up investigation. After surgery 12 patients dropped out because of a second endoprosthetic surgery (n = 2), severe illness (n = 2) and withdrawal of consent (n = 8). This left a group of twenty patients with unilateral primary hip OA (mean age 63.25±9.46 (SD) years, 10 female) who were investigated four times: before surgery (pain state) and again 6–8 and 12–18 weeks and 10–14 months after endoprosthetic surgery, when completely pain free. All patients with primary hip OA had a pain history longer than 12 months, ranging from 1 to 33 years (mean 7.35 years) and a mean pain score of 65.5 (ranging from 40 to 90) on a visual analogue scale (VAS) ranging from 0 (no pain) to 100 (worst imaginable pain). We assessed any occurrence of minor pain events, including tooth-, ear- and headache up to 4 weeks prior to the study. We also randomly selected the data from 20 sex- and age matched healthy controls (mean age 60,95±8,52 (SD) years, 10 female) of the 32 of the above mentioned pilot study [17]. None of the 20 patients or of the 20 sex- and age matched healthy volunteers had any neurological or internal medical history. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.


    Behavioural Data


    We collected data on depression, somatization, anxiety, pain and physical and mental health in all patients and all four time points using the following standardized questionnaires: Beck Depression Inventory (BDI) [18], Brief Symptom Inventory (BSI) [19], Schmerzempfindungs-Skala (SES = pain unpleasantness scale) [20] and Health Survey 36-Item Short Form (SF-36) [21] and the Nottingham Health Profile (NHP). We conducted repeated measures ANOVA and paired two-tailed t-Tests to analyse the longitudinal behavioural data using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL), and used Greenhouse Geisser correction if the assumption for sphericity was violated. The significance level was set at p<0.05.


    VBM – Data Acquisition


    Image acquisition. High-resolution MR scanning was performed on a 3T MRI system (Siemens Trio) with a standard 12-channel head coil. For each of the four time points, scan I (between 1 day and 3 month before endoprosthetic surgery), scan II (6 to 8 weeks after surgery), scan III (12 to 18 weeks after surgery) and scan IV (10–14 months after surgery), a T1 weighted structural MRI was acquired for each patient using a 3D-FLASH sequence (TR 15 ms, TE 4.9 ms, flip angle 25°, 1 mm slices, FOV 256×256, voxel size 1×1×1 mm).


    Image Processing and Statistical Analysis


    Data pre-processing and analysis were performed with SPM2 (Wellcome Department of Cognitive Neurology, London, UK) running under Matlab (Mathworks, Sherborn, MA, USA) and containing a voxel-based morphometry (VBM)-toolbox for longitudinal data, that is based on high resolution structural 3D MR images and allows for applying voxel-wise statistics to detect regional differences in gray matter density or volumes [22], [23]. In summary, pre-processing involved spatial normalization, gray matter segmentation and 10 mm spatial smoothing with a Gaussian kernel. For the pre-processing steps, we used an optimized protocol [22], [23] and a scanner- and study-specific gray matter template [17]. We used SPM2 rather than SPM5 or SPM8 to make this analysis comparable to our pilot study [17]. as it allows an excellent normalisation and segmentation of longitudinal data. However, as a more recent update of VBM (VBM8) became available recently (, we also used VBM8.


    Cross-Sectional Analysis


    We used a two-sample t-test in order to detect regional differences in brain gray matter between groups (patients at time point scan I (chronic pain) and healthy controls). We applied a threshold of p<0.001 (uncorrected) across the whole brain because of our strong a priory hypothesis, which is based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], that gray matter increases will appear in the same (for pain processing relevant) regions as in our pilot study (17). The groups were matched for age and sex with no significant differences between the groups. To investigate whether the differences between groups changed after one year, we also compared patients at time point scan IV (pain free, one year follow-up) to our healthy control group.


    Longitudinal Analysis


    To detect differences between time points (Scan I–IV) we compared the scans before surgery (pain state) and again 6–8 and 12–18 weeks and 10–14 months after endoprosthetic surgery (pain free) as repeated measure ANOVA. Because any brain changes due to chronic pain may need some time to recede following operation and cessation of pain and because of the post surgery pain the patients reported, we compared in the longitudinal analysis scan I and II with scan III and IV. For detecting changes that are not closely linked to pain, we also looked for progressive changes over all time intervals. We flipped the brains of patients with OA of the left hip (n = 7) in order to normalize for the side of the pain for both, the group comparison and the longitudinal analysis, but primarily analysed the unflipped data. We used the BDI score as a covariate in the model.




    Behavioral Data


    All patients reported chronic hip pain before surgery and were pain free (regarding this chronic pain) immediately after surgery, but reported rather acute post-surgery pain on scan II which was different from the pain due to osteoarthritis. The mental health score of the SF-36 (F(1.925/17.322) = 0.352, p = 0.7) and the BSI global score GSI (F(1.706/27.302) = 3.189, p = 0.064) showed no changes over the time course and no mental co-morbidity. None of the controls reported any acute or chronic pain and none showed any symptoms of depression or physical/mental disability.


    Before surgery, some patients showed mild to moderate depressive symptoms in BDI scores that significantly decreased on scan III (t(17) = 2.317, p = 0.033) and IV (t(16) = 2.132, p = 0.049). Additionally, the SES scores (pain unpleasantness) of all patients improved significantly from scan I (before the surgery) to scan II (t(16) = 4.676, p<0.001), scan III (t(14) = 4.760, p<0.001) and scan IV (t(14) = 4.981, p<0.001, 1 year after surgery) as pain unpleasantness decreased with pain intensity. The pain rating on scan 1 and 2 were positive, the same rating on day 3 and 4 negative. The SES only describes the quality of perceived pain. It was therefore positive on day 1 and 2 (mean 19.6 on day 1 and 13.5 on day 2) and negative (n.a.) on day 3 & 4. However, some patients did not understand this procedure and used the SES as a global “quality of life” measure. This is why all patients were asked on the same day individually and by the same person regarding pain occurrence.


    In the short form health survey (SF-36), which consists of the summary measures of a Physical Health Score and a Mental Health Score [29], the patients improved significantly in the Physical Health score from scan I to scan II (t(17) = −4.266, p = 0.001), scan III (t(16) = −8.584, p<0.001) and IV (t(12) = −7.148, p<0.001), but not in the Mental Health Score. The results of the NHP were similar, in the subscale “pain” (reversed polarity) we observed a significant change from scan I to scan II (t(14) = −5.674, p<0.001, scan III (t(12) = −7.040, p<0.001 and scan IV (t(10) = −3.258, p = 0.009). We also found a significant increase in the subscale “physical mobility” from scan I to scan III (t(12) = −3.974, p = 0.002) and scan IV (t(10) = −2.511, p = 0.031). There was no significant change between scan I and scan II (six weeks after surgery).


    Structural Data


    Cross-sectional analysis. We included age as a covariate in the general linear model and found no age confounds. Compared to sex and age matched controls, patients with primary hip OA (n = 20) showed pre-operatively (Scan I) reduced gray matter in the anterior cingulate cortex (ACC), the insular cortex, operculum, dorsolateral prefrontal cortex (DLPFC), right temporal pole and cerebellum (Table 1 and Figure 1). Except for the right putamen (x = 31, y = −14, z = −1; p<0.001, t = 3.32) no significant increase in gray matter density was found in patients with OA compared to healthy controls. Comparing patients at time point scan IV with matched controls, the same results were found as in the cross-sectional analysis using scan I compared to controls.


    Figure 1 Statistical Parametric Maps
    Figure 1: Statistical parametric maps demonstrating the structural differences in gray matter in patients with chronic pain due to primary hip OA compared to controls and longitudinally compared to themselves over time. Significant gray matter changes are shown superimposed in color, cross-sectional data is depicted in red and longitudinal data in yellow. Axial plane: the left side of the picture is the left side of the brain. top: Areas of significant decrease of gray matter between patients with chronic pain due to primary hip OA and unaffected control subjects. p<0.001 uncorrected bottom: Gray matter increase in 20 pain free patients at the third and fourth scanning period after total hip replacement surgery, as compared to the first (preoperative) and second (6–8 weeks post surgery) scan. p<0.001 uncorrected Plots: Contrast estimates and 90% Confidence interval, effects of interest, arbitrary units. x-axis: contrasts for the 4 timepoints, y-axis: contrast estimate at −3, 50, 2 for ACC and contrast estimate at 36, 39, 3 for insula.


    Table 1 Cross-Sectional Data


    Flipping the data of patients with left hip OA (n = 7) and comparing them with healthy controls did not change the results significantly, but for a decrease in the thalamus (x = 10, y = −20, z = 3, p<0.001, t = 3.44) and an increase in the right cerebellum (x = 25, y = −37, z = −50, p<0.001, t = 5.12) that did not reach significance in the unflipped data of the patients compared to controls.


    Longitudinal analysis. In the longitudinal analysis, a significant increase (p<.001 uncorrected) of gray matter was detected by comparing the first and second scan (chronic pain/post-surgery pain) with the third and fourth scan (pain free) in the ACC, insular cortex, cerebellum and pars orbitalis in the patients with OA (Table 2 and Figure 1). Gray matter decreased over time (p<.001 whole brain analysis uncorrected) in the secondary somatosensory cortex, hippocampus, midcingulate cortex, thalamus and caudate nucleus in patients with OA (Figure 2).


    Figure 2 Increases in Brain Gray Matter
    Figure 2: a) Significant increases in brain gray matter following successful operation. Axial view of significant decrease of gray matter in patients with chronic pain due to primary hip OA compared to control subjects. p<0.001 uncorrected (cross-sectional analysis), b) Longitudinal increase of gray matter over time in yellow comparing scan I&IIscan III>scan IV) in patients with OA. p<0.001 uncorrected (longitudinal analysis). The left side of the picture is the left side of the brain.


    Table 2 Longitudinal Data


    Flipping the data of patients with left hip OA (n = 7) did not change the results significantly, but for a decrease of brain gray matter in the Heschl’s Gyrus (x = −41, y = −21, z = 10, p<0.001, t = 3.69) and Precuneus (x = 15, y = −36, z = 3, p<0.001, t = 4.60).


    By contrasting the first scan (presurgery) with scans 3+4 (postsurgery), we found an increase of gray matter in the frontal cortex and motor cortex (p<0.001 uncorrected). We note that this contrast is less stringent as we have now less scans per condition (pain vs. non-pain). When we lower the threshold we repeat what we have found using contrast of 1+2 vs. 3+4.


    By looking for areas that increase over all time intervals, we found changes of brain gray matter in motor areas (area 6) in patients with coxarthrosis following total hip replacement (scan I<scan II<scan III<scan IV)). Adding the BDI scores as a covariate did not change the results. Using the recently available software tool VBM8 including DARTEL normalisation ( we could replicate this finding in the anterior and mid-cingulate cortex and both anterior insulae.


    We calculated the effect sizes and the cross-sectional analysis (patients vs. controls) yielded a Cohen’s d of 1.78751 in the peak voxel of the ACC (x = −12, y = 25, z = −16). We also calculated Cohen’s d for the longitudinal analysis (contrasting scan 1+2 vs. scan 3+4). This resulted in a Cohen’s d of 1.1158 in the ACC (x = −3, y = 50, z = 2). Regarding the insula (x = −33, y = 21, z = 13) and related to the same contrast, Cohen’s d is 1.0949. Additionally, we calculated the mean of the non-zero voxel values of the Cohen’s d map within the ROI (comprised of the anterior division of the cingulate gyrus and the subcallosal cortex, derived from the Harvard-Oxford Cortical Structural Atlas): 1.251223.



    Dr. Alex Jimenez’s Insight

    Chronic pain patients can experience a variety of health issues over time, aside from their already debilitating symptoms. For instance, many individuals will experience sleeping problems as a result of their pain, but most importantly, chronic pain can lead to various mental health issues as well, including anxiety and depression. The effects that pain can have on the brain may seem all too overwhelming but growing evidence suggests that these brain changes are not permanent and can be reversed when chronic pain patients receive the proper treatment for their underlying health issues. According to the article, gray matter abnormalities found in chronic pain do not reflect brain damage, but rather, they are a reversible consequence which normalizes when the pain is adequately treated. Fortunately, a variety of treatment approaches are available to help ease chronic pain symptoms and restore the structure and function of the brain.




    Monitoring whole brain structure over time, we confirm and expand our pilot data published recently [17]. We found changes in brain gray matter in patients with primary hip osteoarthritis in the chronic pain state, which reverse partly when these patients are pain free, following hip joint endoprosthetic surgery. The partial increase in gray matter after surgery is nearly in the same areas where a decrease of gray matter has been seen before surgery. Flipping the data of patients with left hip OA (and therefore normalizing for the side of the pain) had only little impact on the results but additionally showed a decrease of gray matter in the Heschl’s gyrus and Precuneus that we cannot easily explain and, as no a priori hypothesis exists, regard with great caution. However, the difference seen between patients and healthy controls at scan I was still observable in the cross-sectional analysis at scan IV. The relative increase of gray matter over time is therefore subtle, i.e. not sufficiently distinct to have an effect on the cross sectional analysis, a finding that has already been shown in studies investigating experience dependant plasticity [30], [31]. We note that the fact that we show some parts of brain-changes due to chronic pain to be reversible does not exclude that some other parts of these changes are irreversible.


    Interestingly, we observed that the gray matter decrease in the ACC in chronic pain patients before surgery seems to continue 6 weeks after surgery (scan II) and only increases towards scan III and IV, possibly due to post-surgery pain, or decrease in motor function. This is in line with the behavioural data of the physical mobility score included in the NHP, which post-operatively did not show any significant change at time point II but significantly increased towards scan III and IV. Of note, our patients reported no pain in the hip after surgery, but experienced post-surgery pain in surrounding muscles and skin which was perceived very differently by patients. However, as patients still reported some pain at scan II, we also contrasted the first scan (pre-surgery) with scans III+IV (post-surgery), revealing an increase of gray matter in the frontal cortex and motor cortex. We note that this contrast is less stringent because of less scans per condition (pain vs. non-pain). When we lowered the threshold we repeat what we have found using contrast of I+II vs. III+IV.


    Our data strongly suggest that gray matter alterations in chronic pain patients, which are usually found in areas involved in supraspinal nociceptive processing [4] are neither due to neuronal atrophy nor brain damage. The fact that these changes seen in the chronic pain state do not reverse completely could be explained with the relatively short period of observation (one year after operation versus a mean of seven years of chronic pain before the operation). Neuroplastic brain changes that may have developed over several years (as a consequence of constant nociceptive input) need probably more time to reverse completely. Another possibility why the increase of gray matter can only be detected in the longitudinal data but not in the cross-sectional data (i.e. between cohorts at time point IV) is that the number of patients (n = 20) is too small. It needs to be pointed out that the variance between brains of several individuals is quite large and that longitudinal data have the advantage that the variance is relatively small as the same brains are scanned several times. Consequently, subtle changes will only be detectable in longitudinal data [30], [31], [32]. Of course we cannot exclude that these changes are at least partly irreversible although that is unlikely, given the findings of exercise specific structural plasticity and reorganisation [4], [12], [30], [33], [34]. To answer this question, future studies need to investigate patients repeatedly over longer time frames, possibly years.


    We note that we can only make limited conclusions regarding the dynamics of morphological brain changes over time. The reason is that when we designed this study in 2007 and scanned in 2008 and 2009, it was not known whether structural changes would occur at all and for reasons of feasibility we chose the scan dates and time frames as described here. One could argue that the gray matter changes in time, which we describe for the patient group, might have happened in the control group as well (time effect). However, any changes due to aging, if at all, would be expected to be a decrease in volume. Given our a priori hypothesis, based on 9 independent studies and cohorts showing decreases in gray matter in chronic pain patients [7], [8], [9], [15], [24], [25], [26], [27], [28], we focussed on regional increases over time and therefore believe our finding not to be a simple time effect. Of note, we cannot rule out that the gray matter decrease over time that we found in our patient group could be due to a time effect, as we have not scanned our control group in the same time frame. Given the findings, future studies should aim at more and shorter time intervals, given that exercise dependant morphometric brain changes may occur as fast as after 1 week [32], [33].


    In addition to the impact of the nociceptive aspect of pain on brain gray matter [17], [34] we observed that changes in motor function probably also contribute to the structural changes. We found motor and premotor areas (area 6) to increase over all time intervals (Figure 3). Intuitively this may be due to improvement of motor function over time as the patients were no more restricted in living a normal life. Notably we did not focus on motor function but an improvement in pain experience, given our original quest to investigate whether the well-known reduction in brain gray matter in chronic pain patients is in principle reversible. Consequently, we did not use specific instruments to investigate motor function. Nevertheless, (functional) motor cortex reorganization in patients with pain syndromes is well documented [35], [36], [37], [38]. Moreover, the motor cortex is one target in therapeutic approaches in medically intractable chronic pain patients using direct brain stimulation [39], [40], transcranial direct current stimulation [41], and repetitive transcranial magnetic stimulation [42], [43]. The exact mechanisms of such modulation (facilitation vs. inhibition, or simply interference in the pain-related networks) are not yet elucidated [40]. A recent study demonstrated that a specific motor experience can alter the structure of the brain [13]. Synaptogenesis, reorganisation of movement representations and angiogenesis in motor cortex may occur with special demands of a motor task. Tsao et al. showed reorganisation in the motor cortex of patients with chronic low back pain that seem to be back pain-specific [44] and Puri et al. observed a reduction in left supplemental motor area gray matter in fibromyalgia sufferers [45]. Our study was not designed to disentangle the different factors that may change the brain in chronic pain but we interpret our data concerning the gray matter changes that they do not exclusively mirror the consequences of constant nociceptive input. In fact, a recent study in neuropathic pain patients pointed out abnormalities in brain regions that encompass emotional, autonomic, and pain perception, implying that they play a critical role in the global clinical picture of chronic pain [28].


    Figure 3 Statistical Parametric Maps
    Figure 3: Statistical parametric maps demonstrating a significant increase of brain gray matter in motor areas (area 6) in patients with coxarthrosis before compared to after THR (longitudinal analysis, scan I<scan II<scan III<scan IV). Contrast estimates at x = 19, y = −12, z = 70.


    Two recent pilot studies focussed on hip replacement therapy in osteoarthritis patients, the only chronic pain syndrome which is principally curable with total hip replacement [17], [46] and these data are flanked by a very recent study in chronic low back pain patients [47]. These studies need to be seen in the light of several longitudinal studies investigating experience-dependent neuronal plasticity in humans on a structural level [30], [31] and a recent study on structural brain changes in healthy volunteers experiencing repeated painful stimulation [34]. The key message of all these studies is that the main difference in the brain structure between pain patients and controls may recede when the pain is cured. However, it must be taken into account that it is simply not clear whether the changes in chronic pain patients are solely due to nociceptive input or due to the consequences of pain or both. It is more than likely that behavioural changes, such as deprivation or enhancement of social contacts, agility, physical training and life style changes are sufficient to shape the brain [6], [12], [28], [48]. Particularly depression as a co-morbidity or consequence of pain is a key candidate to explain the differences between patients and controls. A small group of our patients with OA showed mild to moderate depressive symptoms that changed with time. We did not find the structural alterations to covary significantly with the BDI-score but the question arises how many other behavioural changes due to the absence of pain and motor improvement may contribute to the results and to what extent they do. These behavioural changes can possibly influence a gray matter decrease in chronic pain as well as a gray matter increase when pain is gone.


    Another important factor which may bias our interpretation of the results is the fact that nearly all patients with chronic pain took medications against pain, which they stopped when they were pain free. One could argue that NSAIDs such as diclofenac or ibuprofen have some effects on neural systems and the same holds true for opioids, antiepileptics and antidepressants, medications which are frequently used in chronic pain therapy. The impact of pain killers and other medications on morphometric findings may well be important (48). No study so far has shown effects of pain medication on brain morphology but several papers found that changes in brain structure in chronic pain patients are neither solely explained by pain related inactivity [15], nor by pain medication [7], [9], [49]. However, specific studies are lacking. Further research should focus the experience-dependent changes in cortical plasticity, which may have vast clinical implications for the treatment of chronic pain.


    We also found decreases of gray matter in the longitudinal analysis, possibly due to reorganisation processes that accompany changes in motor function and pain perception. There is little information available about longitudinal changes in brain gray matter in pain conditions, for this reason we have no hypothesis for a gray matter decrease in these areas after the operation. Teutsch et al. [25] found an increase of brain gray matter in the somatosensory and midcingulate cortex in healthy volunteers that experienced painful stimulation in a daily protocol for eight consecutive days. The finding of gray matter increase following experimental nociceptive input overlapped anatomically to some degree with the decrease of brain gray matter in this study in patients that were cured of long-lasting chronic pain. This implies that nociceptive input in healthy volunteers leads to exercise dependant structural changes, as it possibly does in patients with chronic pain, and that these changes reverse in healthy volunteers when nociceptive input stops. Consequently, the decrease of gray matter in these areas seen in patients with OA could be interpreted to follow the same fundamental process: exercise dependant changes brain changes [50]. As a non-invasive procedure, MR Morphometry is the ideal tool for the quest to find the morphological substrates of diseases, deepening our understanding of the relationship between brain structure and function, and even to monitor therapeutic interventions. One of the great challenges in the future is to adapt this powerful tool for multicentre and therapeutic trials of chronic pain.


    Limitations of this Study


    Although this study is an extension of our previous study expanding the follow-up data to 12 months and investigating more patients, our principle finding that morphometric brain changes in chronic pain are reversible is rather subtle. The effect sizes are small (see above) and the effects are partly driven by a further reduction of regional brain gray matter volume at the time-point of scan 2. When we exclude the data from scan 2 (directly after the operation) only significant increases in brain gray matter for motor cortex and frontal cortex survive a threshold of p<0.001 uncorrected (Table 3).


    Table 3 Longitudinal Data




    It is not possible to distinguish to what extent the structural alterations we observed are due to changes in nociceptive input, changes in motor function or medication consumption or changes in well-being as such. Masking the group contrasts of the first and last scan with each other revealed much less differences than expected. Presumably, brain alterations due to chronic pain with all consequences are developing over quite a long time course and may also need some time to revert. Nevertheless, these results reveal processes of reorganisation, strongly suggesting that chronic nociceptive input and motor impairment in these patients leads to altered processing in cortical regions and consequently structural brain changes which are in principle reversible.




    We thank all volunteers for the participation in this study and the Physics and Methods group at NeuroImage Nord in Hamburg. The study was given ethical approval by the local Ethics committee and written informed consent was obtained from all study participants prior to examination.


    Funding Statement


    This work was supported by grants from the DFG (German Research Foundation) (MA 1862/2-3) and BMBF (The Federal Ministry of Education and Research) (371 57 01 and NeuroImage Nord). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


    Endocannabinoid System | El Paso, TX Chiropractor


    The Endocannabinoid System: The Essential System You’ve Never Heard Of


    In case you haven’t heard of the endocannabinoid system, or ECS, there’s no need to feel embarrassed. Back in the 1960’s, the investigators that became interested in the bioactivity of Cannabis eventually isolated many of its active chemicals. It took another 30 years, however, for researchers studying animal models to find a receptor for these ECS chemicals in the brains of rodents, a discovery which opened a whole world of inquiry into the ECS receptors existence and what their physiological purpose is.


    We now know that most animals, from fish to birds to mammals, possess an endocannabinoid, and we know that humans not only make their own cannabinoids that interact with this particular system, but we also produce other compounds that interact with the ECS, those of which are observed in many different plants and foods, well beyond the Cannabis species.


    As a system of the human body, the ECS isn’t an isolated structural platform like the nervous system or cardiovascular system. Instead, the ECS is a set of receptors widely distributed throughout the body which are activated through a set of ligands we collectively know as endocannabinoids, or endogenous cannabinoids. Both verified receptors are just called CB1 and CB2, although there are others which were proposed. PPAR and TRP channels also mediate some functions. Likewise, you will find just two well-documented endocannabinoids: anadamide and 2-arachidonoyl glycerol, or 2-AG.


    Moreover, fundamental to the endocannabinoid system are the enzymes that synthesize and break down the endocannabinoids. Endocannabinoids are believed to be synthesized in an as-needed foundation. The primary enzymes involved are diacylglycerol lipase and N-acyl-phosphatidylethanolamine-phospholipase D, which respectively synthesize 2-AG and anandamide. The two main degrading enzymes are fatty acid amide hydrolase, or FAAH, which breaks down anandamide, and monoacylglycerol lipase, or MAGL, which breaks down 2-AG. The regulation of these two enzymes may increase or decrease the modulation of the ECS.


    What is the Function of the ECS?


    The ECS is the principal homeostatic regulatory system of the body. It may readily be viewed as the body’s internal adaptogenic system, always working to maintain the balance of a variety of function. Endocannabinoids broadly work as neuromodulators and, as such, they regulate a broad range of bodily processes, from fertility to pain. Some of those better-known functions from the ECS are as follows:


    Nervous System


    From the central nervous system, or the CNS, general stimulation of the CB1 receptors will inhibit the release of glutamate and GABA. In the CNS, the ECS plays a role in memory formation and learning, promotes neurogenesis in the hippocampus, also regulates neuronal excitability. The ECS also plays a part in the way the brain will react to injury and inflammation. From the spinal cord, the ECS modulates pain signaling and boosts natural analgesia. In the peripheral nervous system, in which CB2 receptors control, the ECS acts primarily in the sympathetic nervous system to regulate functions of the intestinal, urinary, and reproductive tracts.


    Stress and Mood


    The ECS has multiple impacts on stress reactions and emotional regulation, such as initiation of this bodily response to acute stress and adaptation over time to more long-term emotions, such as fear and anxiety. A healthy working endocannabinoid system is critical to how humans modulate between a satisfying degree of arousal compared to a level that is excessive and unpleasant. The ECS also plays a role in memory formation and possibly especially in the way in which the brain imprints memories from stress or injury. Because the ECS modulates the release of dopamine, noradrenaline, serotonin, and cortisol, it can also widely influence emotional response and behaviors.


    Digestive System


    The digestive tract is populated with both CB1 and CB2 receptors that regulate several important aspects of GI health. It’s thought that the ECS might be the “missing link” in describing the gut-brain-immune link that plays a significant role in the functional health of the digestive tract. The ECS is a regulator of gut immunity, perhaps by limiting the immune system from destroying healthy flora, and also through the modulation of cytokine signaling. The ECS modulates the natural inflammatory response in the digestive tract, which has important implications for a wide range of health issues. Gastric and general GI motility also appears to be partially governed by the ECS.


    Appetite and Metabolism


    The ECS, particularly the CB1 receptors, plays a part in appetite, metabolism, and regulation of body fat. Stimulation of the CB1 receptors raises food-seeking behaviour, enhances awareness of smell, also regulates energy balance. Both animals and humans that are overweight have ECS dysregulation that may lead this system to become hyperactive, which contributes to both overeating and reduced energy expenditure. Circulating levels of anandamide and 2-AG have been shown to be elevated in obesity, which might be in part due to decreased production of the FAAH degrading enzyme.


    Immune Health and Inflammatory Response


    The cells and organs of the immune system are rich with endocannabinoid receptors. Cannabinoid receptors are expressed in the thymus gland, spleen, tonsils, and bone marrow, as well as on T- and B-lymphocytes, macrophages, mast cells, neutrophils, and natural killer cells. The ECS is regarded as the primary driver of immune system balance and homeostasis. Though not all the functions of the ECS from the immune system are understood, the ECS appears to regulate cytokine production and also to have a role in preventing overactivity in the immune system. Inflammation is a natural part of the immune response, and it plays a very normal role in acute insults to the body, including injury and disease ; nonetheless, when it isn’t kept in check it can become chronic and contribute to a cascade of adverse health problems, such as chronic pain. By keeping the immune response in check, the ECS helps to maintain a more balanced inflammatory response through the body.


    Other areas of health regulated by the ECS:


    • Bone health
    • Fertility
    • Skin health
    • Arterial and respiratory health
    • Sleep and circadian rhythm


    How to best support a healthy ECS is a question many researchers are now trying to answer. Stay tuned for more information on this emerging topic.


    In conclusion, chronic pain has been associated with brain changes, including the reduction of gray matter. However, the article above demonstrated that chronic pain can alter the overall structure and function of the brain. Although chronic pain may lead to these, among other health issues, the proper treatment of the patient’s underlying symptoms can reverse brain changes and regulate gray matter. Furthermore, more and more research studies have emerged behind the importance of the endocannabinoid system and it’s function in controlling as well as managing chronic pain and other health issues. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain

    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news


    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



    The post Brain Changes Associated with Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 Figure 1 Statistical Parametric Maps Table 1 Cross-Sectional Data Figure 2 Increases in Brain Gray Matter Table 2 Longitudinal Data Dr-Jimenez_White-Coat_01.png Figure 3 Statistical Parametric Maps Table 3 Longitudinal Data Endocannabinoid System | El Paso, TX Chiropractor Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17731
    The Connection Between Anxiety and Inflammation Tue, 10 Jul 2018 19:48:10 +0000

    Anxiety is the most common mental health disorder in the United States, impacting more than 40 million adults. Though some instances can be moderate and short-lived, others may be painfully debilitating, lasting for years, or becoming a chronic problem. While almost anyone can experience temporary anxiety before a variety of events, anxiety is regarded as problematic when it starts to interfere in one way or another with regular, everyday function, including sleep disturbances, social stress, or self-care. Anxiety is connected to a number of lifestyle, health, and nutritional aspects, but understanding the triggers and root causes can result in a more effective treatment approach.


    The thought of the existence of an interaction between the immune system and the central nervous system, or CNS, has prompted extensive research attention into the subject of "psychoneuroimmunology", carrying the area

    The post The Connection Between Anxiety and Inflammation appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Anxiety is the most common mental health disorder in the United States, impacting more than 40 million adults. Though some instances can be moderate and short-lived, others may be painfully debilitating, lasting for years, or becoming a chronic problem. While almost anyone can experience temporary anxiety before a variety of events, anxiety is regarded as problematic when it starts to interfere in one way or another with regular, everyday function, including sleep disturbances, social stress, or self-care. Anxiety is connected to a number of lifestyle, health, and nutritional aspects, but understanding the triggers and root causes can result in a more effective treatment approach.


    The thought of the existence of an interaction between the immune system and the central nervous system, or CNS, has prompted extensive research attention into the subject of “psychoneuroimmunology”, carrying the area to an intriguing level where new hypotheses are being increasingly tested. So far, the presence of inflammatory reactions and the crucial effects of depression have received most attention. But considering a large socioeconomic impact due to an alarming increase in anxiety disorder patients, there is an urgent research need for better comprehension of the role of inflammation in anxiety and how this relationship can influence one another. The purpose of the article below is to demonstrate the results as well as discuss the outcome measures of a large cohort study conducted in order to determine the possible connection between anxiety disorders and brain inflammation.


    Anxiety Disorders and Inflammation in a Large Adult Cohort




    Although anxiety disorders, like depression, are increasingly being associated with metabolic and cardiovascular burden, in contrast with depression, the role of inflammation in anxiety has sparsely been examined. This large cohort study examines the association between anxiety disorders and anxiety characteristics with several inflammatory markers. For this purpose, persons (18–65 years) with a current (N=1273) or remitted (N=459) anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and healthy controls (N=556) were selected from the Netherlands Study of Depression and Anxiety. In addition, severity, duration, age of onset, anxiety subtype and co-morbid depression were assessed. Inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6 and tumor-necrosis factor (TNF)-α. Results show that after adjustment for sociodemographics, lifestyle and disease, elevated levels of CRP were found in men, but not in women, with a current anxiety disorder compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l−1, P=0.04, Cohen’s d=0.18). No associations were found with IL-6 or TNF-α. Among persons with a current anxiety disorder, those with social phobia, in particular women, had lower levels of CRP and IL-6, whereas highest CRP levels were found in those with an older age of anxiety disorder onset. Especially in persons with an age of onset after 50 years, CRP levels were increased compared with controls (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l−1, P=0.01, Cohen’s d=0.37). In conclusion, elevated inflammation is present in men with current anxiety disorders. Immune dysregulation is especially found in persons with a late-onset anxiety disorder, suggesting the existence of a specific late-onset anxiety subtype with a distinct etiology, which could possibly benefit from alternative treatments.


    Keywords: anxiety disorder, anxiety characteristics, cohort study, inflammation




    Anxiety disorders are among the most prevalent and disabling mental disorders.1, 2 Increasing evidence links anxiety to cardiovascular risk factors and diseases such as atherosclerosis,3 metabolic syndrome,4 and coronary heart disease.5, 6 As low-grade systemic inflammation is clearly involved in the etiology of these somatic conditions,7, 8, 9 it has been hypothesized that inflammation has a role in anxiety disorders and may form the link between anxiety disorders and cardiovascular burden.10 Anxiety disorders are also highly co-morbid with depression,11 which has recurrently been associated with immune dysregulation.12, 13 However, unlike depression, very few studies have investigated the relationship between anxiety disorders and inflammation. Two recent studies have correlated anxiety symptoms with increased cytokine levels, in particular C-reactive protein (CRP).14, 15 With regard to anxiety disorders, research has mainly focused on posttraumatic stress disorder, in which high levels of inflammatory markers have been found.16, 17 Sparse evidence from relatively small clinical studies (n≈100) suggests increased inflammatory activation in patients with panic disorder18 and generalized anxiety disorder,19 which seems to be independent of co-morbid depression.


    As there is yet limited research on immune dysregulation and anxiety, one can only speculate on the mechanisms linking these two conditions. Experimentally induced stress has been shown to produce an inflammatory reaction,20 which has led researchers to suggest that it is in particular the experience of acute stress, such as present in panic disorders, causing the high levels of inflammation in anxiety.18 On the other hand, chronic stress may initiate changes in the hypothalamic–pituitary–adrenal (HPA) axis and the immune system, which in turn can trigger depression as well as anxiety.21 These pathways are not independent as the HPA-axis and the immune system are closely linked. Although the HPA axis in normal situations should temper inflammatory reactions, prolonged hyperactivity of the HPA axis could result in blunted anti-inflammatory responses to glucocorticoids resulting in increased inflammation.22, 23 Likewise, it can be hypothesized that immune changes associated with chronic disease and aging,24 could induce similar anxiety-enhancing effects. Although several mechanisms might explain an association between inflammation and anxiety disorders, it can be expected that immune dysregulation is not a general phenomenon in anxiety disorders, but might be restricted to specific subgroups. Whether this anxiety subgroup is defined by the type of disorder, the severity or duration of the disorder, the co-morbidity with depression, or its age of onset, is yet to be examined.


    The present study investigates the association between several common anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and heightened inflammation (CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-α) in a large sample of persons with current and remitted anxiety disorders and healthy controls. In addition, it will be examined whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) further discriminate those anxiety patients with elevated inflammation.


    Subjects and Methods




    The Netherlands Study of Depression and Anxiety (NESDA) includes 2981 persons with and without depressive and anxiety disorders, aged 18–65 years at the baseline assessment in 2004–2007. Participants were recruited from the community (19%), general practice (54%) and secondary mental health care (27%) in order to reflect the broad range and developmental trajectory of psychopathology. Persons with insufficient command of the Dutch language or a primary clinical diagnosis of bipolar disorder, obsessive compulsive disorder, severe substance use disorder, psychotic disorder or organic psychiatric disorder, as reported by themselves or their mental health practitioner, were excluded. A detailed description of the NESDA study design and sampling procedures can be found elsewhere.25 The research protocol was approved by the ethics committee of participating universities and after complete description of the study all respondents provided written informed consent.


    During the baseline interview, the presence of anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia) and depressive disorder (major depressive disorder, dysthymia) was established using the Composite Interview Diagnostic Instrument (CIDI) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria.26 The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders27 and was administered by specially trained research staff. In addition, the severity of anxiety was measured in all participants using the 21-item self-report Beck Anxiety Inventory.28 For the present analyses, we selected persons with a current (that is, past 6 months) or remitted (lifetime, but not current) anxiety disorder and healthy controls. Healthy controls had no lifetime anxiety or depressive disorder and a Beck Anxiety Inventory score below 10, as a score of 10 or above indicates mild anxiety.29 Persons with anxiety disorders were allowed to have a co-morbid depression. Of these 2342 persons, 54 were excluded due to missing information on inflammatory markers, leaving a sample of 2288 persons for the present study. Persons with missing data on inflammation were less often female (55.6 versus 66.9%, P=0.08), but did not differ from included persons in terms of age, years of education and the presence of anxiety disorder.


    Anxiety Characteristics


    Next to subtype of CIDI anxiety disorder diagnosis (generalized anxiety disorder, social phobia, panic disorder, agoraphobia), anxiety characteristics included anxiety symptoms severity as measured by the Beck Anxiety Inventory, and anxiety symptoms duration, using the Life Chart Interview (LCI).30 The LCI uses a calendar method to determine life events during the past 4 years to refresh memory after which the presence of anxiety and avoidance symptoms during that period is assessed. From this, the per cent of time patients reported anxiety symptoms was computed. The LCI has been used by other large cohort studies31 and event history calendars such as the LCI have been suggested a natural method of choice for retrospective data collection.32 To be able to test whether inflammation was in particular associated with anxiety disorders with a later onset, as we had found for depression,33 age of anxiety onset was derived from the CIDI interview. Last, the presence of a current co-morbid depressive disorder (major depressive disorder, dysthymia) was taken from the CIDI to check whether a possible inflammation–anxiety association was independent of co-morbid depression.


    Inflammatory Markers


    Markers of inflammation were assessed at the baseline NESDA measurement and included CRP, IL-6 and TNF-α. Fasting blood samples of NESDA participants were obtained in the morning between 0800 and 0900 hours and kept frozen at −80 °C. CRP and IL-6 were assayed at the Clinical Chemistry Department of the VU University Medical Center. High-sensitivity plasma levels of CRP were measured in duplicate by an in-house ELISA based on purified protein and polyclonal anti-CRP antibodies (Dako, Glostrup, Denmark). Intra- and inter-assay coefficients of variation were 5% and 10%, respectively. Plasma IL-6 levels were measured in duplicate by a high sensitivity ELISA (PeliKine CompactTM ELISA, Sanquin, Amsterdam, The Netherlands). Intra- and inter-assay coefficients of variation were 8% and 12%, respectively. Plasma TNF-α levels were assayed in duplicate at Good Biomarker Science, Leiden, The Netherlands, using a high-sensitivity solid phase ELISA (Quantikine® HS Human TNF-α Immunoassay, R&D systems, Minneapolis, MN, USA). Intra- and inter-assay coefficients of variation were 10% and 15%, respectively.




    Sociodemographic characteristics included sex, age and years of education. As lifestyle characteristics can be associated with both anxiety and inflammation, smoking status (never, former, current), alcohol intake (<1, 1–14 (women)/1–21 (men), >14 (women)/>21 (men) drinks per week), physical activity (measured with the International Physical Activity Questionnaire34 in MET-minutes (ratio of energy expenditure during activity compared with rest times the number of minutes performing the activity) per week) and body mass index (weight in kilograms divided by height in meters squared) were assessed. In addition, several disease-related covariates were taken into account including the presence of cardiovascular disease (assessed by self-report supported by appropriate medication use (see Vogelzangs et al.6 for detailed description)), the presence of diabetes (fasting plasma glucose level ⩾7.0 mmol l−1 or use of anti-diabetic medication (ATC code A10)) and the number of other self-reported chronic diseases for which persons received treatment (including lung disease, osteoarthritis or rheumatic disease, cancer, ulcer, intestinal problem, liver disease, epilepsy and thyroid gland disease). Medication use was assessed based on drug container inspection of all drugs used in the past month and classified according to the World Health Organization Anatomical Therapeutic Chemical classification.35 Statin use (C10AA, C10B) and use of systemic anti-inflammatory medication (M01A, M01B, A07EB, A07EC) were assessed. Antidepressant medication included regular use (>50% of the time) of selective serotonin reuptake inhibitors (SSRI; N06AB), serotonin-norepinephrine reuptake inhibitors (SNRI; N06AX16, N06AX21), tricyclic antidepressants (TCA; N06AA) and tetracyclic antidepressants (TeCA; N06AX03, N06AX05, N06AX11).


    Statistical Analyses


    Baseline characteristics were compared between men and women using χ2 test for dichotomous and categorical variables, independent samples t-test for continuous variables, and Mann–Whitney U-test for inflammatory markers. For subsequent analyses, CRP, IL-6 and TNF-α were ln-transformed to normalize distributions, but back-transformed values are presented to enhance interpretation. Associations between anxiety disorders and inflammatory markers were examined using analyses of (co)variance, and (adjusted) means across anxiety groups (no, remitted, current) are presented. To take the effects of potential confounding factors into account, three different models were tested: unadjusted, adjusted for sociodemographics (sex, age, education) and additionally adjusted for lifestyle and disease (smoking status, alcohol intake, physical activity, body mass index, cardiovascular disease, diabetes, number of other chronic diseases, statins, anti-inflammatory medication). As depression has been reported to differentially affect inflammation in men and women,33 a sex-interaction for anxiety disorders is plausible. Therefore, we tested sex-interactions by including a sex × anxiety disorder status interaction term. When present, analyses were repeated sex stratified.


    To test whether specific anxiety characteristics were related to elevated inflammation levels, we performed linear regression analyses with inflammatory markers as the outcome for each anxiety characteristic (severity, duration, age of onset, subtype, depression co-morbidity) within the sample of persons with a current anxiety disorder.



    Dr. Alex Jimenez’s Insight

    Anxiety is a common term which is often used to refer to situational stress or to describe momentary tenseness, however, for individuals living with an anxiety disorder, the symptoms associated with this mental health issue can be debilitating. Anxiety can be caused by a wide variety of factors, including depression and chronic pain, however, research studies have started to hypothesize that another common factor may be the true source as to why some people develop anxiety while other don’t: inflammation. The connection between anxiety and inflammation, as well as depression and inflammation, is becoming increasingly understood. Anxiety isn’t likely caused by inflammation alone, but, measuring inflammatory levels in the body could help determine the best treatment approach for a variety of anxiety disorders and for underlying health issues most commonly associated with inflammation, such as chronic pain.




    Mean age of the study sample was 41.8 (s.d.=13.1) years and 66.9% were women. Baseline characteristics of the total sample and for men and women separately are shown in Table 1. Women were younger, more often non-drinkers, had a lower body mass index, less often cardiovascular disease or diabetes and less often used statins than men. In addition, women had higher levels of CRP than men. All covariates were associated with at least one of the inflammation markers, which has been presented elsewhere.33 Pearson’s correlations between inflammatory markers were modest (CRP–IL-6: r=0.31; CRP–TNF-α: r=0.13; IL-6–TNF-α: r=0.12; all P<0.001).


    Table 1 Baseline Characteristics


    Table 2 shows (adjusted) mean inflammation levels across anxiety groups (controls, remitted, current) based on analyses of (co)variance. In the total sample, higher CRP levels were found in persons with a current anxiety disorder compared with controls in unadjusted analyses (1.36 (s.e.=1.04) versus 1.11 (s.e.=1.05) mg l−1, P=0.001), but after adjustment, there were no associations between anxiety disorders and any of the inflammation markers. However, a significant sex × anxiety disorder interaction was found for CRP (remitted: P=0.57; current: P=0.002). Stratified analyses for CRP showed that even after full adjustment for lifestyle and disease, men with current anxiety disorders had higher levels of CRP compared with controls (1.18 (s.e.=1.05) versus 0.98 (s.e.=1.07) mg l−1, P=0.04, Cohen’s d=0.18). In women, anxiety disorders were not significantly associated with CRP. No sex interactions were found for IL-6 (remitted: P=0.47; current: P=0.40) or TNF-α (remitted: P=0.92; current: P=0.87). As we have previously reported associations between inflammatory levels and antidepressant use within currently depressed persons,33 we checked the influence of antidepressant use on our current results. Higher levels of CRP were found in TCA/TeCA users within our present sample of persons with current anxiety disorders (N=1273; P=0.001). To examine whether the finding of elevated CRP in currently anxious men was independent of TCA/TeCA use, we excluded all men using TCA/TeCA (N=36). Results remained similar, although no longer significant (men with current anxiety disorders versus controls: 1.13 (s.e.=1.05) versus 0.97 (s.e.=1.07) mg l−1, P=0.08, Cohen’s d=0.15). In addition, to reduce the possible confounding effects of acute illness on inflammatory levels at the time of blood draw, all persons who reported having had a cold or fever in the week before blood draw were excluded (N=645), but findings remained alike (men with current anxiety disorders versus controls: 1.09 (s.e.=1.06) versus 0.91 (s.e.=1.07) mg l−1, P=0.06, Cohen’s d=0.19).


    Table 2 Adjusted Mean Marker Levels


    To investigate whether specific anxiety characteristics (severity, duration, age of onset, subtype, depression co-morbidity) were associated with inflammation, linear regression analyses were performed within the subgroup of persons with current anxiety disorders (N=1273; Table 3). Anxiety severity and duration did not correlate with inflammation. Later age of anxiety disorder onset was associated with elevated CRP levels (β=0.053, P=0.05), even after additional adjustment for TCA/TeCA use (β=0.053, P=0.05). Persons with social phobia had lower levels of CRP (β=−0.053, P=0.04) and IL-6 (β=−0.052, P=0.05) compared with persons with other types of anxiety disorders. The association between social phobia and IL-6 appeared to be specific for women (β=−0.089, P=0.007), but not men (β=0.025, P=0.61; P sex-interaction=0.05). Co-morbid depressive disorder did not further differentiate anxious persons with elevated inflammation.


    Table 3 Association of Characteristics


    To further illustrate the findings with regard to age of onset, we constructed five age of anxiety disorder onset groups (<20, 20–30, 30–40, 40–50, ⩾50). Figure 1 presents adjusted means of back-transformed CRP levels across controls and age of onset groups based on analysis of covariance. CRP levels were only increased in persons with an age of onset after 50 years (1.95 (s.e.=1.18) versus 1.27 (s.e.=1.05) mg l−1 in controls, P=0.01, Cohen’s d=0.37). For comparison, adjusted mean CRP levels for persons with cardiovascular disease were 1.62 (s.e=1.11), illustrating the clinical relevance of this finding. Excluding persons reporting having had a cold or fever in the week before blood draw (N=513), yielded similar findings (age of onset after 50 years versus controls: 1.73 (s.e.=1.20) versus 1.18 (s.e.=1.05) mg l−1, P=0.04, Cohen’s d=0.35). Results were also similar when the analysis of Figure 1 was restricted to the sample of persons aged 50 years or above (N=589; age of onset after 50 years versus controls: 2.05 (s.e.=1.16) versus 1.35 (s.e.=1.08) mg l−1, P=0.01, Cohen’s d=0.40), underlining that higher CRP in those with an age of onset of 50 years or above was not due to the higher age itself in these persons. Last, in a post-hoc analysis, we directly compared CRP levels between persons with a late versus early onset of anxiety disorder at a cutoff of 50 years, and found significantly higher CRP levels in the late onset group (1.91 (s.e.=1.19) versus 1.35 (s.e.=1.03) mg l−1, P=0.05, Cohen’s d=0.30).


    Figure 1 Adjusted Mean CRP Levels




    The current study is one of the first and the largest to date to examine the association between anxiety disorders and inflammation. The results show that men with a current anxiety disorder have somewhat increased levels of CRP, even after taking a large set of lifestyle and disease factors into account. Elevated levels of CRP were in particular found in those persons with a late onset of the anxiety disorder.


    Our results are in line with the few previous studies examining the relationship between anxiety symptoms or disorders with inflammation. Available evidence until now was limited to assessing anxiety symptoms in the general population,14, 15 confined to specific anxiety disorders in small clinical samples16, 17, 18 or in a heart disease population.19 Our study adds to the literature by showing that elevated CRP levels can be found among several common anxiety disorders in a relatively large cohort of anxious persons and controls, specifically in those with a later onset of the anxiety disorder. CRP levels were in particular elevated among men with anxiety disorders, which is in line with the large-scale study by Liukkonen et al.,15 which showed an association between anxiety symptoms and CRP only in men. In contrast, Pitsavos et al.14 found associations between an anxiety symptoms score and CRP levels in both men and women. Persons included in the study by Pitsavos et al. were much older (18–89 years; mean age 45 years) than those in the study by Liukkonen et al. (all 31 years old), and slightly older than those in the present study (18–65 years; mean age 42 years). Perhaps sex differences become less clear with increasing age, as a result of hormonal changes across the lifespan of women, which affect inflammation levels.36 This could be in line with our finding that CRP levels were elevated in both men and women with a late onset of anxiety disorders.


    Our findings with respect to anxiety disorders are also very comparable to our earlier findings regarding depressive disorders and inflammation.33 In that study, we found elevated inflammation, specifically CRP, in depressed men, especially among those with a later depression onset. The effect sizes for CRP in men with a current disorder are also comparable for anxiety (Cohen’s d=0.18) and depressive (Cohen’s d=0.21) disorders. A trend for association with IL-6, which was found for current depressive disorders in men, was not found for current anxiety disorders. Of note is that in persons with an anxiety disorder, a co-morbid depressive disorder was not associated with higher inflammation levels, suggesting that the effects found for anxiety disorders are independent of depression.


    In line with our previous findings for current depressive disorders,33 CRP levels were in particular elevated among persons with a later onset of anxiety disorders. In contrast, characteristics that are more often associated with an early age of onset, such as higher severity and longer duration were not associated with increased inflammation. Also, in our sample, women had an earlier age of anxiety disorder onset than men, possibly contributing to the lack of an overall association between anxiety disorders and inflammation in women. Furthermore, we found that CRP levels were lowest among persons with social phobia when compared with other anxiety disorders, in particular in women. Social phobia has been reported to have a much earlier age of onset compared with generalized anxiety disorder or panic disorder,37 which was confirmed in our sample (16.6 versus 25.9 years, P<0.001). To our knowledge, no other study has yet examined the association between social phobia and inflammation. In our study, only nine persons with social phobia had an disorder onset at or after 50 years. Therefore, low inflammation levels in persons with social phobia cannot explain our findings for elevated CRP levels in persons with an age of anxiety disorder onset after 50 years. A recent study by Copeland et al.38 showed that, after taking health-related behaviors into account, generalized anxiety disorder was not associated with elevated CRP levels among children and adolescents. These findings argue against the idea that the inflammation–anxiety association is merely a result of acute stress experienced in anxiety disorders. Although we cannot make inferences about etiology based on our cross-sectional analyses, our current findings are in line with the growing evidence suggesting a distinct etiology involving vascular/metabolic/inflammatory factors in depression or anxiety disorders with an onset later in life.39, 40, 41, 42 Possibly, accumulating psychological and physical stress across the life-span might induce immunological changes24 that eventually results in depression and anxiety.


    In our previous report,33 we had found differences in inflammation levels among different classes of antidepressant medication use, which was confirmed for higher CRP in TCA/TeCA users within our present sample of persons with current anxiety disorders. Excluding persons using TCA or TeCA, resulted in a slightly weaker effect size for the association between current anxiety disorder and CRP in men. This might suggest that the elevated CRP levels in men with current anxiety disorders are for some part due to use of TCA/TeCA. On the other hand, persons using TCA/TeCA might represent the more severe cases of anxiety disorders, in which case exclusion of these persons leads to an underestimation of the association. Adjustment for TCA/TeCA use had no effect on our findings for age of anxiety disorder onset, suggesting that late-onset anxiety disorders are independently associated with higher levels of CRP.


    What are the clinical implications of our findings? First, our finding of increased CRP levels in particularly those with a late onset of the anxiety disorder might implicate the existence of a specific late-onset anxiety subtype with a distinct etiology. As we have found similar results for depression33 and because depression and anxiety are highly co-morbid disorders,11 this might suggest that depression and anxiety with a late onset share a similar etiology and represent one particular group of disorders, which might be more distinct from other depressive or anxiety disorders, which present earlier in life. As we can only speculate on etiology based on our cross-sectional research, longitudinal research is needed to validate the existence of an etiologically distinct late-onset subtype. Second, if confirmed, a distinct etiology for late-onset disorders implicates different treatment strategies for this subgroup. Perhaps anti-inflammatory medication or lifestyle interventions, such as exercise, for which (some) evidence exists that they normalize immune and metabolic dysregulation,43 as well as improve depressive symptoms to some degree,44, 45 could be beneficial in persons with late onset anxiety disorders as well.


    Our study has some important strengths such as a large sample size, assessment of multiple inflammatory markers, clinical diagnoses of several anxiety disorders, adequate adjustment for potential confounders and the ability to examine the role of anxiety characteristics. However, some limitations need to be acknowledged. As our data are cross-sectional, we cannot make any inferences about the direction of the association. Also, although we adjusted for a large set of possible confounding factors, unmeasured poor lifestyle behaviors or health factors may be the explaining link between inflammation and anxiety disorders. For instance, subclinical cardiovascular disease could possibly precede both inflammation and anxiety. On the other hand, subclinical disease may be one pathway of how inflammation leads to anxiety in later life. Longitudinal studies are needed to investigate whether immune dysregulation is a precursor or the result of anxiety, or whether this relationship is bidirectional. Further, like most other studies, we assessed circulating levels of inflammatory markers, which show a high degree of intra-individual variation that could explain the rather modest overall associations between anxiety disorders and inflammation in our study.


    In conclusion, our results show that low-grade systemic inflammation is present in men with anxiety disorders. Elevated inflammation is in particular found in both men and women with the onset of anxiety disorder later in life. Longitudinal studies are needed to confirm inflammation as an etiological factor in anxiety disorders with a late-life onset, followed by intervention trials investigating new treatment strategies (for example, anti-inflammatory medication, lifestyle interventions) for this subset of persons with late-onset anxiety.




    The infrastructure for the NESDA study ( is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care (IQ Healthcare), the Netherlands Institute for Health Services Research (NIVEL) and the Netherlands Institute of Mental Health and Addiction (Trimbos)). NV was supported through a fellowship from the EMGO Institute for Health and Care Research and BP through a VICI grant (NWO grant g1811602). Assaying of inflammatory markers was supported by the Neuroscience Campus Amsterdam.




    The authors declare no conflict of interest.


    Supporting the Endocannabinoid System | El Paso, TX Chiropractor


    Beyond CBD – Supporting the Entire Endocannabinoid System


    Every day, more and more health-conscious consumers are starting to take great interest in nutritional supplements that encourage the proper function of the endocannabinoid system, or ECS. Although marijuana and substances derived from or related to marijuana were believed to be the only options to achieve this effect, the focus in the consumer market has largely shifted to a single chemical: cannabidiol.


    What’s CBD?


    Cannabidiol, commonly known as CBD, is a chemical found in marijuana and in hemp which does interact with the ECS. CBD is just one of a wide group of chemicals known as phytocannabinoids. Cannabidiol has turned into a well-known phytocannabinoid because it is being researched to turn into a new medication and also the benefits demonstrated by CBD have created a lot of attention in this compound.


    What Can CBD Do?


    Although CBD does perform multiple actions within the human body, its own best-known function in the ECS, or endocannabinoid system, is in its potential to inhibit the activity of the enzyme called fatty acid amide hydrolase, or FAAH. FAAH breaks down anandamide, among the body’s endogenous cannabinoids, which is known to bind to the ECS’s CB1 receptor. The ECS’s CB1 receptor, primarily found in the brain, is the exact same receptor which THC, or tetrahydrocannabinol, binds to. In other words, anandamide, often referred to as “the bliss molecule”, is the human body’s natural THC.


    Significantly, however, whereas THC could have negative effects, such as triggering feelings of anxiety, mild hallucinations, dizziness, rapid heart rate, slowed reaction times, and food cravings, the anandamide made naturally by the body appears to exert positive effects on mood, memory, brain function and pain. Because anandamide is normally rapidly broken up by FAAH and because CBD modulates FAAH, Cannabidiol’s primary importance is in the way it can maintain anandamide levels, thus enhancing anandamide’s beneficial impact in the ECS. CBD also binds directly to CB1 and CB2 receptors and has a selection of activity outside of the ECS which can result in its many health benefits.


    CBD is a Drug According to the FDA


    Because CBD is comparatively safe, lacks the unwanted side effects of THC, and may be easily derived from hemp instead of marijuana, the natural products industry was flooded with products labeled as CBD. However, before this recent phenomenon, a British pharmaceutical company began studying the merits of CBD as an alternate to the drugs and/or medications being utilized to treat resistant childhood epilepsy.


    This company, GW Pharmaceuticals (dba Greenwich Biosciences) began pre-clinical operations on CBD in 2007 and contains an investigational new drug called Epidiolex® in late stage clinical trials.


    In multiple warning letters in 2017 sent to a number of businesses, the FDA noted ,”If an article, such as CBD, has been approved for investigation as a new drug and/or medication for which substantial clinical investigations have been instituted and for which the existence of such investigations have been made public, then products containing that chemical are outside the definition of a dietary supplement” Since the investigational work completed on CBD as a drug predates the promotion of CBD as a dietary supplement, products containing purified CBD or enriched with CBD are considered by the FDA to be medication and not dietary supplements.


    Why Support the Entire ECS?


    The ECS is not just a bodily system which completes a single function, as a matter of fact it’s far from it. ECS receptors are widely dispersed throughout the entire body. CBD is an isolated molecule which acts primarily on just a single component of the ECS; i.e., it inhibits the degrading enzyme FAAH, thus allowing the anandamide naturally produced by your endocannabinoid system to possess higher action. But what about the rest of the ECS?


    The ECS has at least two major receptors, CB1 and CB2 receptors. And along with anandamide, humans also produce an endocannabinoid called 2-archidonoyl glycerol, or 2-AG, which can be degraded by the enzyme monoacylglycerol lipase, or MAGL. If our intention is to support and nourish the whole ECS, then focusing on a single molecule like CBD that only works on one portion of the ECS might not be the best approach.


    Hemp includes heaps of active molecules, including a range of phytocannabinoids. Some such as cannabigerol, or CBG, bind weakly to the CB1 and CB2 receptors. Both CBG and cannabichromene, or CBC, may also help maintain wholesome anandamide levels. The phytocannabinoid beta-caryophyllene, or BCP, that is found in plants like black pepper and clove, binds to the CB2 receptor, which supports the actions of 2AG. Other natural plant compounds, particularly specific terpenoids, have functions which are complementary to that of phytocannabinoids.


    The “Entourage” Impact


    Although isolated CBD does have a part in overall health and wellness, cannabidiol is not anywhere near the entire process for encouraging the ECS. By using a whole hemp stalk infusion combined with hops, pepper, clove and rosemary that include naturally occurring complementary compounds, hemp oil nourishes the whole ECS, giving a holistic approach to a system that’s often neglected and out of equilibrium in today’s stressful world.


    Hemp oil nourishes the entire ECS, giving a holistic approach to a system that’s frequently ignored and out of equilibrium in today’s stressful world. Scientists who research the ECS refer to the approach as the”entourage” effect, and several top researchers believe this approach to be extremely effective in keeping the health and tone of the valuable endocannabinoid system as well as controlling the symptoms of inflammation and anxiety in the human body.


    In conclusion, anxiety is one of the most common mental health disorders in the United States. This debilitating health issue can be caused by a variety of factors, however, many research studies have started to demonstrate a connection between anxiety disorders and brain inflammation. According to the article above, stress has been shown to produce an inflammatory reaction, which has led researchers to suggest that anxiety may be causing high levels of inflammation. The outcome measures of te cohort study found that low-grade inflammation is present in individuals with anxiety disorders. Further research studies are still required to confirm the connection between anxiety and inflammation. Furthermore, supporting the function of the endocannabinoid system, or ECS, with the use of CBD or cannabidiol, has been found to have many health benefits, including helping with inflammation and anxiety.  Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain

    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news


    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



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    ]]> 0 Dr-Jimenez_White-Coat_01.png Table 1 Baseline Characteristics Table 2 Adjusted Mean Marker Levels Table 3 Association of Characteristics Figure 1 Adjusted Mean CRP Levels Supporting the Endocannabinoid System | El Paso, TX Chiropractor Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17713
    The Connection Between Inflammation and Depression Mon, 09 Jul 2018 19:20:31 +0000

    One standard hypothesis of depression is that individuals who are depressed have a lack in monoamine receptors within the body, which in turn leads to reduced levels of neurotransmitters, such as serotonin and norephinephrine, in the brain. But growing evidence supports that at least some kinds of depression might also be linked to continuing low-grade inflammation in the body.

    Previous research studies have linked depression with higher level of inflammatory markers when compared with people who aren't depressed. When individuals are given pro-inflammatory cytokines, they report experiencing more symptoms of depression and anxiety. Chronically high levels of inflammation due to health issues, including chronic pain conditions, are also associated with high rates of depression. Even brain imaging of patients with depression show their brain scans have improved neuroinflammation. If

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    One standard hypothesis of depression is that individuals who are depressed have a lack in monoamine receptors within the body, which in turn leads to reduced levels of neurotransmitters, such as serotonin and norephinephrine, in the brain. But growing evidence supports that at least some kinds of depression might also be linked to continuing low-grade inflammation in the body.

    Previous research studies have linked depression with higher level of inflammatory markers when compared with people who aren’t depressed. When individuals are given pro-inflammatory cytokines, they report experiencing more symptoms of depression and anxiety. Chronically high levels of inflammation due to health issues, including chronic pain conditions, are also associated with high rates of depression. Even brain imaging of patients with depression show their brain scans have improved neuroinflammation. If your body is in an inflammatory state, fighting off the common cold or influenza, you can experience symptoms overlapping with depression, including, interrupted sleep, depressed mood, fatigue, foggy-headedness and impaired concentration.

    A new study published in The Journal of Clinical Psychiatry supports the assumption that an increase in inflammation might play a role in depression. The huge study analyzed data from 14,275 people who have been interviewed between 2007 and 2012 using the Patient Health Questionnaire, or PHQ-9, to screen for depression and had blood samples drawn. They found that people who had depression had 46 percent greater levels of C-reactive protein, or CRP, a marker of inflammatory disease, in their own blood samples. The research study was just able to establish an association between inflammation and depression but not causation, even though it confirms the association of depression with high levels of inflammation as measured through CRP.

    The theory that depression might be viewed as a psychoneuroimmunological disorder may also help explain why attempts to reduce chronic inflammation in the body also enhances and helps prevent depression. The purpose of the article below is to demonstrate as well as thoroughly discuss the role of inflammation in depression. Furthermore, the article will describe the evolutionary imperative to the modern treatment target, including a discussion of phytocannabinoids and their association with the treatment of a variety of health issues, including chronic pain symptoms.

    The Role of Inflammation in Depression: from Evolutionary Imperative to Modern Treatment Target


    Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.


    Depression is a devastating disorder, afflicting up to 10% of the adult population in the United States and representing one of the leading causes of disability worldwide1. Although effective treatments are available, approximately one third of all patients with depression fail to respond to conventional antidepressant therapies2, further contributing to the global burden of the disease. Accordingly, there is a pressing need for new conceptual frameworks for understanding the development of depression to develop better treatments. In this Review, we outline emerging data that point to the immune system — and, in particular, the inflammatory response — as a potentially important contributor to the pathophysiology of depression. We first consider the origins of this notion from an evolutionary perspective, examining the advantages of depressive behaviours in the context of host immune responses to pathogens, predators and conspecifics in ancestral environments. The pivotal role of psychosocial stress in the modern world are then examined, highlighting inflammasome activation and immune cell trafficking as novel mechanisms by which stress-induced inflammatory signals can be transmitted to the brain. Neurotransmitters and neurocircuits that are targets of the inflammatory response are also explored followed by an examination of brain–immune interactions as risk and resilience factors for depression. Finally, these interactions are discussed as a foundation for a new era of therapeutics that target the immune system to treat depression, with a focus on how immunological biomarkers can be used to personalize care.

    An Evolutionary Perspective

    Data from humans and laboratory animals provide compelling evidence that stress-relevant neurocircuitry and immunity form an integrated system that evolved to protect organisms from a wide range of environmental threats. For example, in the context of a laboratory stressor that entails delivering a speech to a judgmental panel of supposed ‘behavioural experts’, subjects experience a classic ‘fight or flight’ response characterized by increases in heart rate and blood pressure as well as in cortisol and catecholamines. But something else happens within the body that demands a deeper explanation. The stressor activates key inflammatory pathways in peripheral blood mononuclear cells, including activation of the transcription factor nuclear factor–κB (NF-κB), and leads to marked increases in circulating levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6)3,4. In essence, the body mounts an immune response not against a pathogen, but against a threat to the subject’s self-esteem. Moreover, individuals at high risk of developing depression (for example, those who have experienced early-life trauma) show increased inflammatory responses to such laboratory stressors compared with low-risk individuals3. Furthermore, the greater the inflammatory response to a psychosocial stressor, the more probable the subject is to develop depression over the ensuing months5. Two questions immediately present themselves: why should a stimulus devoid of any pathogen induce an inflammatory response, and why should this response promote the development of depression?

    Pathogen Host Defense and Depression

    No coherent answer to these questions is apparent if immunity is viewed as merely another physiological system within the body. However, when seen against the back-drop of millions of years of co-evolution between mammals and the world of microorganisms and parasites, the human inflammatory bias exposed by laboratory stressors and reflected in the association between immune activation and depression not only makes imminent adaptive sense but also provides insight into a paradox deep within the heart of depression itself; namely, why are the genetic alleles that are most frequently associated with depression so common in the modern gene pool6 (FIG. 1)

    Figure 1 Evolutionary Legacy of an Inflammatory Bias | El Paso, TX Chiropractor
    Figure 1: Evolutionary legacy of an inflammatory bias. Early evolutionary pressures derived from human interactions with pathogens, predators and human conspecifics (such as rivals) resulted in an inflammatory bias that included an integrated suite of immunological and behavioural responses that conserved energy for fighting infection and healing wounds, while maintaining vigilance against attack. This inflammatory bias is believed to have been held in check during much of human evolution by exposure to minimally pathogenic, tolerogenic organisms in traditional (that is, rural) environments that engendered immunological responses characterized by the induction of regulatory T (TReg) cells, regulatory B (BReg) cells and immunoregulatory M2 macrophages as well as the production of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGFβ). In modern times, sanitized urban environments of more developed societies are rife with psychological challenges but generally lacking in the types of infectious challenges that were primary sources of morbidity and mortality across most of human evolution. In the absence of traditional immunological checks and balances, the psychological challenges of the modern world instigate ancestral immunological and behavioural repertoires that represent a decided liability, such as high rates of various inflammation-related disorders including depression.

    Most adaptive theories of depression have focused on the potential benefits of depressive symptoms for relationships with other humans7. However, recent models have shifted the focus away from relationships with people, to relationships — both detrimental and beneficial — with pathogens6,8. These theories, which are supported by converging evidence (BOX 1), posit that modern humans have inherited a genomic bias towards inflammation because this response — and the depressive symptoms it promotes — enhanced host survival and reproduction in the highly pathogenic environments in which humans evolved6. From this theoretical perspective, at least some of the human vulnerability to depression evolved out of a behavioural repertoire — often referred to as ‘sickness behaviour’ — which promoted host survival in the face of infection. Indeed, it has been hypothesized that the social avoidance and anhedonia characteristic of depression serve to shunt energy resources to fighting infection and wound healing, whereas the hypervigilance characteristic of anxiety disorders, commonly comorbid with depression, subserves protection from attack and subsequent pathogen exposure6,9. Even psychological stress can be understood from this theoretical perspective, given that the vast majority of stressors faced by mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or competing for reproductive access or status. In all of these circumstances, the risk of pathogen invasion — and subsequent death from infection — was greatly increased as a result of wounding. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution favoured organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often a ‘false alarm’ (REF. 6).

    Pathogen Host Defense Hypothesis of Depression

    Several lines of evidence support the notion that the evolution and persistence of depression risk alleles and depressive symptoms in human populations are based on their relevance to ‘pathogen host defence’. This evidence includes:

    • Until recently, approximately 50% of humans died from infectious causes before adulthood, thereby providing strong selective pressure for genetic alleles that enhance host defence124.
    • As a result of strong selective pressure, microbial interactions have been a primary driver of human evolution125.
    • Patterns of inflammatory activation associated with depression promote survival in highly pathogenic environments while increasing mortality in sanitary conditions common in the developed world126.
    • The best replicated risk alleles for depression have pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure6.
    • Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory13.
    • Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression and that can be ameliorated by treatment with antidepressants23. In addition, the onset of depression is often mistaken with development of sickness, and symptoms
    • associated with infections are often mistaken with the onset of depression127.
    • Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression6,9.
    • Symptoms shared by depression and sickness behaviour — such as hyperthermia and reduced iron availability — that lack any conceivable social value have potent anti-pathogen effects6.

    The ‘pathogen host defence’ hypothesis of depression may also provide insight into the twofold increase in depression in women compared to men, especially during the reproductive years10. Recent data indicate that women are more sensitive to the behavioural effects of inflammation, demonstrating greater increases in depressed mood than men following endotoxin exposure despite a similar magnitude in cytokine (IL-6 and tumour necrosis factor (TNF)) responses11. Women also exhibit a greater likelihood than men to develop depression in response to standardized doses of interferon-α (IFNα)12. By being more sensitive to inflammation-induced depressive symptoms, women may have benefited more from the protection provided by these symptoms in terms of fighting infection, healing wounds and avoiding subsequent pathogen exposure. Given the potentially negative impact of inflammation on reproductive success (for example, by reducing fertility and impairing lactation), the increase of depressive symptoms in women across evolutionary time may have given women of reproductive age an advantage in coping with and avoiding pathogens and the related inflammation, with increased depressive disorders being the ultimate trade-off in modern times.

    Modern Exaggeration of the Inflammatory Bias

    The prevalence of autoimmune, allergic and inflammatory diseases has markedly increased in the past 100 years, and rates of these conditions follow a similar upward trajectory in societies transitioning from traditional (that is, rural) to modern (that is, urban) ways of life13. Increasing evidence suggests that this pattern of widespread immune dysregulation may result from disruptions in our relationship and/or contact with a variety of co-evolved, non-lethal immunoregulatory microorganisms and parasites, especially commensals and symbiotes in the microbiotas of the gut, skin and nasal and oral cavities, that were ubiquitous in the natural environments in which humans evolved14. Although widely disparate, these organisms (often referred to as ‘old friends’) share a tendency to reduce inflammation and suppress effector immune cells through the induction of IL-10 and transforming growth factor-β (TGFβ) while promoting the development of anti-inflammatory immune cell populations, such as alternatively activated (also referred to as ‘M2’) macrophages and regulatory T (TReg) cells and regulatory B cells13,14 (FIG. 1). Owing to various cultural changes, including the loss of exposure to microbial diversity with the advent of sanitation practices, modern humans now lack this immunoregulatory input — especially during infancy and childhood. Consequently, we find ourselves in a condition of an exacerbated inflammatory bias, with the particular conditions afflicting any given individual largely the result of genetic predisposition and environmental (for example, psychosocial) exposures13,14, ultimately accounting for the high co-morbidity between depression and autoimmune, allergic and inflammatory disorders13,15.

    Inflammation and Depression

    Data supporting the role of inflammation in depression are extensive and include findings that span experimental paradigms. Patients with major depressive disorder exhibit all of the cardinal features of an inflammatory response, including increased expression of pro-inflammatory cytokines and their receptors and increased levels of acute-phase reactants, chemokines and soluble adhesion molecules in peripheral blood and cerebrospinal fluid (CSF)16,17. Peripheral blood gene expression profiles consistent with a pro-inflammatory ‘M1’ macrophage phenotype and an over-representation of IL-6, IL-8 and type I IFN-induced signalling pathways have also been described18–20. In addition, increased expression of a variety of innate immune genes and proteins, including IL-1β, IL-6, TNF, Toll-like receptor 3 (TLR3) and TLR4, has been found in post-mortem brain samples from suicide victims that had depression16,18,19,21. Meta-analyses of the literature conclude that peripheral blood IL-1β, IL-6, TNF and C-reactive protein (CRP) are the most reliable biomarkers of inflammation in patients with depression16. Polymorphisms in inflammatory cytokine genes, including those encoding IL-1β, TNF and CRP, have also been associated with depression and its response to treatment22. Moreover, other genes implicated in depression derived from meta-analyses of genome-wide association studies have been linked to the immune response and the response to pathogens including TNF6 (BOX 1). Administration of inflammatory cytokines (for example, IFNα) or their inducers (for example, endotoxin or typhoid vaccination) to otherwise non-depressed individuals causes symptoms of depression23–26. Furthermore, blockade of cytokines, such as TNF, or of inflammatory signalling pathway components, such as cyclooxygenase 2, has been shown to reduce depressive symptoms in patients with medical illnesses, including rheumatoid arthritis, psoriasis and cancer, as well as in patients with major depressive disorder27–29.

    As the field has matured, it has become increasingly apparent that inflammatory markers are elevated not only in a subgroup of patients with depression30,31 but also in patients with other neuropsychiatric disorders including anxiety disorders and schizophrenia32,33. Moreover, as described below, it may be more accurate to characterize the impact of inflammation on behaviour as being associated not wholly with depression but with specific symptom dimensions across diagnoses that align with the Research Domain Criteria framework put forth by the National Institute of Mental Health (US Department of Health and Human Services). These symptoms, including positive and negative valence systems, relate to altered motivation and motor activity (anhedonia, fatigue and psychomotor impairment) and increased threat sensitivity (anxiety, arousal and alarm)34. Finally, inflammation has been associated with antidepressant treatment non-responsiveness9,32,35–37. For example, in a recent study, 45% of patients with non-response to conventional antidepressants exhibited a CRP >3 mg L−1 (REF. 30), which is considered indicative of a high level of inflammation on the basis of widely accepted cut-off points38. Of note, however, the percentage of patients with high CRP levels can vary as a function of the population being studied, with higher percentages in patients with depression and treatment resistance, childhood maltreatment, medical illnesses and metabolic syndrome.

    Immune Pathways Involved in Depression

    Inflammasomes: Stress in Translation

    Exposure to psychosocial stress is one of the most robust and reproducible predictors of developing depression in humans and is the primary experimental pathway to depressive-like behaviour in laboratory animals. Thus, the observation that exposure to a psychosocial laboratory stressor can activate an inflammatory response in humans was a major breakthrough in linking inflammation to depression3,4. An important question for the field, however, is by what mechanism is stress translated into inflammation? Although considerable attention has been paid to stress-induced neuroendocrine pathways, including the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS), both of which have immunomodulatory functions39, recent focus has been shifted towards inflammasomes, which may represent a crucial immunological interface between stress and inflammation40 (FIG. 2). Inflammasomes are cytosolic protein complexes that form in myeloid cells in response to pathogenic microorganisms and non-pathogenic or ‘sterile’ stressors. Assembly of the inflammasome leads to activation of caspase 1, which then cleaves the precursor forms of IL-1β and IL-18 into the active cytokines41. Given the relatively sterile nature of psychosocial stress, primary interest has been directed towards understanding how inflammasome activation in depression may be triggered by endogenous damage-associated molecular patterns (DAMPs), including ATP, heat shock proteins (HSPs), uric acid, high mobility group box 1 (HMGB1) and a variety of molecules linked with oxidative stress. Indeed, all of these DAMPs are induced by the psychological and mixed (that is, psychological and physiological) stressors used in animal models of depression42; an effect that is in part mediated by stress-induced release of catecholamines43. Moreover, studies in laboratory animals indicate that chronic mild-stress activates the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is well-known to respond to DAMPs44,45. Blockade of NLRP3 reverses stress-induced increases in IL-1β in the peripheral blood and brain, while also abrogating depressive-like behaviour in mice45. Interestingly, NLRP3 inflammasome upregulation and caspase-mediated cleavage of the glucocorticoid receptor can cause resistance to the effects of glucocorticoids, which are among the most potent anti-inflammatory hormones in the body46,47. Stress-induced glucocorticoid resistance is a well-characterized biological abnormality in patients with major depressive disorder and has been associated with increased inflammation48,49.

    Figure 2 Transmitting Stress Induced Inflammatory Signals | El Paso, TX Chiropractor
    Figure 2: Transmitting stress-induced inflammatory signals to the brain. In the context of psychosocial stress, catecholamines (such as noradrenaline) released by activated sympathetic nervous system fibres stimulate bone marrow production and the release of myeloid cells (for example, monocytes) that enter the periphery where they encounter stress-induced damage-associated molecular patterns (DAMPs), bacteria and bacterial products such as microbial-associated molecular patterns (MAMPs) leaked from the gut. These DAMPs and MAMPs subsequently activate inflammatory signalling pathways such as nuclear factor-κB (NF-κB) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Stimulation of NLRP3 in turn activates caspase 1, which leads to the production of mature interleukin-1β (IL-1β) and IL-18 while also cleaving the glucocorticoid receptor contributing to glucocorticoid resistance. Activation of NF-κB stimulates the release of other pro-inflammatory cytokines including tumour necrosis factor (TNF) and IL-6, which together with IL-1β and IL-18 can access the brain through humoral and neural routes. Psychosocial stress can also lead to the activation of microglia to a M1 pro-inflammatory phenotype, which release CC-chemokine ligand 2 (CCL2) that in turn attracts activated myeloid cells to the brain via a cellular route. Once in the brain, activated macrophages can perpetuate central inflammatory responses. ASC, apoptosis-associated speck-like protein containing a CARD; HMGB1, high mobility group box 1; HSP, heat shock protein; LPS, lipopolysaccharide; TLR, Toll-like receptor.

    Supporting the potential role of the NLRP3 inflammasome in human depression are data demonstrating that increased expression of NLRP3 and caspase 1 in peripheral blood mononuclear cells of patients with depression is associated with increased blood concentrations of IL-1β and IL-18, which in turn correlate with depression severity19,50. In addition, DAMPs that are known to activate NLRP3 are increased in patients with mood disorders, with examples including HSPs, reactive oxygen species and other markers of oxidative stress such as xanthine oxidase, peroxides and F2-isoprostanes51–53. Finally, there is increasing interest in the potential role of the gut microbiome in mood regulation, which may be mediated in part by the inflammasomes54. Indeed, non-pathogenic commensal bacteria and derived microbial-associated molecular patterns (MAMPs) in the gut can leak into the peripheral circulation during stress and activate the inflammasomes55, a process mediated by the SNS and catecholamines56 (FIG. 2). Of note, stress-induced increases in IL-1β and IL-18 were attenuated by treating animals with antibiotics or neutralizing lipopolysaccharide (LPS), demonstrating the importance of the composition of the gut microbiome and gut permeability in stress-induced inflammatory responses55. Taken together, these data support the notion that the inflammasome may be a key immunological point of integration of stress-induced danger signals that ultimately drive inflammatory responses relevant to depression.

    Transmitting Inflammatory Signals to the Brain

    In addition to increased expression of innate immune cytokines and TLRs in post-mortem brain samples from suicide victims with depression, evidence of microglial and astroglial activation in several brain regions including frontal cortex, anterior cingulate cortex (ACC) and thalamus in post-mortem studies of patients with depression have been described57–59,60. Moreover, a well-controlled neuroimaging study using positron emission tomography (PET) and a radiolabelled tracer for the translocator protein (TSPO) — which is overexpressed in activated microglia, macrophages and astrocytes — revealed increased immune activation in the brains of patients with major depressive disorder compared with control subjects61. Of note, not all studies have revealed increased TSPO binding in patients with depression, possibly owing to effects of medication and/or a paucity of subjects with increased inflammation61,62. However, data from endotoxin administration to healthy volunteers indicates that radiolabelled TSPO ligands can readily identify cellular activation in several regions of the brain following a potent peripheral immune stimulus63.

    Work from laboratory animal studies has elucidated several pathways through which inflammatory signals can be transmitted from the periphery to the brain (FIG. 2). These data support the idea that inflammatory responses in peripheral tissues may drive inflammation in the brain leading to depression. Much of the early work focused on how inflammatory cytokines, which are relatively large molecules, could cross the blood–brain barrier (BBB) and influence brain function64. Two major pathways have been described: the ‘humoral pathway’, which involves cytokine passage through leaky regions in the BBB, such as the circumventricular organs, and the binding of cytokines to saturable transport molecules on the BBB; and the ‘neural pathway’, which involves the binding of cytokines to peripheral afferent nerve fibres, such as the vagus nerve, that in turn stimulate ascending catecholaminergic fibres in the brain and/or are translated back into central cytokine signals16. More recently, however, attention has shifted to a third pathway referred to as the ‘cellular pathway’, which involves the trafficking of activated immune cells, typically monocytes, to the brain vasculature and parenchyma. The details of this pathway have been elegantly dissected in the context of behavioural changes in mice that are associated with peripherally induced inflammation in the liver65. In these studies, the release of TNF from inflamed liver was found to stimulate microglial cell production of CC-chemokine ligand 2 (CCL2; also known as MCP1) that then attracted monocytes to the brain65. Blockade of monocyte infiltration to the brain using antibodies specific for the adhesion molecules P-selectin and α4 integrin abrogated depressive-like behaviour in this animal model65. Of note, cytokine-stimulated astrocytes also may be major producers of chemokines, such as CCL2 and CXC-chemokine ligand 1 (CXCL1), that attract immune cells to the brain66. The cellular pathway additionally has been elucidated in the context of social defeat stress, whereby GFP-labelled monocytes coalesced in several regions of the brain associated with the detection of threat (for example, amygdala) — an effect that was dependent on CCL2 and was facilitated by mobilization of monocytes from the bone marrow as a result of stress-induced release of catecholamines67,68 (FIG. 2). Of note, initial microglial activation during social defeat stress appeared to be a result of neuronal activation by catecholamines and decreased neuronal production of CX3C-chemokine ligand 1 (CX3CL1; also known as fractalkine), which maintains microglia in a quiescent state67,68. Interestingly, this cellular pathway has received intriguing support from post-mortem analyses of brain tissue from patients with depression who committed suicide that showed increased numbers of perivascular macrophages in association with increased gene expression of allograft inflammatory factor 1 (AIF1, also known as IBA1) and CCL2, which are associated with macrophage activation and cellular trafficking59.

    This evidence of peripheral myeloid cells trafficking to the brain during depression constitutes some of the first data supporting the existence of a central inflammatory response in human depression that is primarily driven by peripheral inflammatory events. Moreover, data demonstrate that antibodies that are specific for TNF but which do not cross the BBB, can block stress-induced depression in mice69. These findings indicate that peripheral inflammatory responses not only can provide important clues to the immunological mechanisms of inflammation in depression but also may serve as biomarkers and targets of immune-based therapies for depression. Protein biomarkers such as plasma CRP and TNF as well as immunotherapies targeting individual cytokines such as TNF, IL-1 and IL-6 may be most relevant in this regard. Of note, plasma CRP is a strong response predictor in anti-cytokine therapy70.

    Cytokines and Neurotransmitters

    Given the pivotal importance of neurotransmission to mood regulation, attention has been paid to the impact of inflammation and inflammatory cytokines on the monoamines serotonin, noradrenaline and dopamine, as well as on the excitatory amino acid glutamate (FIG. 3). There are several pathways through which inflammatory cytokines can lead to reduced synaptic availability of the monoamines, which is believed to be a fundamental mechanism in the pathophysiology of depression71. For example, IL-1β and TNF induction of p38 mitogen-activated protein kinase (MAPK) has been shown to increase the expression and function of the reuptake pumps for serotonin, leading to decreased synaptic availability of serotonin and depressive-like behaviour in laboratory animals72. Through the generation of reactive oxygen and nitrogen species, inflammatory cytokines have also been found to decrease the availability of tetrahydrobiopterin (BH4), a key enzyme co-factor in the synthesis of all monoamines that is highly sensitive to oxidative stress73. Indeed, CSF concentrations of BH4 have been shown to be negatively correlated with CSF levels of IL-6 in patients treated with the inflammatory cytokine IFNα74. In addition, the plasma phenylalanine to tyrosine ratio, an indirect measure of BH4 activity, was shown to correlate with CSF concentrations of dopamine as well as symptoms of depression in IFNα-treated patients74. Activation of the enzyme indoleamine 2,3-dioxygenase (IDO) is also believed to be involved in cytokine-induced neurotransmitter alterations, in part by diverting the metabolism of tryptophan (the primary amino acid precursor of serotonin) into kynurenine, a compound that can be converted into the neurotoxic metabolite quinolinic acid by activated microglia and infiltrating monocytes and macrophages in the brain75,76. Of note, increased levels of quinolinic acid have been found in microglia in the ACC of suicide victims who suffered from depression77. Quinolinic acid directly activates receptors for glutamate (that is, N-methyl-D-aspartate (NMDA) receptors) while also stimulating glutamate release and blocking glutamate reuptake by astrocytes78. The effects of quinolinic acid on glutamate converge with the direct effects of pro-inflammatory cytokines on glutamate metabolism that include decreasing the expression of astrocyte glutamate reuptake pumps and stimulating astrocytic glutamate release79, ultimately contributing to excessive glutamate both within and outside the synapse. The binding of glutamate to extrasynaptic NMDA receptors leads to increased excitotoxicity and decreased production of brain-derived neurotrophic factor (BDNF)80. BDNF fosters neurogenesis, an important prerequisite for an antidepressant response, and has been shown to be reduced by IL-1β and TNF and their downstream signalling pathways including NF-κB in stress-induced animal models of depression81,82. Increased levels of glutamate in the basal ganglia and dorsal ACC (dACC) — as measured by magnetic resonance spectroscopy (MRS) — have been described in patients receiving IFNα, and higher levels of glutamate correlated with an increase in depressive symptoms83. More recent data indicate that in patients with depression, increased inflammation as reflected by a CRP >3 mg L−1 is also associated with increased basal ganglia glutamate (compared with patients with a CRP <1 mg L−1) that correlated with anhedonia and decreased psychomotor speed84. Interestingly, blocking glutamate receptors with ketamine or inhibiting IDO activity protects mice from LPS- or stress-induced depressive-like behaviour but leaves the inflammatory response intact85,86. These results indicate that increased activation of glutamate receptors by glutamate and/or quinolinic acid may be a common pathway through which inflammation causes depressive-like behaviour, suggesting that drugs that block glutamate receptor signalling and/or activation of the IDO pathway and its downstream metabolites might have unique applicability to patients with depression and increased inflammation. Importantly, conventional antidepressant medications act by increasing synaptic availability of monoamines and increasing neurogenesis through induction of BDNF87. Therefore, cytokines such as IL-1β and TNF serve to undermine these activities as they decrease the synaptic availability of monoamines while also decreasing BDNF and increasing extracellular glutamate, which is not a target of conventional antidepressant therapy. These cytokine-driven effects may explain the observations that increased inflammation is associated with less robust antidepressant treatment responses and that treatment-resistant patients exhibit increased inflammatory markers88.

    Figure 3 Cytokine Targets in the Brain | El Paso, TX Chiropractor
    Figure 3: Cytokine targets in the brain: neurotransmitters and neurocircuits. Once in the brain, the inflammatory response can affect metabolic and molecular pathways influencing neurotransmitter systems that can ultimately affect neurocircuits that regulate behaviour, especially behaviours relevant to decreased motivation (anhedonia), avoidance and alarm (anxiety), which characterize several neuropsychiatric disorders including depression. On a molecular level, pro-inflammatory cytokines including type I and II interferons (IFNs), interleukin-1β (IL-1β) and tumour necrosis factor (TNF) can reduce the availability of monoamines — serotonin (5-HT), dopamine (DA) and noradrenaline (NE) — by increasing the expression and function of the presynaptic reuptake pumps (transporters) for 5-HT, DA and NE through activation of mitogen-activated protein kinase (MAPK) pathways and by reducing monoamine synthesis through decreasing enzymatic co-factors such as tetrahydrobiopterin (BH4), which is highly sensitive to cytokine-induced oxidative stress and is involved in the production of nitric oxide (NO) by NO synthase (NOS). Many cytokines, including IFNγ, IL-1β and TNF, can also decrease relevant monoamine precursors by activating the enzyme indoleamine 2,3-dioxygenase (IDO), which breaks down tryptophan, the primary precursor for serotonin, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid (QUIN), which binds to the N-methyl-D-aspartate receptor (NMDAR), a glutamate (Glu) receptor, and together with cytokine-induced reduction in astrocytic Glu reuptake and stimulation of astrocyte Glu release, in part by induction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), can lead to excessive Glu, an excitatory amino acid neurotransmitter. Excessive Glu, especially when binding to extrasynaptic NMDARs, can in turn lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Inflammation effects on growth factors such as BDNF in the dentate gyrus of the hippocampus can also affect fundamental aspects of neuronal integrity including neurogenesis, long-term potentiation and dendritic sprouting, ultimately affecting learning and memory. Cytokine effects on neurotransmitter systems, especially DA, can inhibit several aspects of reward motivation and anhedonia in corticostriatal circuits involving the basal ganglia, ventromedial prefrontal cortex (vmPFC) and subgenual and dorsal anterior cingulate cortex (sgACC and dACC, respectively), while also activating circuits regulating anxiety, arousal, alarm and fear including the amygdala, hippocampus, dACC and insula. BH2, dihydrobiopterin; DAT, dopamine transporter; EAAT2, excitatory amino acid transporter 2; NET, noradrenaline transporter; NF-κB, nuclear factor-κB; SERT, serotonin transporter; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase. Copyrighted 2015. Advanstar. 120580:1115BN.

    Effects of Inflammation on Neurocircuitry

    Given the impact of cytokines on neurotransmitter systems that regulate the functional activity of neurocircuits throughout the brain, it is no surprise that neuroimaging studies have revealed cytokine-induced alterations in regional brain activity. Consistent with the evolutionary advantages of the partnership between the brain and the immune system, primary cytokine targets in the CNS involve those brain regions that regulate motivation and motor activity (promoting social avoidance and energy conservation) as well as arousal, anxiety and alarm (promoting hypervigilance and protection against attack) (FIG. 3).

    Dopamine has a fundamental role in motivation and motor activity, and cytokines have been shown to decrease the release of dopamine in the basal ganglia in association with decreased effort-based motivation as well as reduced activation of reward circuitry in the basal ganglia, in particular the ventral striatum89–91. Inflammatory stimuli have been associated with reductions in reward responsiveness in the striatum across many neuroimaging platforms, demonstrating the validity and reproducibility of these cytokine-mediated effects on the brain in otherwise non-depressed individuals peripherally administered IFNα, endotoxin or typhoid vaccination and imaged by PET, functional magnetic resonance imaging (fMRI), MRS and quantitative magnetization transfer imaging83,89,90,92,93. Interestingly, recent fMRI studies suggest that inflammation-induced decreases in responsiveness to positive reward are also associated with increased sensitivity to aversive stimuli (that is, negative reinforcement) and reduced responsiveness to novelty in the substantia nigra (which is another dopamine-rich structure in the basal ganglia)93,94. Typhoid vaccination has also been shown to activate the subgenual ACC (sgACC), a brain region implicated in depression, and to decrease connectivity of the sgACC with the ventral striatum, an effect modulated by plasma IL-6 (REF. 26). These fMRI findings have recently been extended to patients with depression whose increased plasma CRP level is associated with decreased functional connectivity within reward-related circuits including the ventral striatum and the ventromedial prefrontal cortex that, in turn, mediates the relationship between CRP and anhedonia95. Indeed, patients with depression with a CRP >3 mg L−1 had little, if any, connectivity within reward-related circuits as measured by fMRI, whereas connectivity in patients with depression with a CRP <1 mg L−1 was similar to healthy controls95. Taken together, these data support the notion that the effect of cytokines on the brain in general and dopaminergic pathways in particular lead to a state of decreased motivation or anhedonia, which is a core symptom of depression.

    fMRI studies have demonstrated that increased inflammation is also associated with increased activation of threat- and anxiety-related neurocircuitry, including the dACC as well as the insula and amygdala26,96,97. Of note, the dACC and amygdala are regions that exhibit increased activity in patients with high-trait anxiety and neuroticism98, conditions that often accompany depression and are associated with increased inflammation. For example, increased concentrations of oral IL-6 and soluble TNF receptor 2 (also known as TNFRSF1B) in response to a public speaking stressor was significantly correlated with the response of the dACC to a social rejection task97. In addition, increased oral IL-6 expression in response to a social evaluation stressor was significantly correlated with activation of the amygdala, with subjects who exhibited the highest IL-6 responses to stress demonstrating the greatest connectivity within threat circuitry, including the amygdala and the dorsomedial prefrontal cortex, as measured by fMRI99. Interestingly, these data are consistent with the trafficking of monocytes to the amygdala during social defeat stress in mice68.

    Risk and Resilience

    Increased Inflammation and the Risk for Depression

    Consistent with the emerging recognition that inflammation may cause depression in certain subgroups of individuals, epidemiological studies on large community samples — as well as smaller samples of medically ill individuals — have demonstrated that increased inflammation serves as a risk factor for the future development of depression. For example, increased peripheral blood CRP and IL-6 concentrations were found to significantly predict depressive symptoms after 12 years of follow up in the Whitehall II study of over 3,000 individuals, whereas no association was found between the presence of depressive symptoms and subsequent blood CRP and IL-6 levels100. Similar findings were reported in the English Longitudinal Study of Ageing in which a CRP >3 mg L−1 predicted depressive symptoms and not vice versa101. Of note, however, some studies have found no longitudinal relationship between depression and inflammation, and others have found that depression leads to increased inflammation102. Other factors known to be associated with increased peripheral inflammation, including childhood and adult trauma, have also been shown to be predictive of a greater risk of developing depression103,104.

    Both genetic and epigenetic mechanisms may explain why childhood or adult traumas can contribute to exaggerated or persistent inflammation and, ultimately, depression. For example, polymorphisms in CRP were associated not only with increased peripheral blood concentrations of CRP but also with symptoms of post-traumatic stress disorder, especially heightened arousal, in individuals exposed to civilian trauma32. Moreover, gene–environment interactions have been found to influence depression severity in response to chronic interpersonal stress: individuals carrying polymorphisms in IL1B that are associated with higher expression of peripheral IL-1β exhibited more severe depressive symptoms in the context of interpersonal stress than individuals without the IL1B risk allele105. Similarly, mice in which peripheral blood leukocytes produced high concentrations of LPS-induced IL-6 ex vivo before stress exposure showed decreased social exploration after social defeat stress, whereas mice that produced low levels of IL-6 before stress exposure exhibited no behavioural effects in response to social defeat88. Of note, adoptive transfer of bone marrow progenitor cells from mice producing high levels of IL-6 ex vivo to mice that produced low levels of IL-6 made these formerly stress-resilient animals sensitive to the depressive effects of social defeat88.

    Epigenetic changes in genes related to inflammation may also affect the risk for depression and anxiety in the context of psychosocial stress. Indeed, the well-documented association of childhood trauma with increased inflammation is linked to stress-induced epigenetic changes in FKBP5, a gene implicated in the development of depression and anxiety as well as in the sensitivity to glucocorticoids106. Allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5 were found to be associated with decreased sensitivity of peripheral blood immune cells to the inhibitory effects of the synthetic glucocorticoid dexamethasone on LPS-induced production of IL-6 in vitro106. Of note, decreased activation of glucocorticoid receptor-responsive genes in association with increased activation of genes regulated by NF-κB has been found to be a ‘fingerprint’ of the effects of chronic stress in several studies examining a variety of psychosocial stressors39,107.

    T Cells and Resilience to Depression

    Some of the most intriguing data regarding the role of the immune system in depression come from studies showing that T cells may protect against stress and depression in laboratory animals. For example, the adoptive transfer of T cells from animals exposed to chronic social defeat stress led to an antidepressant behavioural phenotype in stress-naive mice, which was associated with decreased pro-inflammatory cytokines in serum, a shift towards a neuroprotective M2 phenotype in microglia and increased neurogenesis in the hippocampus108. Similar results have been reported following acute stress in mice, in which effector T cell migration to the choroid plexus as a result of glucocorticoid induction of intercellular adhesion molecule 1 (ICAM1) expression in the choroid plexus was associated with reduced anxiety-like behaviour109. Mice with impaired release of glucocorticoids in response to stress were anxiety prone109. Immunization of anxiety-prone animals with a CNS-specific antigen restored T cell trafficking to the brain during stress and reversed anxiety-like behaviour in association with increased neurogenesis109. Immunization with a CNS-specific antigen also blocked stress-induced depression in mice110. The mechanism by which T cells influence resilience is believed to be related to their production of IL-4 within the meningeal space. Through as yet uncharacterized pathways, IL-4 then stimulates astrocytes to produce BDNF, and also promotes the conversion of meningeal monocytes and macrophages from a pro-inflammatory M1 phenotype to a less inflammatory M2 phenotype111. The movement of T cells throughout the brain, including the meningeal space, has become an area of special interest with the recent description of a brain lymphatic system that heretofore had gone unrecognized112. Data also indicate that TReg cells may have a role in reducing inflammation and supporting neuronal integrity during stress113. Similar reports have characterized T cells that are activated by vagal nerve stimulation to produce acetylcholine, which can inhibit NF-κB activation by binding to the α7 subunit of the nicotinic acetylcholine receptor114.

    Relevant to depression, however, peripheral T cell trafficking in response to glucocorticoids has been shown to be impaired in patients with depression, possibly owing to glucocorticoid resistance as a result of genetically mediated (for example, FKBP5) or inflammasome-mediated mechanisms targeting the glucocorticoid receptor46,115. In addition, inflammatory cytokines and their signalling pathways, including p38 MAPK, have direct inhibitory effects on glucocorticoid receptor function116. Moreover, patients with depression have been shown to have increased numbers of peripheral blood myeloid-derived suppressor cells, which inhibit T cell function117. Of note, activation of the NLRP3 inflammasome leads to increased accumulation of myeloid-derived suppressor cells118. Decreased numbers of peripheral blood TReg cells and reduced concentrations of anti-inflammatory cytokines in the blood, including TGFβ and IL-10, have also been reported in depression119. Thus, it appears that patients with depression may have impairments in neuroprotective and anti-inflammatory T cell responses.

    These findings suggest that therapies that boost such T cell responses could be used in patients with depression. Examples include immunization strategies (with CNS antigens as discussed above) that attract T cells to the brain or administration of bacteria, such as Mycobacterium vaccae, or parasites that stimulate TReg cell responses or T cell production of IL-4 (REFS 14,109,110,120). Indeed, colonization of pregnant dams with helminths attenuated the increase of hippocampal IL-1β in neonatal rats infected with bacteria and protected these animals from the subsequent development of microglial sensitization and cognitive dysfunction in adulthood. This effect was associated with increased ex vivo production of IL-4 and decreased production of IL-1β and TNF by splenic macrophages in response to LPS stimulation120. Finally, vagus nerve stimulation could be used to induce anti-inflammatory acetylcholine-producing T cells121. Although many strategies exist to activate anti-inflammatory T cell responses including the induction of TReg cells by administration of mesenchymal stem cells122, the majority of the approaches discussed above have proof-of-concept data in animal models of depression. Nevertheless, the clinical relevance of these approaches has yet to be determined by randomized clinical trials in patients with depression.

    Translational Considerations

    Our increasing understanding of how inflammatory processes contribute to depression, combined with the growing frustration over the lack of discovery of new antidepressants, have stimulated interest in the possibility that various classes of anti-inflammatory medications or other anti-inflammatory strategies (as discussed above) may hold promise as novel ‘all-purpose’ antidepressants. Unfortunately, it appears that anti-inflammatory agents may only demonstrate effective antidepressant activity in subgroups of patients who show evidence of increased peripheral inflammation, for example individuals with medical conditions including osteoarthritis and psoriasis that are characterized by increased levels of peripheral inflammation and patients with depression with increased inflammatory markers29,30. Moreover, in patients with depression who do not show elevated peripheral levels of inflammation, anti-inflammatory treatments may actually impair placebo responses that contribute to the effectiveness of all known antidepressant modalities123. In the only study to date examining the antidepressant effect of a cytokine antagonist in medically healthy adults with treatment-resistant depression, post hoc analysis revealed a dose-response relationship between baseline levels of peripheral inflammation and subsequent antidepressant response to the TNF inhibitor infliximab30. In patients with baseline plasma CRP concentrations ≥5 mg L−1, infliximab outperformed placebo with an effect size similar to that observed in studies of standard antidepressants. Patients with a CRP >3 mg L−1, the standard cut-off for high inflammation, also exhibited separation from placebo. Of note, this latter finding along with data demonstrating the relevance of a CRP >3 mg L−1 to altered reward circuitry and glutamate metabolism in depression as well as the prediction of subsequent depressive episodes (described above) aligns well with other diseases in which a CRP >3 mg L−1 is relevant to prediction and pathology including cardiovascular disease and diabetes. These data suggest that the cut-off for high inflammation in depression may be consistent with other disorders (BOX 2). Importantly, however, in patients with lower levels of inflammation, blockade of TNF with infliximab actually impaired the placebo response30, suggesting that anti-inflammatory treatments in patients without inflammation may be detrimental, highlighting the growing recognition that the immune system has an important role in several processes central to neuronal integrity.

    Guidelines for Anti-Inflammatory Clinical Trials in Depression

    Based on the animal and human literature on the effects of cytokines on the brain, the following guidelines can inform clinical trials designed to test the cytokine hypothesis of depression.

    • Inflammation only occurs in subgroups of patients with depression30. Clinical trials should enrich for patient populations with evidence of increased inflammation, particularly those identified by a C-reactive protein (CRP) >3 mg L−1, which has been shown to characterize patients with depression with altered reward circuitry and increased basal ganglia glutamate, as well as those who have shown a response to anti-cytokine therapy30,84,95.
    • Anti-inflammatory drugs may harm patients without increased inflammation. Inflammatory cytokines and the innate immune response have pivotal roles in synaptic plasticity, neurogenesis, long-term potentiation (which is a fundamental process in learning and memory) and possibly antidepressant response123,128.
    • Primary behavioural outcome variables should include measures of anhedonia and anxiety. Neuroimaging studies coupled with studies administering a variety of inflammatory stimuli, including the inflammatory cytokine interferon-α, endotoxin and typhoid vaccination, have revealed that inflammation targets neurocircuits in the brain that regulate motivation and reward as well as anxiety, arousal and alarm35. In addition, these symptoms have been shown to respond to anti-cytokine therapy in limited studies.
    • Drugs that specifically target inflammatory cytokines and/or their signalling pathways are preferable. The majority of clinical trials to date have used anti-inflammatory drugs (non-steroidal anti-inflammatory agents and minocycline, a tetracycline antibiotic) that have several off-target effects making the extant data relevant to testing the cytokine hypothesis of depression difficult to interpret31.
    • Target engagement must be established in the periphery and ultimately the brain. Protein and gene expression markers of inflammation in the peripheral blood can serve as relevant proxies for inflammation in the brain129, especially given evidence of trafficking of activated peripheral immune cells to the brain in stress-induced animal models of depression. Relevant therapeutic interventions should decrease peripheral inflammatory markers in concert with improvement of specific depressive symptoms. Translocator protein neuroimaging ligands may ultimately serve as direct measures of neuroinflammation and its inhibition by anti-inflammatory therapies in future clinical trials61.

    We conclude by offering the balanced perspective that anti-inflammatory therapies are unlikely to be all-purpose antidepressants. Perhaps we only think of standard antidepressants as all-purpose agents because we have never succeeded in developing predictive biomarkers that would reliably inform us of who will respond to any given agent. If so, then we view these agents as all-purpose, not because it is true but out of hope and ignorance. Thus, instead of being a negative, perhaps the finding that baseline inflammatory biomarkers such as CRP can predict subsequent symptomatic response to anti-inflammatory strategies is, in fact, the most positive development thus far in our quest to understand how the immune system might be harnessed to improve the treatment of depression.


    Dr. Alex Jimenez’s Insight

    When you catch a cold, certain symptoms are triggered by inflammatory markers released in response to illness. While sneezing, coughing and a sore throat serve as the most “obvious” signs you may be sick, what truly keeps you in bed when you have a cold is the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain and apathetic withdrawal. These symptoms are similar to the wide array of symptoms that define depression. Many research studies have demonstrated that depression may occur due to an inflammatory response to illness, just as in the case of a common cold. The connection between inflammation and depression has long been argued among healthcare professionals and researchers, where new evidence could open the doors to additional treatment approaches which could help better manage this debilitation health issue.


    In ancestral times, integration of inflammatory responses and behaviours of avoidance and alarm provided an evolutionary advantage in managing the microbial world. In the absence of the temporizing influence of commensal organisms that were rife in environments in which humans evolved, the inflammatory bias of the human species in the civilized world has been increasingly engaged in the complex world of psychosocial interactions and the inevitable stress it engenders. Responding to these sterile insults with activation of the inflammasome and mobilization of myeloid cells to the brain, the resultant release of inflammatory cytokines impinges on neurotransmitters and neurocircuits to lead to behaviours that are poorly suited for functioning in modern society. This inevitability of our evolutionary past is apparent in the high rates of depression that are seen in society today. There is also an increasing recognition of mechanisms of resilience that derive from our emerging understanding of the neuroprotective effects of a variety of T cell responses ranging from effector T cells that produce IL-4 to TReg cells with anti-inflammatory properties. A better understanding of these neuroprotective pathways and of the inflammatory mechanisms — from inflammasome activation to cell trafficking to the brain — that operate in patients with depression may lead to the development of novel anti-depressant therapies.

    For glossary and footnotes visit:

    Understanding the Phytocannabinoids

    The discovery of the body’s endocannabinoid system, or ECS, in the 1980s provided researchers a totally new outlook on the chemicals in marijuana and hemp that had formerly been identified 40 years earlier, including how these chemicals interacted with and acted on a prevalent regulatory system in the human body. The title given to those chemicals was phytocannabinoids, meaning “phyto” for plantlife. Over 80 phytocannabinoids are identified in marijuana and hemp. The psychoactive phytocannabinoid in marijuana, tetrahydrocannabinol, or THC, represents only one of many phytocannabinoids now being extensively studied for its numerous health benefits. The more science learns about the far-reaching effects of the ECS in encouraging brain health, in improving immune function, in keeping a healthy inflammatory response, and in promoting GI health, fertility, bone health, and much more, the more interest there is in locating these phytocannabinoids in nature and learning how they affect human health. Due to this widespread interest, phytocannabinoids have been identified in many plants outside the Cannabis species; for instance, plants such as clove, black pepper, Echinacea, ginseng, broccoli, and carrots, all contain phytocannabinoids.

    Phytocannabinoids in Hemp

    Although the majority of people have now heard of cannabadiol (CBD), it’s only one of lots of the constituents in hemp which interact with the ECS. Two other notable phytocannabinoids include:

    Cannabichromene (CBC)

    CBC was first analyzed in the 1980s as it was found to modulate a normal inflammatory response in a rat model. More recently CBC has been shown to promote brain health, skin health, and preserve normal motility in the digestive tract.

    Cannabigerol (CBG)

    CBG has been increasingly studied for its capacity to support nervous system health. CBG has multiple roles from the ECS, such as inhibiting the reuptake of anandamide, an extremely beneficial endocannabinoid we make within our own bodies. CBG might also provide help for immune function, skin health, and a positive disposition. CBG is typically found in much higher concentrations in industrial hemp than in marijuana.

    Phytocannabinoids in Other Crops

    There is also ongoing research in discovering phytocannabionids in many other plants. Some of them include:

    Beta-Caryophyllene (BCP)

    Although BCP is located from the flowers and leaves of hemp, since just the hemp stalk is used in nutritional supplements, even BCP content is lost. But, BCP is contained in many other plants, like cloves and black pepper. BCP binds to the CB2 cannabinoid receptor in the body, and by doing so it helps maintain a healthy inflammatory reaction and promotes the overall health of the digestive tract, skin, and liver disease.

    Diindolylmethane (DIM)

    DIM is a compound we create in our bodies when we eat cruciferous vegetables like broccoli, cauliflower, cabbage, and Brussels sprouts. DIM is also a readily available nutritional supplement. Much like beta-caryophyllene, DIM binds to the CB2 cannabinoid receptor. Since the immune system is rich with CB2 receptors, this may clarify the immune-supportive health benefits of the foods.


    Located in the familiar herb Echinacea, alkylamides are also drawing interest for their part in the ECS. These unique compounds act on the CB2 cannabinoid receptor to regulate cytokine synthesis and also to support immune function. This activity probably helps clarify some of the common uses of Echinacea.


    Found in carrots, celery, parsley, and Panax ginseng, this interesting compound may not be one need to touch. Falcarinol binds to the CB1 cannabinoid receptor which also has the reverse effect of anandamide, that the cannabinoid our bodies make that binds to the receptor. Because of this trend, falcarinol can cause an allergic skin reaction that’s regarded because it prevents our very own ECS from modulating local inflammation.


    This phytocannabinoid, found from the Kava plant (Piper methysticum), binds to CB1 cannabinoid receptors and also acts on GABA receptors in the nervous system. Although yangonin appears to promote relaxation and modulate responses to stress, it might also be bad for the liver.

    Understanding of the endocannabinoid system is growing quickly. As this knowledge does enlarge, science will continue to find more phytocannabinoids in plants and foods that are useful in supporting health in many ways.

    In conclusion, many research studies have found a connection between inflammatory pathways and neurocircuits in the brain which can lead to a variety of behavioral responses, such as avoidance and alarm, however, growing evidence has demonstrated that chronic inflammation can lead to depression. Depression is a debilitating disorder which amounts to one of the leading causes of disability worldwide. The article above describes the connection between inflammation and depression. New insights on the results of the research studies could open the possibilities for new treatments to treat depression, among other associated health issues. Moreover, understanding the role of phytocannabinoids in the human body can function as another treatment approach for inflammation associated with depression.  Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain

    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

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    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



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    How the Nervous System Processes Chronic Pain Fri, 06 Jul 2018 20:21:58 +0000

    How does your brain know when you are experiencing pain? How does it know the difference between the soft touch of a feather and a needle prick? And, how does that information get to your body in time to respond? How can acute pain become chronic pain? These aren't simple answers, but with a small explanation about how the nervous system works, you need to have the ability to comprehend the basics before considering any type of treatment approach for chronic pain.


    Your nervous system is made up of 2 main parts: the brain and the spinal cord, which unite to form the central nervous system; and both sensory and motor nerves, that form the peripheral nervous system. The names make it easy to picture: the brain and spinal cord are the hubs, whereas the sensory and motor nerves stretch out

    The post How the Nervous System Processes Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    How does your brain know when you are experiencing pain? How does it know the difference between the soft touch of a feather and a needle prick? And, how does that information get to your body in time to respond? How can acute pain become chronic pain? These aren’t simple answers, but with a small explanation about how the nervous system works, you need to have the ability to comprehend the basics before considering any type of treatment approach for chronic pain.


    Your nervous system is made up of 2 main parts: the brain and the spinal cord, which unite to form the central nervous system; and both sensory and motor nerves, that form the peripheral nervous system. The names make it easy to picture: the brain and spinal cord are the hubs, whereas the sensory and motor nerves stretch out to provide access to all areas of the body. Put simply, sensory nerves send impulses about what is going on in our environment to the brain through the spinal cord. The brain sends data back into the motor nerves, which help us execute tasks. It is like using an extremely complicated inbox and outbox for everything. The purpose of the article below is to demonstrate the process by which the human nervous system processes chronic pain.


    Pain Processing in the Human Nervous System: A Selective Review of Nociceptive and Biobehavioral Pathways




    This selective review discusses the psychobiological mediation of nociception and pain. Summarizing literature from physiology and neuroscience, first an overview of the neuroanatomic and neurochemical systems underpinning pain perception and modulation is provided. Second, findings from psychological science are used to elucidate cognitive, emotional, and behavioral factors central to the pain experience. This review has implications for clinical practice with patients suffering from chronic pain, and provides strong rationale for assessing and treating pain from a biopsychosocial perspective.


    Keywords: pain, nociception, neurobiology, autonomic, cognitive, affective




    Pain is a complex, biopsychosocial phenomenon that arises from the interaction of multiple neuroanatomic and neurochemical systems with a number of cognitive and affective processes. The International Association for the Study of Pain has offered the following definition of pain: “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”[1] (p210) Thus, pain has sensory and affective components, as well as a cognitive component reflected in the anticipation of future harm. The purpose of the following review is to integrate the literature on the neurobiological pathways within the central, autonomic, and peripheral nervous systems that mediate pain processing, and discuss how psychological factors interact with physiology to modulate the experience of pain.


    Functional Neuroanatomy and Neurochemistry of Pain


    Pain Processing in the Nervous System


    When noxious stimuli impinge upon the body from external or internal sources, information regarding the damaging impact of these stimuli on bodily tissues is transduced through neural pathways and transmitted through the peripheral nervous system to the central and autonomic nervous systems. This form of information processing is known as nociception. Nociception is the process by which information about actual tissue damage (or the potential for such damage, should the noxious stimulus continue to be applied) is relayed to the brain. Nociception is mediated by specialized receptors known as nociceptors that are attached to thin myelinated Aδ and unmyelinated C fibers, which terminate in the dorsal horn of the spine. Sufficiently intense mechanical stimulation (such as stretching, cutting, or pinching), intense warming of the skin, or exposure to noxious chemicals can activate nociceptors.[2] In turn, activation of nociceptors is modulated by inflammatory and bio-molecular influences in the local extracellular environment.[3] Although under most circumstances transmission of nociceptive information results in pain perception, many physicians and patients are unaware that nociception is dissociable from the experience of pain. In other words, nociception can occur in the absence of awareness of pain, and pain can occur in the absence of measurably noxious stimuli. This phenomenon is observable in instances of massive trauma (such as that which might be incurred by a motor vehicle accident) when victims exhibit a stoic painless state despite severe injury, and conversely, when individuals with functional pain syndromes report considerable anguish in spite of having no observable tissue damage.


    In contrast, perception of pain occurs when stimulation of nociceptors is intense enough to activate Aδ fibers, resulting in a subjective experience of a sharp, prickling pain.[4] As stimulus strength increases, C fibers are recruited, and the individual experiences an intense, burning pain that continues after the cessation of the stimulus. These types of experiences occur during the two phases of pain perception that occur following an acute injury.[2] The first phase, which is not particularly intense, comes immediately after the painful stimulus and is known as fast pain. The second phase, known as slow pain, is more unpleasant, less discretely localized, and occurs after a longer delay.


    Activation of nociceptors is transduced along the axons of peripheral nerves which terminate in the dorsal horn of the spine. There, messages are relayed up the spinal cord and through the spinothalamic tract to output on the thalamus. In turn, the thalamus serves as the major “relay station” for sensory information to the cerebral cortex.[5] Nociceptive pathways terminate in discrete subdivisions of thalamic nuclei known as the ventral posterior lateral nucleus and the ventromedial nucleus.[6] From these nuclei, nociceptive information is relayed to various cortical and subcortical regions, including the amygdala, hypothalamus, periaqueductal grey, basal ganglia, and regions of cerebral cortex. Most notably, the insula and anterior cingulate cortex are consistently activated when nociceptors are stimulated by noxious stimuli, and activation in these brain regions is associated with the subjective experience of pain.[7] In turn, these integrated thalamocortical and corticolimbic structures, which collectively have been termed the pain “neuromatrix,” process somatosensory input and output neural impulses which influence nociception and pain perception.[8]


    Neurochemistry of Pain


    Nociception is mediated by the function of numerous intra- and extra-cellular molecular messengers involved in signal transduction in the peripheral and central nervous systems. All nociceptors, when activated by the requisite mechanical, thermal, or chemical stimulus, transmit information via the excitatory neurotransmitter glutamate.[9] In addition, inflammatory mediators are secreted at site of the original injury to stimulate nociceptor activation. This “inflammatory soup” is comprised of chemicals such as peptides (e.g., bradykinin), neurotransmitters (e.g., serotonin), lipids (e.g., prostaglandins), and neurotrophins (e.g., NGF). The presence of these molecules excites nociceptors or lowers their activation threshold, resulting in the transmission of afferent signals to the dorsal horn of the spinal cord as well as initiating neurogenic inflammation.[3] Neurogenic inflammation is the process by which active nociceptors release neurotransmitters such as substance P from the peripheral terminal to induce vasodilation, leak proteins and fluids into the extracellular space near the terminal end of the nociceptor, and stimulate immune cells which contribute to the inflammatory soup. As a result of these neurochemical changes in the local environment of nociceptors, the activation of Aδ and C fibers increases, and peripheral sensitization occurs.[10]


    In turn, nociceptive signal transduction up the spinothalamic tract results in elevated release of norepinephrine from the locus coeruleus neurons projecting to thalamus, which in turn relays nociceptive information to somatosensory cortex, hypothalamus, and hippocampus.[11,12] As such, norepinephrine modulates the “gain” of nociceptive information as it is relayed for processing in other cortical and subcortical brain regions. Concomitantly, opioid receptors in the peripheral and central nervous systems (e.g., those in neurons of the dorsal horn of the spine and the periaqueductal grey in the brain) result in inhibition of pain processing and analgesia when stimulated by opiates or endogenous opioids like endorphin, enkephalin, or dynorphin.[13] The secretion of endogenous opioids is largely governed by the descending modulatory pain system.[14] The neurotransmitter GABA is also involved in the central modulation of pain processing, by augmenting descending inhibition of spinal nociceptive neurons.[15] A host of other neurochemicals are also involved in pain perception; the neurochemistry of nociception and central-peripheral pain modulation is extremely complex.


    Descending Central Modulation of Pain


    The brain does not passively receive pain information from the body, but instead actively regulates sensory transmission by exerting influences on the spinal dorsal horn via descending projections from the medulla.[16] In their seminal Gate Control theory of pain, Melzack and Wall proposed that the substantia gelatinosa of the dorsal horn gates the perception of noxious stimuli by integrating upstream afferent signals from the peripheral nervous system with downstream modulation from the brain.[17] Interneurons in the dorsal horn can inhibit and potentiate impulses ascending to higher brain centers, and thus they provide a site where the central nervous system controls impulse transmission into consciousness.


    The descending pain modulatory system exerts influences on nociceptive input from the spinal cord. This network of cortical, subcortical, and brainstem structures includes prefrontal cortex, anterior cingulate cortex, insula, amygdala, hypothalamus, periaqueductal grey, rostral ventromedial medulla, and dorsolateral pons/tegmentum.7 The coordinated activity of these brain structures modulates nociceptive signals via descending projections to the spinal dorsal horn. By virtue of the somatotopic organization of these descending connections, the central nervous system can selectively control signal transmission from specific parts of the body.


    The descending pain modulatory system has both anti- and pro-nociceptive effects. Classically, the descending pain modulatory system has been construed as the means by which the central nervous system inhibits nociceptive signals at the spinal outputs.[16] In a crucial early demonstration, Reynolds observed that direct electrical stimulation of the periaqueductal grey could produce dramatic analgesic effects as evidenced by the ability to undergo major surgery without pain.[18] Yet, this brain system can also facilitate nociception. For instance, projections from the periaqueductal grey to the rostral ventromedial medulla have been shown to enhance spinal transmission of nociceptive information from peripheral nociceptors.[19]


    Central modulation of pain may have been a conserved across human evolution due to its potentially adaptive effects on survival. For instance, in situations of serious mortal threat (for example, in the face of war and civil accidents, or more primordially, when being attacked by a vicious animal), suppression of pain might enable a severely-injured individual to continue intense physical activity such as fleeing from danger or fighting a deadly opponent. Yet, the neurobiological linkages between the brain, the spinothalamic tract, the dorsal horn, and the peripheral nerves also provide a physiological pathway by which negative emotions and stress can amplify and prolong pain, causing functional interference and considerable suffering.


    Cognitive, Affective, Psychophysiological, and Behavioral Processes in Pain Perception and Regulation


    In addition to the somatosensory elements of pain-processing described above, cognitive and emotional factors are implicit within the definition of pain offered by the International Association for the Study of Pain. Pain perception involves a number of psychological processes, including attentional orienting to the painful sensation and its source, cognitive appraisal of the meaning of the sensation, and the subsequent emotional, psychophysiological, and behavioral reaction, which then feedback to influence pain perception (see Figure 1). Each of these processes will be detailed below.


    Schematic of the Human Nervous System Diagram 1 | El Paso, TX Chiropractor
    Figure 1: A schematic of nociception, pain perception and the biobehavioral response to pain in the human nervous system.


    Attention to Chronic Pain


    In the brain, attention allows salient subsets of data to gain preeminence in the competitive processing of neural networks at the expense of other subsets of data.[20] The goal-relevance of a stimulus guides attention to select and distinguish it from the environmental matrix in which it is embedded.[21] Thus, attended stimuli receive preferential information processing and are likely to govern behavior. In this sense, attention allows for the evaluation of salient stimuli, and facilitates execution of approach behaviors in response to appetitive stimuli or avoidance behaviors in response to aversive ones. Thus, depending on its salience to the survival of the organism, the object of attention elicits the motivation to approach or avoid, while the resultant emotional state, as the manifestation of approach or avoidance motivations, tunes and directs attention.[22,23] By virtue of its significance for health and well-being, pain automatically and involuntarily attracts attention.[24,25] Yet pain experience varies according to the locus of attention; when attention is focused on pain, it is perceived as more intense,[26] and whereas when attention is distracted from pain, it is perceived as less intense.[27]


    Attentional modulation of pain experience correlates with changes in activation of the pain neuromatrix; for instance, attentional distraction reduces pain-related activations in somatosensory cortices, thalamus, and insula, among other brain regions.[7] Concomitantly, distraction results in strong brain activations in prefrontal cortex, anterior cingulate cortex, and periaqueductal grey, suggesting an overlap and interaction between brain systems involved in attentional modulation of pain and the descending pain modulatory system.[28] In contrast, attentional hypervigilance for pain, a high degree of monitoring internal and external stimuli that is often observed among persons with chronic pain,[29] amplifies pain intensity and is associated with the interpretation of harmless sensations (like moderate levels of pressure) as painfully unpleasant.[30,31]


    Cognitive Appraisal of Pain


    Pain involves a process of cognitive appraisal, whereby the individual consciously or unconsciously evaluates the meaning of sensory signals emanating from the body to determine the extent to which they signify the presence of an actual or potential harm. This evaluation is decidedly subjective. For instance, experienced weightlifters or runners typically construe the “burn” they feels in their muscles as pleasurable and indicative of increasing strength and endurance; in contrast, a novice might view the same sensation as signaling that damage had occurred. The inherent variability of cognitive appraisal of pain may stem from the neurobiological dissociation between the sensory and affective aspects of the pain experience; change in pain intensity results in altered activation of somatosensory cortex, whereas change in pain unpleasantness results in altered activation of the anterior cingulate cortex.[32,33] Thus, a sensory signal originating from the muscles of lower back might be perceived as a warmth and tightness, or viewed as a terrible agony, in spite of the stimulus intensity being held constant. The manner in which the bodily sensation is appraised may in turn influence whether it is experienced as unpleasant pain or not.[34]


    The extent to which a given bodily sensation is interpreted as threatening is in part dependent on whether or not the individual believes he or she is able to cope with that sensation. If, during this complex cognitive process of appraisal, available coping resources are deemed sufficient to deal with the sensation, then pain can be perceived as controllable. Pain intensity is reduced when pain is perceived to be controllable, whether or not the individual acts to control the pain. Ventrolateral prefrontal cortex activation is positively associated with the extent to which pain is viewed as controllable and negatively correlated with subjective pain intensity. This brain region is implicated in emotion regulation efforts, such as when threatening stimuli are reappraised to be benign.[35,36] Concomitantly, reinterpreting pain as a harmless sensation (e.g., warmth or tightness) predicts higher perceived control over pain,[37] and psychological interventions have been shown to reduce pain severity by increasing reinterpretation of pain sensations as innocuous sensory information.[38] In contrast, pain catastrophizing (i.e., viewing pain as overwhelming and uncontrollable) is associated with greater pain intensity irrespective of the extent of physical impairment[39] and prospectively predicts the development of low back pain.[40]


    Emotional and Psychophysiological Reactions to Chronic Pain


    The aversive nature of pain elicits a powerful emotional reaction that feeds back to modulate pain perception. Pain often results in feelings of anger, sadness, and fear depending on the how the pain is cognitively appraised. For instance, the belief “It’s not fair that I have to live with this pain” is likely to lead to anger, whereas the belief “My life is hopeless now that I have this pain” will likely result in sadness. Fear is a common reaction to pain when individuals interpret the sensations from the body as indicating the presence of serious threat.


    These emotions are coupled with autonomic, endocrine, and immune responses which may amplify pain through a number of psychophysiological pathways. For example, pain induction significantly elevates sympathetic nervous system activity, marked by increased anxiety, heart rate, and galvanic skin response.[41] Furthermore, negative emotions and stress increase contraction of muscle tissue; elevated electromyographic activity occurs in the muscles of the back and neck under conditions of stress and negative affect and is perceived as painful spasms.[42,43] This sympathoexcitatory reaction coupled with emotions like anger and fear may reflect an evolutionarily conserved, active coping response to escape the painful stimulus. Yet negative emotional states intensify pain intensity, pain unpleasantness, and pain-induced cardiovascular autonomic responses, while reducing the sense of perceived control over pain.[44] Stress and negative emotions like anger and fear may temporarily dampen pain via norepinephrine release, but when the sympathetic “fight or flight” response is prolonged it can increase blood flow to the muscle and increase muscle tension which may aggravate the original injury.[45] Alternatively, pain inputs from the viscera and muscles may stimulate cardiac vagal premotor neurons, leading to hypotension, bradycardia, and hyporeactivity to the environment – a pattern of autonomic response that corresponds with passive pain coping and depressed affect.[46] In addition to autonomic reactivity, pro-inflammatory cytokines and the stress hormone cortisol are released during the experience of negative emotion; these bio-molecular factors enhance nociception, facilitate processing of aversive information in the brain, and when their release is chronic or recurrent, may cause or exacerbate tissue damage.[8,47,48]


    Moreover, negative emotions are associated with increased activation in the amygdala, anterior cingulate cortex, and anterior insula – these brain structures not only mediate the processing of emotions, but are also important nodes of the pain neuromatrix that tune attention toward pain, intensify pain unpleasantness, and amplify interoception (the sense of the physical condition of the body).[49,50] Thus, when individuals experience negative emotions like anger or fear as a result of pain or other emotionally salient stimuli, the heightened neural processing of threat in affective brain circuits primes the subsequent perception of pain[51,52] and increases the likelihood that sensations from within the body will be interpreted as painful.[53–55] The fear of pain, a clinical feature of chronic pain patients, is associated with hypervigilance for and sustained attention to pain-related stimuli.[56] Thus, negative emotions bias attention toward pain, which then increase its unpleasantness. In addition, negative emotions and stress impair prefrontal cortex function, which may reduce the ability to regulate pain using higher order cognitive strategies like reappraisal or viewing the pain as controllable and surmountable.[57,58] Thus, anger, sadness, and fear may result from acute or chronic pain and in turn feedback into the bio-behavioral processes that influence pain perception to exacerbate anguish and suffering.


    Behavioral Reactions to Pain


    Pain is not only a sensory, cognitive, and emotional experience, but also involves behavioral reactions that may alleviate, exacerbate, or prolong pain experience. Typical pain behaviors in low back pain include grimacing, rubbing, bracing, guarded movement, and sighing.[59] These behaviors facilitate the communication of pain and exert social influences that may have vicarious gain for the individual suffering from pain; such benefits include sympathy, acts of kindness and generosity, tolerance, lowered expectations, and social bonding, among others.[60] In addition, guarding or avoidance of activities associated with pain may be negatively reinforcing by virtue of the temporary alleviation of pain experience.[61] The fact that these avoidant behaviors decrease the occurrence of pain results in increasing use of avoidance as a coping strategy. Yet, greater use of avoidance as a result of fear of pain predicts higher levels of functional disability.[62] It is not merely that persons with greater pain-related disability engage in more avoidant behaviors, but rather studies indicate that avoidant behavior and beliefs are a precursor to disability.[63–65] Avoidance contributes to negative clinical outcomes in patients with chronic low back pain. Fear-avoidance of pain influences physical impairment and is more strongly associated with functional disability than pain severity.[66–68] In contrast, progressive increase in activity through exercise has been shown to result in significant benefits in pain, disability, physical impairment, and psychological distress for low back pain patients.[69] In light of the robust relation between coping behaviors and pain, behavioral and psychosocial interventions hold great promise in reducing pain intensity and pain-related functional disability in chronic pain conditions such as low back pain.[70]



    Dr. Alex Jimenez’s Insight

    Different sensory nerve fibers respond to different stimulations and produce different chemical reactions which determine how different sensations are interpreted. Special pain receptors, known as nociceptors, activate when there has been trauma from an injury or even through potential damage to the human body. This impulse, immediately sends a signal through the nerve and into the spinal cord, eventually reaching all the way to the brain. The role of the spinal cord in pain perception is also to simultaneously direct impulses to the brain and back down the spinal cord to the region of the injury. These are referred to as reflexes. However, the pain signal still needs to continue to the brain so it can respond accordingly. The brain will assess the type of pain and where it came from, triggering a healing response as well as a variety of other bodily responses to address the pain signal effectively. In the case of chronic pain, pain perception may not be working accordingly along any of the pathways mentioned above. Treatment can help improve chronic pain as well as manage the painful symptoms.




    The foregoing review attests to the multidimensionality of pain. Pain is a biopsychosocial experience that goes well beyond mere nociception. In this regard, identification of the physical pathology at the site of injury is necessary but not sufficient to explicate the complex process by which somatosensory information is transformed into the physiological, cognitive, affective, and behavioral response labeled as pain. Indeed, in the case of chronic low back pain, the magnitude of tissue damage may be out of proportion to the reported pain experience, there may be no remaining structural impairment, and physical signs that have a predominantly nonorganic basis are likely to be present.[71,72] In this and other chronic conditions, to consider such pain as malingering or somatization would be to grossly oversimplify the matter. Pain, whether linked with injured tissue, inflammation, or functional impairment, is mediated by processing in the nervous system. In this sense, all pain is physical. Yet, regardless of its source, pain may result in hypervigilance, threat appraisals, emotional reactions, and avoidant behavior. So in this sense, all pain is psychological. Our nomenclature and nosology struggle to categorize the pain experience, but in the brain, all such categories are moot. Pain is fundamentally and quintessentially a psychophysiological phenomenon.


    Key Points


    • Pain is a biopsychosocial experience that goes well beyond mere nociception. In this regard, identification of the physical pathology at the site of injury is necessary but not sufficient to explicate the complex process by which somatosensory information is transformed into the physiological, cognitive, affective, and behavioral response labeled as pain
    • In the case of chronic low back pain, the magnitude of tissue damage may be out of proportion to the reported pain experience, there may be no remaining structural impairment, and physical signs that have a predominantly nonorganic basis are likely to be present.
    • Pain, whether linked with injured tissue, inflammation, or functional impairment, is mediated by processing in the nervous system. In this sense, all pain is physical. Yet, regardless of its source, pain may result in hypervigilance, threat appraisals, emotional reactions, and avoidant behavior. So in this sense, all pain is psychological.
    • Our nomenclature and nosology struggle to categorize the pain experience, but in the brain, all such categories are moot. Pain is fundamentally and quintessentially a psychophysiological phenomenon.




    ELG was supported by grant DA032517 from the National Institute on Drug Abuse in the preparation of this manuscript.





    Plants as Medicine: Are Cannabinoids the Next Breakthrough in Plant Medicine?


    If you’ve ever eaten a carrot, then you have consumed a cannabinoid. Most people associate cannabinoids with marijuana. The most commonly recognized cannabinoid is tetrahydrocannabinol, or THC, the chemical in marijuana that causes feelings of euphoria. Until recently, scientists had identified cannabinoids just in the cannabis plant, commonly called hemp or marijuana. Current research, however, has found cannabinoids in several plants, including clove, black pepper, Echinacea, ginseng and broccoli as well as carrots. No matter how many carrots you crunch, however, they will not get you too high. But understanding how the cannabinoids in different plants affect the human body may contribute to important health discoveries.


    Plants as Medicine


    Some of the most appreciated modern drugs were developed by analyzing plants used in conventional medicine. Researching the chemicals in these plants led to the discovery of life-saving drugs and furthered our knowledge of how the human body works. For instance, the foxglove plant introduced us to digoxin and digitoxin, two important heart medications.[1] As well as the Pacific yew contains paclitaxel, which can be used in the treatment of many cancers.[1] Throughout history, people have been especially adept at finding plants which either increase pleasure or reduce pain. Caffeine from tea and tea provides energy and keeps us awake, while smoking from tobacco is believed to be concurrently stimulating and relaxing, likely explaining why tobacco remains popular despite the known health risks of smoking.[2]


    Several sorts of pain-relieving drugs originated with plants:




    By analyzing opium from the poppy plant, scientists discovered opiate receptors in the human body and their role in pain control, which led to the development of morphine, codeine, and other opiate drugs and/or medications.[3]




    As far back as ancient Egypt, health practitioners used tea made from the willow tree to decrease pain and fever. It took tens of thousands of years for scientists to find and isolate the active chemical, or the fatty acid, which led to the discovery of aspirin and from there, finding insights into the processes involved with inflammation.[4]




    The leaves of the coca plant were used from the ancient Incan Empire from South America to deal with headaches, wounds and fractures. Coca eventually yielded the drug cocaine, which is a drug of misuse and abuse, but also an effective anesthetic. Recognizing how cocaine blocked pain led to the development of common anesthetics such as lidocaine, famous for making invasive dental procedures more comfortable.[5]


    Cannabis and Human Health


    Such as other medicinal plants, the cannabis species has been used for centuries. A Chinese text from the year AD 1 records the usage of hemp to treat more than 100 ailments dating back to 2737 BC.[6] Afterwards, the flowering tops of the Cannabis plant began to be cultivated for their psychoactive properties, while a different selection of the plant was increased as industrial hemp to be used in producing garments, paper, biofuels, foods, and other products.


    Because of the controversy surrounding marijuana as a recreational drug, researchers have not been able to readily study the effects of the many non-THC ingredients in Cannabis. Although THC was identified from the 1940s, it was not until 50 years after that studies demonstrated that individuals, and nearly all animals,  have an inner system of cannabinoid receptors. What is more, we really make cannabinoids in our bodies, known as endocannabinoids, that act on these receptors.[7]


    This physiological system is called the endocannabinoid system, or ECS, and new science appears almost daily about its function in human health. The ECS is involved in multiple functions, such as pain feeling, hunger, memory, and disposition. If you’ve ever stubbed your toe, digested an apple, then forgotten a password, or happily smile, then your ECS was involved, little did you know.


    The discovery of the ECS gave science and medicine a whole new outlook about the organic compounds being identified in Cannabis. Researchers started referring to these chemicals as phytocannabinoids, from the work “phyto” for plant. More than 80 phytocannabinoids have been found in hemp and marijuana. THC is only one of many compounds being studied for the advantages they can provide.[8]


    Past Cannabis and THC


    Now that many different crops are known to contain chemicals that influence the ECS, phytocannabinoids are no longer just associated with the cannabis plant.[9] Chances are you have some source of phytocannabinoids in your diet right now. But it might be a small quantity, rather than all of phytocannabinoids interact strongly with the ECS.


    What exactly do we know up to now? Current research shows that a number of the phytocannabinoids in hemp, clove, and black pepper can encourage the ECS to promote relaxation, decrease nerve distress, and improve digestive health. As these compounds don’t possess the mind-altering effects of THC, more individuals are likely to flip to phytocannabinoids to acquire their health benefits without having high.[10] Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news


    EXTRA IMPORTANT TOPIC: Low Back Pain Management


    MORE TOPICS: EXTRA EXTRA: Chronic Pain & Treatments



    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



    The post How the Nervous System Processes Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.

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    Depression and Anxiety in Chronic Pain Thu, 05 Jul 2018 20:18:55 +0000

    Everyone will experience some type of pain throughout their lifetime, however, for those people who have anxiety or depression, pain can become especially intense and it can be challenging to treat. Individuals experiencing depression, for instance, often experience more severe and long-term pain than other individuals. The overlap of anxiety, depression, and pain is very evident in chronic pain and sometimes debilitating syndromes, such as fibromyalgia, irritable bowel syndrome, low back pain, headaches, and nerve pain. Psychiatric disorders not only bring about pain intensity but also contribute to increased risk of disability.


    Researchers once believed that the connection between pain, anxiety, and depression resulted mostly from psychological rather than biological factors. Chronic

    The post Depression and Anxiety in Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Everyone will experience some type of pain throughout their lifetime, however, for those people who have anxiety or depression, pain can become especially intense and it can be challenging to treat. Individuals experiencing depression, for instance, often experience more severe and long-term pain than other individuals. The overlap of anxiety, depression, and pain is very evident in chronic pain and sometimes debilitating syndromes, such as fibromyalgia, irritable bowel syndrome, low back pain, headaches, and nerve pain. Psychiatric disorders not only bring about pain intensity but also contribute to increased risk of disability.


    Researchers once believed that the connection between pain, anxiety, and depression resulted mostly from psychological rather than biological factors. Chronic pain can lead to depression, and also, major depression may feel emotionally painful. But as researchers have learned more about how the brain works, and how the nervous system interacts with other areas of the body, they’ve found that pain shares some biological mechanisms with depression and anxiety. Therapy is challenging when pain overlaps with anxiety or depression. Focus on pain can conceal both the clinician’s and patient’s awareness that a psychiatric disorder is also present. Even when the two types of problems are properly diagnosed, they can be difficult to treat.


    Depression and Anxiety in Pain




    • Mood disorders, especially depression and anxiety, play an important role in the exacerbation of pain perception in all clinical settings.
    • Depression commonly occurs as a result of chronic pain and needs treating to improve outcome measures and quality of life.
    • Anxiety negatively affects thoughts and behaviours which hinders rehabilitation.
    • Anxiety and depression in acute hospital settings also negatively affect pain experience and should be considered in both adults and children.
    • Poor pain control and significant mood disorders perioperatively contribute to the development of chronic postoperative pain.




    Pain concepts have moved radically away from the early nociceptive Cartesian principle, where a specific lesion in the body is experienced as pain by the brain. This has been replaced by the widely accepted biopsychosocial model, where tissue damage, psychology and environmental factors all interact to determine pain experience. The IASP’s definition of pain as “an unpleasant sensory or emotional experience associated with tissue damage…” further emphasises the significant role of mood and emotions for pain perception. Among these, depression and anxiety have been implicated as important contributors to the experience of pain, and have been extensively studied.




    Depression is characterised by a pervasive low mood, loss of interest in usual activities and diminished ability to experience pleasure. Within this definition there exists a whole spectrum of severity, symptoms and signs together with their classifications. The DSM-IV (Diagnostic and Statistical Manual) is a common diagnostic classification system for psychiatric conditions and is also used for research, insurance and administration[1]. A common prerequisite for diagnosis of depression or other psychiatric disorders is that any symptoms experienced should result in clinically significant distress or impairment of social, occupational, or other important areas of functioning.


    The Scale of the Problem


    The association of chronic pain with depression has been of great interest in the past few decades. Chronic musculoskeletal pain patients have higher depression than individuals without pain in a general population study[2]. A third of patients in a pain clinic population had ‘major depression’ according to the criteria of the Diagnostic and Statistical Manual (DSM IV) following structured interviews[3]. The presence of pain can make recognition of depression more difficult, even though increased severity of pain worsens depressive symptoms[4].


    Diagnostic and Assessment Issues


    The association between depression and chronic pain, though widely accepted, is marred by diagnostic difficulties. In research for ‘depression’ various definitions exist in studies, leading to a variety of assessment methods, including self report instruments, chart reviews and structured or unstructured clinical interviews. Many studies relating to depression and chronic pain include heterogenous groups of patients with different chronic pain conditions and unspecified diagnostic criteria for depression. This clearly questions the validity of studies.


    In the clinical setting many tools exist for the assessment of the severity and nature of depression. In chronic pain, the Zung Self-Rating Depression Scale (SDS), Beck’s Depression Inventory (BDI) and Depression, Anxiety and Stress Scale (DASS) are commonly used. The SDS and DASS in particular, have shown high internal consistency and validity in chronic pain patients. However many criteria for depression, like fatigue, insomnia and weight change, are symptoms attributable to chronic pain itself. The DSM-IV places emphasis on weight loss, appetite change and fatigue on diagnosis, and the Beck’s Depression Inventory and Zung Self-Rating Depression Scales also include a substantial number of such somatic items. Such ‘criterion contamination’ may lead to overestimation of depression. The DASS excludes such somatic items and is thought to provide a more accurate assessment of depression, especially in chronic pain patients[5]. Another questionnaire designed specifically for chronic pain patients is the Depression, Anxiety and Positive Outlook Scale (DAPOS). This also contains no somatic items and includes measures of optimism[6].


    These points illustrate the unique difficulty present in the study of depression in chronic pain patients. It is not surprising that meta-analyses or systematic reviews in this area are relatively scarce. Just as depression is not a single entity but a spectrum, chronic pain patients are also a very heterogenous group of patients. All these have to be borne in mind when reviewing papers and studies of depression in chronic pain.


    Depression and Pain: Chicken and Egg?


    Physiological similarities exist between chronic pain and depression. For example, noradrenaline and serotonin involved in the pathophysiology of depression also coincide with the anatomical ‘descending inhibition’ of pain perception. These two neurotransmitters act in the limbic system and periaqueductal areas to modulate incoming pain stimuli. Antidepressants working through these neurotransmitters are also analgesic regardless of the presence of depression.


    This leads to the question of whether depression follows the establishment of chronic pain or whether chronic pain is a manifestation of a form of depression or a spectrum thereof. Some evidence exists for both views. For example, patients with preexisting depression were found to be more likely to develop chest pain and headaches in a three year period[7]. Conversely a review of forty studies supported the notion that depression is a consequence of protracted pain[8]. The ‘diathesis-stress’ model for this conundrum is now growing in acceptance which supports that depression is a sequalae of chronic pain. Accordingly people with a psychological predisposition (diathesis), superimposed with the stresses of chronic pain go on to develop clinical depression.


    Chronic pain is also associated with anxiety disorders (discussed below), somatoform disorders, substance use disorders, and personality disorders. As with depression, pre-existing, semidormant characteristics of the individual before the onset of chronic pain are activated and exacerbated by the stress of chronic pain, eventually resulting in diagnosable psychopathology[9]. Psychosocial elements which predict chronic pain and disability (yellow flags) used in clinical practice may well fit into this construct.


    Yellow Flags are psychosocial factors that increase the risk of developing or perpetuating long-term disability and work loss associated with low back pain. Such include:


    • Attitudes and Beliefs about back pain. The belief that pain is harmful or disabling resulting in fear-avoidance behaviour.
    • Behaviours. Use of extended rest, disproportionate ‘downtime’.
    • Compensation Issues. Lack of financial incentive to return to work.
    • Diagnosis and Treatment. Health professional sanctioning disability, not providing interventions that will improve function.
    • Emotions. Fear of increased pain with activity or work.
    • Family and Work. Over-protective partner/spouse, emphasising fear of harm or encouraging catastrophising. Manual work and job dissatisfaction.


    The Costs of Depression in Pain


    Social functioning, work and physical activities are all decreased whilst utilisation of medical services increases if depression coexists with pain[10]. Motivation and compliance with treatment is also affected[11]. Such negative outcomes leave little doubt as to the quality of life of such patients. Clearly pain and depression should not be seen as separate dimensions but as interactive in nature. Attempting to treat pain without considering depression is likely to be a futile venture.


    Anxiety in Chronic Pain


    Anxiety is a physiological state characterized by cognitive, somatic, emotional, and behavioral components producing fear and worry. Anxiety is often accompanied by physical sensations such as heart palpitations and shortness of breath whilst the cognitive component entails expectation of a diffuse and certain danger. As with depression, anxiety disorders are categorised in the DSM-IV, with subtypes including generalised anxiety disorder (GAD), panic disorder and phobias. GAD is the most commonly diagnosed anxiety disorder in chronic pain populations. The coexistence of pain and anxiety is perhaps not surprising: Both signal impending danger and the necessity for action which confer survival value to the individual.


    Anxiety disorders are second only to depression in psychological comorbidity in chronic pain populations. Whilst anxiety is a normal response in everyone, clinical anxiety results in increased intensity and prolongation of the feelings of dread that interfere with normal functioning. Measurements of anxiety with chronic pain also show a strong association: as with depression. One such study showed a doubling in the prevalence of anxiety disorders compared to the general population[12]. Anxiety is thought to be an important mediator in the cognitive constructs of catastrophising, hypervigilance and fear avoidance in the exacerbation of pain experiences.


    • Catastfophising is ‘dwelling on the worst possible outcomes’. It is associated with higher disability and pain severity and is an important cognitive measure and prognostic indicator in chronic pain patients.
    • Hypervigilance in pain is the increased attendance to pain and decreased ability to distract oneself from pain-related stimuli.
    • Fear avoidance is the avoidance of movement or activities based on fear of pain or re-injury. This is especially counterproductive for physical rehabilitation and is termed ‘kinesophobia’.


    Measurement of Anxiety in Pain


    As with depression many measures of anxiety states exist. The State-Trait Anxiety Inventory questionnaire is a well-validated tool used in general psychology but has also been used in pain clinics. For chronic pain, more specific measures of anxiety-related to cognitive and behavioural variables have been designed. Such an instrument is the Pain Anxiety Symptoms Scale (PASS) which measures behavioural responses to pain[13]. The Fear of Pain Inventory measures degree of fear in hypothetical pain inducing situations[14]. These are more useful than general anxiety measurements and give more specific information in relation to the pain experienced. The DASS and DAPOS used for depression also measure anxiety.


    Anxiety and Depression Coexist


    Despite their differences in symptoms and classification, depression and anxiety seem to exist concurrently to a surprisingly frequent extent. In psychiatry, terms like ‘agitated depression’ have been coined for a state of depression that presents as anxiety which includes restlessness, insomnia and nonspecific panic.


    Even mild anxiety symptoms can have a major impact on the course of a depressive illness. Depressed or bipolar patients with lifetime panic symptoms have significant delays in remission for depression[15]. To this end, the presence of both depression and anxiety make treatment of pain more challenging but the presence of one should alert rather than deter the diagnosis of the other.


    Treatment of Depression and Anxiety


    Mainstays of treatment of depression and anxiety are psychological and pharmacological. Whilst the scope of these is well beyond this article, it is worth noting that cognitive behavioural therapy, which addresses depression and anxiety, has very good evidence for efficacy in chronic pain patients[16]. Important concepts of CBT are also incorporated into Pain Management Programs for delivery to patients with different types of pain.


    Depression and Anxiety in Acute Pain


    Hitherto depression and anxiety have only been discussed in a chronic setting. Current multidimensional concepts of pain are equally important in the acute setting. Apart from the degree of surgical insult to tissue, psychological and environmental factors influence acute pain experience to a high degree[17].


    Preoperative anxiety is correlated with higher pain intensity postoperatively for a variety of operations. In the hospital setting, anxiety is worsened by sleep deprivation in the postoperative period due to interruptions in the wards for observations, other patients and medications. This vicious circle is exacerbated by fear of complications, loss of control and helplessness. Admission to hospital and having an operation is a highly stressful event for most and that is often forgotten by professionals who are frequently involved in perioperative care. Preoperative depression also increases pain intensity, opioid requirements by any route and number of demands from the PCAS (Patient controlled analgesia system) in the postoperative period. Higher levels of dissatisfaction with analgesia also occur if depression coexists[18].



    Dr. Alex Jimenez’s Insight

    From headaches to muscle tension and body soreness, pain may be all too familiar for individuals who suffer from anxiety and depression. However, many research studies have demonstrated that chronic pain, such as that resulting from conditions like arthritis or fibromyalgia, may in turn lead to a variety of mental health issues. Both anxiety and depression have been implicated to be fundamental contributors in the exacerbation of as well as in the perception of pain. As a result, many healthcare professionals have developed a treatment approach based on therapeutic strategies to help manage symptoms of anxiety and depression. By first controlling these symptoms, many doctors can safely and effectively help in the management of chronic pain. Recent research studies have found a connection between the endocannabinoid system and the management of chronic pain, as well as anxiety and depression.


    Treatment Strategies


    Strategies used include procedural and sensory information, relaxation and attentional strategies, hypnosis and cognitive behavioural treatments. The use of anxiolytic drugs on the morning of procedure or hypnotics the night before are also widespread.


    Combination of procedural information of the surgery together with expected sensations felt by the patient postoperatively have yielded Level I evidence (evidence obtained from at least one properly designed randomised controlled trial) for benefits on pain perception[19]. Another meta-analysis on giving information regarding the conduct of surgical treatment showed decreased hospital stay[20].


    Relaxation techniques involve teaching patients calming methods, including breathing techniques, self hypnosis and muscle relaxation.


    This has been verified in a metanalysis providing Level I evidence for reducing pain as well as blood pressure and pulse[21]. Hypnosis and attention diversion from pain has also garnered evidence for effectiveness. A ‘moderate to large’ effect size on reduction of pain has been shown in yet another meta-analysis of hypnosis, in both laboratory and clinical participants[22].


    Psychological interventions for children are also increasingly recognized and being used. Cognitive behavioural strategies are shown to be effective in procedural related pain in children and adolescents[23].


    Techniques used involve breathing exercises, distraction and incentives. These techniques involve psychologists, parents and medical staff.


    Even in the intensive care, mood disorders need attention. Mechanically ventilated patients without surgery or trauma are known to experience pain, which leads to increased anxiety and adverse physiological effects[24]. Analgesia and sedation thus need to be adjusted with evaluation of pain in mind.


    There is very good evidence to implicate mood disorders, especially anxiety, in worsening pain experience in acute surgical or procedural situations. Evidence extends to oncology and paediatric patients also. As a basic strategy, careful explanation and allaying of fears should be practiced by any healthcare professional involved in interventions. This can be combined with some of the psychological techniques described above. There is a greater wealth of high level evidence for mood disorders in acute compared to chronic pain. Shorter time frames of studies and greater numbers of suitable patients for recruitment are contributory factors to this.


    Bridging the Gap


    What causes acute pain to become chronic? Many patients who do develop chronic pain can pin down an episode of acute pain as a precipitant[25]. Some risk factors are known. Surgical procedures like amputation, thoracotomy and radical mastectomy are notorious for causing chronic pain postoperatively. Psychosocial contributors like ‘psychological vulnerability’ preoperatively, and depression and anxiety postoperatively have been implicated[26]. Treatment or attenuation of anxiety and depression could thus be a vital component of perioperative pain control when considering longer term outcomes. Increased pain intensity is also a risk factor for chronic pain development. Treating acute pain is therefore vital for preventing chronicity.




    Pain is one of the commonest symptoms for which patients seek medical attention. Depression and anxiety symptoms are important to consider not only in primary healthcare settings and pain clinics but also in hospital and palliative care settings. They must be borne in mind not only in adults but in children too. The education of patients of the role of depression and anxiety in pain is paramount, but awareness of these issues by healthcare professionals in all disciplines is the preceding and necessary step for good quality patient management.


    The Endocannabinoid System


    What is the ECS?


    The significance of the ECS, or the endocannabinoid system, has just recently been realized and is currently being referred to as the most essential body system which you may have never heard of. Although the ECS is one of the principal systems in the body, it is not an isolated structural system like the nervous system or the vascular system. Instead, the endocannabinoid system is broadly dispersed throughout the human body and is composed of its own receptor sites, similar to little docking stations, which can in turn be found on nearly every organ in the human body.


    What does the ECS do?


    The ECS is the human body’s main regulatory system. It’s like an inner balancing mechanism, constantly keeping a wide range of bodily functions in equilibrium. The body produces its own endocannabinoids which modulate different biological processes throughout the body, providing these endocannabinoids with a variety of ranging consequences on everything from fertility to pain. Cannabinoid receptors can be found in the brain, nervous system, GI, or gastrointestinal, tract, bones, immune system, skin, and nearly every other organ in the body. Furthermore, the ECS helps regulate:


    • Appetite
    • Bone health
    • Caloric metabolism
    • Fertility
    • Immune function
    • Inflammation
    • Mood
    • Memory
    • Pain sensation
    • Skin health
    • Sleep
    • Stress response


    Are There Any Plant Sources of Cannabinoids?


    To put it simply, yes. We now know that many animals, from fish to birds to mammals, have their own ECS. Additionally, it’s well understood that while humans make their own cannabinoids which interact with the ECS, known as endocannabinoids, there are also compounds which interact with the ECS that are found in an assortment of plants and foods, known as phytocannabinoids. These plant-based cannabinoids either directly attach to, and also have an effect on, cannabinoid receptors, or they may even have an influence on the metabolism of endocannabinoids produced within the body. These can ultimately slow down their destruction, keeping them within the body longer.


    Cannabis cultivated as hemp contains numerous phytocannabinoids, including tetrahydrocannabinolic acid, or THCA, cannabidiol, or CBD, tetrahydrocannabivarin, or THCV, cannabigerol, or CBG, cannabinol, or CBN, among many others. Common non-cannabis plants which contain phytocannabinoids include black pepper, clove, Echinacea, green tea, Panax ginseng, and black truffles. Within nature, chemical substances rarely act in isolation, and this is particularly true of both phytocannabinoids, which actually work together in a carefully coordinated manner.


    What is the Distinction Between Hemp and Marijuana?


    Hemp and marijuana are basically different cultivars of the same plant, Cannabis sativa L. A cultivar is a plant type that has been made or cultivated through a process of selective breeding. Marijuana is a sort of cannabis that has been bred to concentrate high levels of the psychoactive chemical, THC, or tetrahydrocannabinoid, for recreational and medicinal use, often containing about 18 percent  of THC. Conversely, hemp is a version of cannabis that is primarily utilized in clothing, paper, biofuels, bio-plastics, dietary supplements, cosmetics, and foods. Hemp contains less than 0.3 percent of THC as measured in the dried flowering tops.


    In conclusion, recent research studies have found a strong connection between the psychology of chronic pain, especially the relationship between anxiety, depression and pain. For individuals with mental health issues, chronic pain can be a common symptoms which may or may not be directly associated with their specific condition. Fortunately, patients can successfully manage their anxiety, depression and chronic pain through a variety of treatments. The purpose of the article above is to demonstrate the connection between anxiety, depression and chronic pain as well as to discuss the significance of the endocannabinoid system, or ECS, and the use of cannabinoids as chronic pain treatment. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    2. Magni G, Marchetti M, Moreschi C, Merskey H, Luchini SR. Chronic musculoskeletal pain and depression symptoms in the national health and nutrition examination I. Epidemiologic follow-up study. Pain 1993; 53(2): 163–8. [PubMed]
    3. Wilson KG, Eriksson MY, Joyce L, Mikail SF, Emery PC. Major depression and insomnia in chronic pain. Clin J Pain 2002; 18: 77–83. [PubMed]
    4. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med 2003; 163(20): 2433–45. [PubMed]
    5. Taylor R, Lovibond PF, Nicholas MK, Cayley C, Wilson PH. The utility of somatic items in the assessment of depression in patients with chronic pain: a comparison of the zung self-rating depression scale and the depression anxiety stress scales in chronic pain and clinical and community samples. Clin J Pain 2005; 21(1): 91–100. [PubMed]
    6. Pincus T, Williams AC, Vogel S, Field A. The development and testing of the depression, anxiety, and positive outlook scale (DAPOS). Pain 2004; May 109 (1–2): 181–8. [PubMed]
    7. von Korff M, Le Resche L, Dworkin SF. First onset of common pain symptoms: a prospective study of depression as a risk factor. Pain 1993; 55(2): 251–8. [PubMed]
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    10. Worz R. Pain in depression, depression in pain. Pain Clinical Updates 2003; IASP Vol XI, No. 5.
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    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news


    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



    The post Depression and Anxiety in Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 Dr-Jimenez_White-Coat_01.png Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17652
    The Psychology of Chronic Pain Tue, 03 Jul 2018 19:29:26 +0000

    The perception of pain involves a lot more complex processes than mere feeling. As a matter of fact, the affective and evaluative elements of pain tend to be as significant as the creation and transmission of the pain signal itself. These emotional as well as psychological aspects are most prominent in chronic pain sufferers, but knowledge of the psychology of this type of persistent pain can help greatly enhance the treatment of chronic pain.


    Perception of Pain


    The limbic system, where emotions and/or feelings are processed, is in charge of regulating the amount of pain experienced for a given noxious stimulus. It has been proven in cancer patients [1] that their affective part of pain can be completely blocked by frontal lobectomy. Lobectomized patients still register intense pain, however, it doesn't "bother" them. Pain can thus be seen as only a "signal" demonstrat

    The post The Psychology of Chronic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    The perception of pain involves a lot more complex processes than mere feeling. As a matter of fact, the affective and evaluative elements of pain tend to be as significant as the creation and transmission of the pain signal itself. These emotional as well as psychological aspects are most prominent in chronic pain sufferers, but knowledge of the psychology of this type of persistent pain can help greatly enhance the treatment of chronic pain.


    Perception of Pain


    The limbic system, where emotions and/or feelings are processed, is in charge of regulating the amount of pain experienced for a given noxious stimulus. It has been proven in cancer patients [1] that their affective part of pain can be completely blocked by frontal lobectomy. Lobectomized patients still register intense pain, however, it doesn’t “bother” them. Pain can thus be seen as only a “signal” demonstrating that something has gone wrong somewhere in the body, until it reaches the mental performance element of the brain, where this signal becomes what we believe to be perceived as pain.


    The emotional response to pain in the brain requires the function of the anterior cingulate gyrus and the perfect ventral prefrontal cortex. These centers are also activated by social rejection. Serotonin and norepinephrine circuits are also included in the modulation of sensory stimulation, which probably influence how depression and antidepressant drugs and/or medications affect the perception of pain.[2]


    Even the perception of acute pain is highly determined by the context in which it occurs [3]. It’s been revealed that the pain involving battle wounds bears very little connection to the degree of the wounds [4]. There are reports of soldiers in conflict who endure a compound fracture, and report just twinges of pain [5]. In research studies of experimental pain in which context, fear, and anxiety are controlled, the placebo effect and opioids are much less effective. This occurs because the decrease of both the fear and anxiety is a large region of the placebo effect and also the purpose of opioids [6].




    Focusing one’s attention on pain is often believed to make the symptoms worse [1]. Patients that have somatic preoccupation or hypochondriasis are overaware about physiological senses. It’s been found that by attending these sensations, they amplify them towards the purpose of feeling painful [7].


    Conversely, distracting patients is highly effective in reducing their pain. Burn patients undergoing therapies or physical treatment experience excruciating pain, even after they have been given opioids. It has been proven that these patients report only a portion of the pain if they are distracted using a virtual-reality kind of videogame during the process [8].




    Anxiety, stress, fear, and a feeling of loss of control leads to individual suffering. Treating anxiety and supplying emotional support was shown to improve pain and decrease analgesic use in patients. Improving patients’ sense of control and allowing them to participate in their care can also be useful [9]. Healthcare professionals should try to make an environment that’s nonthreatening. For procedures, prepare needles and other gear out of sight from the patient. Besides assuring that procedures are performed in the least painful way possible, use nonthreatening words such as “mild discomfort” rather than “pain”. It’s also helpful to divert patients with dialog about subjects that interest them, such as their hobbies or household [10].




    Patients with low levels of pain remember it as being worse than they originally reported, which will worsen with time. Almost all patients report relief with treatment, even when true measured changes in pain scale are not significant, and occasionally when quantified pain is much worse, and it’s all often due to the memory of their pain [11].


    Learned Pain


    Pain can be a learned response, rather than a purely physical health issue. As cancer sufferers may develop nausea as a learned reaction to treatment and report feeling it even before chemotherapy is administered, patients can learn to get pain even in the absence of a physical stimulation [12]. Sometimes, pain can be completely “in the head,” as in the case of a butcher who slipped and caught his arm on a meat hook, and had been reported to be in tremendous distress. When he learned that the hook had simply captured on to his sleeve and his arm was uninjured, his pain solved [13].


    Patients may learn how to feel different levels of pain by simply watching different men and women. When research study subjects were shown models demonstrating high pain tolerance, they took 3.48 times higher stimulus before they ranked it as painful, in comparison with those that observed models who showed poor tolerance. Nonaversive shock, usually called “tingling,” was rated as painful by just 3 percent of those who had viewed a tolerant model, in comparison with 77 percent of those subjects who viewed models who revealed lower levels of tolerance [14].




    Patients’ expectations of how much pain they ought to have also affected how much pain they feel, their response to treatment [15], and whether or not the illness becomes chronic and disabling. The outcomes of minor whiplash injuries are demonstrated to be very variable in various regions. It was attributed to the local cultures and expectations. Any messages that speak with individuals on whether they have a serious or debilitating injury can lead to deconditioning and maladaptive postures that worsens their pain. Prescribing drugs and/or medications can contribute to the issue. Patients who are not given sick leave and are advised to “act as normal” have much better outcomes [7].


    The placebo effect can be influenced by patients’ and doctors’ expectations [15]. It can be assumed that the “nocebo” effect, or the understanding of harm caused by an individual’s beliefs, may also bring about messages that inadvertently increase the patient’s stress, anxiety and expectations of pain.


    Beliefs and Coping


    Other psychosocial problems, such as what patients believe about their pain [16,17], their abilities to manage [18-21], their tendency to “catastrophize” [17,18,20], self-efficacy [17], locus or restrain [22], and their involvement in the “sick role” [13], have an effect on just how much pain patients feel, and the way it ultimately affects them.


    In successfully getting low back pain sufferers back to work, the most crucial factor identified is a decrease in subjective feelings of disability [23]. Patients diagnosed with fibromyalgia have to quit catastrophizing to enhance their well-being, and they need to be convinced that they have the capacity to be functional [24]. Consequently, healthcare professionals should focus on improved function and long-term management. Patients should be led to know that they themselves have an essential role in distracting themselves, and they can decrease the disturbance that pain has in their own quality of life.


    Chronic Pain


    Chronic pain patients frequently have issues with the psychological and emotional facets of pain [25]. Preexisting psychological variables have been demonstrated to be very significant in the evolution of chronic pain after surgical interventions [26,27] and in complex regional pain syndrome, or CRPS [28,29], tension-type headaches [30], and fibromyalgia [24]. The National Institutes of Health Technology Assessment Conference Statement [31] identified six factors that related to treatment failures of low back pain, and they were all psychosocial. Even chronic, episodic, low back pain may have a vital component of socioeconomic and psychological influences [32].


    There is a vicious cycle in which pain causes stress and handicap, which in turn worsens the perception of pain [21]. An unhealthy lifestyle, lack of social support, depression, and substance abuse are predisposing factors to chronic pain [33]. Chronic pain has been known to become “complicated” if there are interactions of psychological, legal, drugs and/or medication, and family issues [34].




    Immobility may be a factor in adult “reflex sympathetic dystrophy,” that some healthcare professionals feel is overdiagnosed [35]. A research study of reflex neurovascular dystrophy in children revealed that prominent swelling, skin changes, and decreased skin temperature had been due to maintaining the extremity within an immobile, determined position. The prolonged immobility also caused chronic fibrosis of adrenal tissues and contractures of ligaments and tendons. This was effectively relieved with physical treatments, which included active sensory stimulation and usage of the affected extremity [36].


    Inactivity is a serious impediment to progress in chronic pain, and also may produce concurrent myofascial pain [37]. Many fibromyalgia patients are found to have a vicious cycle of maladaptive pain behavior, resulting in further deconditioning, social dysfunction, and subsequent worsening pain [24].


    Obesity can also be an issue in chronic pain. An overview of patients at a rehab clinic found that among those who could not be returned to gainful employment or function of purpose, 78 percent were morbidly obese [38]. Many lower back pain sufferers have been found to be in the lowest quartile for aerobic capacity [39].


    Pain behavior, like guarding, bracing, rubbing, grimacing, and sighing, was shown to be strongly affected by emotional factors [40]. Some chronic pain sufferers demonstrate pain behavior only around staff [41], or decrease this behaviour when they think nobody is watching [42]. Reinforcing this behavior can cause some patients to perceive that they have more pain. Eliminating the behavior leads to improved pain [40]. It’s been noted that when neuropathic pain sufferers are allowed to develop behavioral and guarding disorder, then drugs and/or medications aren’t successful, and the patients need multidisciplinary pain therapy [37].


    Pain may be a conditioned response similar to learned nausea related to chemotherapy. The behavior begins purely in response to the existence of harm. It is then reinforced and becomes a conditioned response, an iatrogenic complication of therapy [12], particularly when wages are made contingent on the term of pain behavior [21]. The effect of reinforcement is exemplified by the case of a 10-year-old girl who had chronic daily abdominal pain for which no medical condition could be discovered. During episodes, her mother allowed her to rest in bed together with her toys and view television, and brought her food and drinks. After an hour or so, she would go back to play. After the mother ceased strengthening the patient’s pain behavior, the episodes rapidly diminished, in addition to her use of belladonna and phenobarbital elixir [43].


    Pain can result from conditioned fear reactions which persist even after the settlement of pain [42], phobic reactions to pain and also to nonpainful activities [44], and posttraumatic stress disorder, or PTSD [45]. Some individuals have experienced good improvement of the pain or work with desensitization therapy [46].


    Psychiatric Disease


    Overall, some psychiatric morbidity is present in around 67 percent of chronic pain patients [47]. Personality disorders have been observed in 31 percent to 59 percent of chronic pain sufferers [48]. Among lower back pain patients admitted to a multidisciplinary pain center, 70 percent were found to have a hysterical conversion disorder, and 8 percent had a sociopathic personality disorder [49].


    Somatoform Pain Disorders


    Somatoform disorders are conditions where the existence of physical symptoms indicates a general medical condition, but cannot be explained by such a condition. One of the somatoform disorders, “pain disorder associated with psychological factors” is specified in the Diagnostic and Statistical Manual of Mental disorders, fourth edition, or DSMIV, [50] as a clinical condition in which pain is the concentration and in which emotional factors have the major role in the onset, severity, maintenance, or exacerbation The epidemiology of the condition isn’t understood, but unexplained chronic pain which causes disability is common in general practice and is often seen in emergency rooms. Pain disorder associated with psychological variables was found in 88 percent of referrals into a pain clinic serving an indigent population [51]. Many somatoform patients had pain which spread to new regions from the site of injury, whereas this did not occur in the patients that had objective signs of injury. Compared with individuals who had severe injuries involving long-term pain, mildly injured somatoform pain patients are over five times as likely to utilize daily opioids [52]. Moreover, one program found a 30 percent prevalence of abuse of opioids among those patients that had somatoform pain disorder, many times greater than that of the other patients [53].


    Hypochondriasis, another sort of somatoform disorder that involves anxiety about having a disease if there is none, has also been diagnosed with chronic pain patients [54]. It’s been found to be worsened by the chronic medical use of morphine [55], and by its own abuse [56].


    Mood Disorders


    In a report on chronic pain patients on opioids, 61 percent have been found to have major depression [57]. It looks like the pain causes depression at least as frequently as depression causes pain [58,59]. However, depression is proven to make the individual’s pain feel worse [48]. In postsurgical pain after cholecystectomy, patients who had subclinical depressive symptoms reported greater pain [60]. Treating depression can improve, and sometimes eliminate, chronic pain [6]. Whether depression is regarded as a cause or an effect of chronic pain, then it needs to be considered at a comorbid condition which needs concurrent therapy [61].


    An anxiety disorder was found in 10.6 percent of chronic work-related musculoskeletal pain patients [62]. The lifetime risk of a major anxiety disorder in men who have chronic low back pain is 30.9 percent, compared with 14.3 percent in men who do not have low back pain [59]. It’s likely that some “chronic pain” sufferers are actually using antipsychotic drugs to self-treat anxiety or depression, rather than relying on more effective anxiolytic or antidepressant agents [57]. These patients aren’t merely using the incorrect medication for their condition, but what small subjective advantage they originally feel is rapidly lost with endurance, and substituted with dependence.




    Due to the influence of psychological variables on chronic pain, at least brief screening needs to be performed on first evaluation. It’s very beneficial to test for Waddell signs or nonphysiological findings, which may be accomplished quickly during the physical evaluation and test [63]. A particularly good evaluation is that the application of pressure at the top of the head once the patient is standing, to place strain on the backbone or spine. The low back pain patient who has a somatoform pain disorder will frequently complain of increased pain. If the pain were only of spinal root origin, this maneuver wouldn’t increase it.


    Whenever psychiatric comorbidity is present or suspected, more comprehensive screening should include tests like the Multidimensional Pain Inventory, or MPI, and the Minnesota Multiphasic Personality Inventory 2, or MMPI-2 [21]. This comprehensive testing is generally impractical in the emergency setting, and ideally should be done by a psychiatric consultant acquainted with chronic pain [48]. Although acute care physicians are not very likely to test themselves, they should insure that it has been finished, or it will be carried out as soon as possible. Failing to address emotional health issues in chronic pain patients might lead to prolonged disability in a substantial number of individuals [25].



    Dr. Alex Jimenez’s Insight

    Whether it’s headaches, back pain, arthritis or fibromyalgia, chronic pain is a common and persistent health issue which often lasts for an extended period of time, greatly affecting an individual’s quality of life. Approximately 30 million people in the United States alone suffer from some for of chronic pain, which is influenced by a variety of factors, including a person’s emotions and memory. Many chronic pain patients report a dull ache or even a throbbing pain and it can last months or years for some people. Other common symptoms associated with chronic pain include mood swings, sleep problems and fatigue. As mentioned in the following article, chronic pain can also lead to stress, anxiety, depression and low self-esteem, among other health issues.


    The Psychology of Opioid Dependence


    The topic of opioid dependence in patients complaining of chronic pain is controversial. It should be mentioned that persistent opioid usage, especially in large doses, can make a condition of enhanced pain sensitivity [64]. Patients dependent on daily doses feel worse as soon as the drug and/or medication wears off, and closer to baseline amounts of pain temporarily when they take that, even though the general pain condition fails to improve [65]. These patients may observe opioids as necessary for survival. It may become hard to control using opioids, and they see the emergency room when they run out. They complain of increased pain from ailments that wouldn’t typically call for opioids. The individual who escalates demands for opioids when these are not coming is typically opioid-dependent, and may have issues of problematic use.


    The psychology of this doctor also influences the use of opioids for chronic pain, and the interpretation of the efficacy. Some patients are insistent that specific medicines must be prescribed. They’ll exaggerate the advantages and deny adverse effects. Some physicians have difficulty setting limits. It is quicker and easier to give into the patient’s requirements than to institute another course. The doctor may understand that the prescription is in excess of regular practice, but rationalizes that for this specific patient, nothing else works. The emergency physician can anticipate these problems, and strategy, with consultation if desired, the way to deal with them.


    CBD for Chronic Pain Relief


    Cannabidiol (CBD) oil is used by some individuals with chronic pain. CBD oil may decrease pain, inflammation, and overall discomfort related to many different health conditions. CBD oil is a product. It’s a kind of cannabinoid, a compound found naturally in marijuana and hemp plants. It doesn’t cause the “high” feeling often related to cannabis, which is brought on by another type of cannabinoid called THC. Studies on CBD oil and chronic pain management have shown a fantastic deal of promise. CBD can supply an alternative for those who have chronic pain and also rely on more dangerous, habit-forming drugs and/or medications like opioids. However there should be more research in order to verify the pain-relieving benefits of CBD oil.


    CBD products are not approved by the U.S. Food and Drug Administration (FDA) for any medical condition. They are not controlled like other drugs and/or medications for dose and purity. Researchers believe that the CBD interacts with pain receptors on the brain and immune system. Receptors are miniature proteins attached to your cells which receive chemical signals from different stimulation and assist your cells to react accordingly to a specific stimulus. This produces anti-inflammatory and painkilling effects which help with pain control. This means that CBD oil may benefit people with chronic pain, including chronic low back pain.


    One 2008 research study evaluated how good CBD works to relieve chronic pain. The review looked at studies conducted between the late 1980s and 2007. Based on these reviews, researchers concluded that CBD was successful in total pain management without adverse side effects. They also noted that CBD was valuable in treating insomnia linked to chronic pain. The authors of this study also noted that CBD was helpful in people with multiple sclerosis, or MS.


    Overall, researchers agree that while there is no conclusive data to support CBD oil as the preferred method of pain control, these kinds of goods have a lot of potential. CBD products may be able to offer relief for many individuals that have chronic pain, all without causing intoxication and dependence. Oil versions of CBD might not be as powerful as other forms, and more human studies are required. CBD oil is available in some clinics in areas where its use is lawful.




    Emotional and evaluative problems are fundamental in the evaluation and treatment of pain. Treating the physical pain can leave these issues unresolved, and potentially exacerbate them during reinforcement. Understanding the effect of anxiety, fear, expectations, and attention can help doctors deal more efficiently with acute pain. Psychological issues are especially notable in chronic pain. Though acute care doctors may not be treating those emotional conditions, they could help by referring patients into the proper psychological or multidisciplinary setting. The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez




    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news


    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



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    The Role of Neurogenic Inflammation Mon, 02 Jul 2018 19:59:18 +0000

    Neurogenic inflammation, or NI, is the physiological process where mediators are discharged directly from the cutaneous nerves to commence an inflammatory response. This results in the creation of local inflammatory reactions including, erythema, swelling, temperature increase, tenderness, and pain. Fine unmyelinated afferent somatic C-fibers, which respond to low intensity mechanical and chemical stimulations, are largely responsible for the release of these inflammatory mediators.


    When stimulated, these nerve pathways in the cutaneous nerves release energetic neuropeptides, or substance P and calcitonin gene related peptide (CGRP), rapidly into the microenvironment, triggering a series of inflammatory responses. There is a significant distinction in immunogenic inflammation, that's the very first protective and reparative response made by the immune system when a pathogen e

    The post The Role of Neurogenic Inflammation appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Neurogenic inflammation, or NI, is the physiological process where mediators are discharged directly from the cutaneous nerves to commence an inflammatory response. This results in the creation of local inflammatory reactions including, erythema, swelling, temperature increase, tenderness, and pain. Fine unmyelinated afferent somatic C-fibers, which respond to low intensity mechanical and chemical stimulations, are largely responsible for the release of these inflammatory mediators.


    When stimulated, these nerve pathways in the cutaneous nerves release energetic neuropeptides, or substance P and calcitonin gene related peptide (CGRP), rapidly into the microenvironment, triggering a series of inflammatory responses. There is a significant distinction in immunogenic inflammation, that’s the very first protective and reparative response made by the immune system when a pathogen enters the body, whereas neurogenic inflammation involves a direct connection between the nervous system and the inflammatory responses. Even though neurogenic inflammation and immunologic inflammation can exist concurrently, the two are not clinically indistinguishable. The purpose of the article below is to discuss the mechanism of neurogenic inflammation and the peripheral nervous system’s role in host defense and immunopathology.


    Neurogenic Inflammation – The Peripheral Nervous System’s Role in Host Defense and Immunopathology




    The peripheral nervous and immune systems are traditionally thought of as serving separate functions. This line is, however, becoming increasingly blurred by new insights into neurogenic inflammation. Nociceptor neurons possess many of the same molecular recognition pathways for danger as immune cells and in response to danger, the peripheral nervous system directly communicates with the immune system, forming an integrated protective mechanism. The dense innervation network of sensory and autonomic fibers in peripheral tissues and high speed of neural transduction allows for rapid local and systemic neurogenic modulation of immunity. Peripheral neurons also appear to play a significant role in immune dysfunction in autoimmune and allergic diseases. Therefore, understanding the coordinated interaction of peripheral neurons with immune cells may advance therapeutic approaches to increase host defense and suppress immunopathology.




    Two thousand years ago, Celsus defined inflammation as involving four cardinal signs – Dolor (pain), Calor (heat), Rubor (redness), and Tumor (swelling), an observation indicating that activation of the nervous system was recognized as being integral to inflammation. However, pain has been mainly thought of since then, only as a symptom, and not a participant in the generation of inflammation. In this perspective, we show that the peripheral nervous system plays a direct and active role in modulating innate and adaptive immunity, such that the immune and nervous systems may have a common integrated protective function in host defense and the response to tissue injury, an intricate interaction that also can lead to pathology in allergic and autoimmune diseases.


    Survival of organisms is critically dependent on the capacity to mount a defense against potential harm from tissue damage and infection. Host defense involves both avoidance behavior to remove contact with a dangerous (noxious) environment (a neural function), and active neutralization of pathogens (an immune function). Traditionally, the role of the immune system in combating infective agents and repairing tissue injury has been considered quite distinct from that of the nervous system, which transduces damaging environmental and internal signals into electrical activity to produce sensations and reflexes (Fig. 1). We propose that these two systems are actually components of a unified defense mechanism. The somatosensory nervous system is ideally placed to detect danger. Firstly, all tissues that are highly exposed to the external environment, such as epithelial surfaces of the skin, lungs, urinary and digestive tract, are densely innervated by nociceptors, high threshold pain-producing sensory fibers. Secondly, transduction of noxious external stimuli is almost instantaneous, orders of magnitude quicker than the mobilization of the innate immune system, and therefore may be the “first responder” in host defense.


    Figure 1 Activation Triggers of the Peripheral Nervous System | El Paso, TX Chiropractor
    Figure 1: Noxious stimuli, microbial and inflammatory recognition pathways trigger activation of the peripheral nervous system. Sensory neurons possess several means of detecting the presence of noxious/harmful stimuli. 1) Danger signal receptors, including TRP channels, P2X channels, and danger associated molecular pattern (DAMP) receptors recognize exogenous signals from the environment (e.g. heat, acidity, chemicals) or endogenous danger signals released during trauma/tissue injury (e.g. ATP, uric acid, hydroxynonenals). 2) Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs) recognize Pathogen associated molecular patterns (PAMPs) shed by invading bacteria or viruses during infection. 3) Cytokine receptors recognize factors secreted by immune cells (e.g. IL-1beta, TNF-alpha, NGF), which activate map kinases and other signaling mechanisms to increase membrane excitability.


    In addition to orthodromic inputs to the spinal cord and brain from the periphery, action potentials in nociceptor neurons can also be transmitted antidromically at branch points back down to the periphery, the axon reflex. These together with sustained local depolarizations lead to a rapid and local release of neural mediators from both peripheral axons and terminals (Fig. 2) 1. Classic experiments by Goltz (in 1874) and by Bayliss (in 1901) showed that electrically stimulating dorsal roots induces skin vasodilation, which led to the concept of a “neurogenic inflammation”, independent of that produced by the immune system (Fig. 3).


    Figure 2 Neuronal Factors Released from Nociceptor Sensory Neurons | El Paso, TX Chiropractor
    Figure 2: Neuronal factors released from nociceptor sensory neurons directly drive leukocyte chemotaxis, vascular hemodynamics and the immune response. When noxious stimuli activate afferent signals in sensory nerves, antidromic axon reflexes are generated that induce the release of neuropeptides at the peripheral terminals of the neurons. These molecular mediators have several inflammatory actions: 1) Chemotaxis and activation of neutrophils, macrophages and lymphocytes to the site of injury, and degranulation of mast cells. 2) Signaling to vascular endothelial cells to increase blood flow, vascular leakage and edema. This also allows easier recruitment of inflammatory leukocytes. 3) Priming of dendritic cells to drive subsequent T helper cell differentiation into Th2 or Th17 subtypes.


    Figure 3 Timeline of Advances in Neurogenic Inflammation | El Paso, TX Chiropractor
    Figure 3: Timeline of advances in understanding of the neurogenic aspects of inflammation from Celsus to the present day.


    Neurogenic inflammation is mediated by the release of the neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP) from nociceptors, which act directly on vascular endothelial and smooth muscle cells 2–5. CGRP produces vasodilation effects 2, 3, whereas SP increases capillary permeability leading to plasma extravasation and edema 4, 5, contributing to the rubor, calor and tumor of Celsus. However, nociceptors release many additional neuropeptides (online database:, including Adrenomedullin, Neurokinins A and B, Vasoactive intestinal peptide (VIP), neuropeptide (NPY), and gastrin releasing peptide (GRP), as well as other molecular mediators such as glutamate, nitric oxide (NO) and cytokines such as eotaxin 6.


    We now appreciate that the mediators released from sensory neurons in the periphery not only act on the vasculature, but also directly attract and activate innate immune cells (mast cells, dendritic cells), and adaptive immune cells (T lymphocytes) 7–12. In the acute setting of tissue damage, we conjecture that neurogenic inflammation is protective, facilitating physiological wound healing and immune defense against pathogens by activating and recruiting immune cells. However, such neuro-immune communications also likely play major roles in the pathophysiology of allergic and autoimmune diseases by amplifying pathological or maladaptive immune responses. In animal models of rheumatoid arthritis for example, Levine and colleagues have shown that denervation of the joint leads to a striking attenuation in inflammation, that is dependent on neural expression of substance P 13, 14. In recent studies of allergic airway inflammation, colitis and psoriasis, primary sensory neurons play a central role in initiating and augmenting the activation of innate and adaptive immunity 15–17.


    We propose therefore, that the peripheral nervous system not only plays a passive role in host defense (detection of noxious stimuli and initiation of avoidance behavior), but also an active role in concert with the immune system in modulating the responses to and combat of harmful stimuli, a role that can be subverted to contribute to disease.


    Shared Danger Recognition Pathways in the Peripheral Nervous and Innate Immune Systems


    Peripheral sensory neurons are adapted to recognize danger to the organism by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli (Fig. 1). Transient receptor potential (TRP) ion channels are the most widely studied molecular mediators of nociception, conducting non-selective entry of cations upon activation by various noxious stimuli. TRPV1 is activated by high temperatures, low pH and capsaicin, the vallinoid irritant component of chili peppers 18. TRPA1 mediates the detection of reactive chemicals including environmental irritants such as tear gas and industrial isothiocyanates 19, but more importantly, it is also activated during tissue injury by endogenous molecular signals including 4-hydroxynonenal and prostaglandins 20, 21.


    Interestingly, sensory neurons share many of the same pathogen and danger molecular recognition receptor pathways as innate immune cells, which enable them also to detect pathogens (Fig. 1). In the immune system, microbial pathogens are detected by germline encoded pattern recognition receptors (PRRs), which recognize broadly conserved exogenous pathogen-associated molecular patterns (PAMPs). The first PRRs to be identified were members of toll-like receptor (TLR) family, which bind to yeast, bacterial derived cell-wall components and viral RNA 22. Following PRR activation, downstream signaling pathways are turned on that induce cytokine production and activation of adaptive immunity. In addition to TLRs, innate immune cells are activated during tissue injury by endogenous derived danger signals, also known as damage-associated molecular patterns (DAMPs) or alarmins 23, 24. These danger signals include HMGB1, uric acid, and heat shock proteins released by dying cells during necrosis, activating immune cells during non-infectious inflammatory responses.


    PRRs including TLRs 3, 4, 7, and 9 are expressed by nociceptor neurons, and stimulation by TLR ligands leads to induction of inward currents and sensitization of nociceptors to other pain stimuli 25–27. Furthermore, activation of sensory neurons by the TLR7 ligand imiquimod leads to activation of an itch specific sensory pathway 25. These results indicate that infection-associated pain and itch may be partly due to direct activation of neurons by pathogen-derived factors, which in turn activate immune cells through peripheral release of neuronal signaling molecules.


    A major DAMP/alarmin released during cellular injury is ATP, which is recognized by purinergic receptors on both nociceptor neurons and immune cells 28–30. Purinergic receptors are made up of two families: P2X receptors, ligand-gated cation channels, and P2Y receptors, G-protein coupled receptors. In nociceptor neurons, recognition of ATP occurs through P2X3, leading to rapidly densensitizing cation currents and pain 28, 30 (Fig. 1), while P2Y receptors contribute to nociceptor activation by sensitization of TRP and voltage-gated sodium channels. In macrophages, ATP binding to P2X7 receptors leads to hyperpolarization, and downstream activation of the inflammasome, a molecular complex important in generation of IL-1beta and IL-18 29. Therefore, ATP is a potent danger signal that activates both peripheral neurons and innate immunity during injury, and some evidence even suggests that neurons express parts of the inflammasome molecular machinery 31.


    The flip side of danger signals in nociceptors is the role of TRP channels in immune cell activation. TRPV2, a homologue of TRPV1 activated by noxious heat, is expressed at high levels in innate immune cells 32. Genetic ablation of TRPV2 led to defects in macrophage phagocytosis and clearance of bacterial infections 32. Mast cells also express TRPV channels, which may directly mediate their degranulation 33. It remains to be determined whether endogenous danger signals activate immune cells in a similar manner as nociceptors.


    A key means of communication between immune cells and nociceptor neurons are through cytokines. Upon activation of cytokine receptors, signal transduction pathways are activated in sensory neurons leading to downstream phosphorylation of membrane proteins including TRP and voltage-gated channels (Fig. 1). The resulting sensitization of nociceptors means that normally innocuous mechanical and heat stimuli can now activate nociceptors. Interleukin 1 beta and TNF-alpha are two important cytokines released by innate immune cells during inflammation. IL-1beta and TNF-alpha are directly sensed by nociceptors which express the cognate receptors, induce activation of p38 map kinases leading to increased membrane excitability 34–36. Nerve growth factor (NGF) and prostaglandin E(2) are also major inflammatory mediators released from immune cells that act directly on peripheral sensory neurons to cause sensitization. An important effect of nociceptor sensitization by immune factors is an increased release of neuropeptides at peripheral terminals that further activate immune cells, thereby inducing a positive feedback loop that drives and facilitates inflammation.


    Sensory Nervous System Control of Innate and Adaptive Immunity


    In early phases of inflammation, sensory neurons signal to tissue resident mast cells and dendritic cells, which are innate immune cells important in initiating the immune response (Fig. 2). Anatomical studies have shown a direct apposition of terminals with mast cells, as well as with dendritic cells, and the neuropeptides released from nociceptors can induce degranulation or cytokine production in these cells 7, 9, 37. This interaction plays an important role in allergic airway inflammation and dermatitis 10–12.


    During the effector phase of inflammation, immune cells need to find their way to the specific site of injury. Many mediators released from sensory neurons, neuropeptides, chemokines, and glutamate, are chemotactic for neutrophils, eosinophils, macrophages, and T-cells, and enhance endothelial adhesion which facilitates immune cell homing 6, 38–41 (Fig. 2). Furthermore, some evidence implies that neurons may directly participate in the effector phase, as neuropeptides themselves may have direct antimicrobial functions 42.


    Neuronally derived signaling molecules can also direct the type of inflammation, by contributing to the differentiation or specification of different types of adaptive immune T cells. An antigen is phagocytosed and processed by innate immune cells, which then migrate to the nearest lymph node and present the antigenic peptide to naïve T cells. Depending on the type of antigen, costimulatory molecules on the innate immune cell, and the combinations of specific cytokines, naïve T cells mature into specific subtypes that best serve the inflammatory effort to clear the pathogenic stimulus. CD4 T cells, or T helper (Th) cells, can be divided into four principle groups, Th1, Th2, Th17, and T regulatory cells (Treg). Th1 cells are mainly involved in regulating immune responses to intracellular microorganisms and organ-specific autoimmune diseases; Th2 are critical for immunity against extracellular pathogens, such as helminths, and are responsible for allergic inflammatory diseases; Th17 cells play a central role in protection against microbial challenges, such as extracellular bacteria and fungi; Treg cells are involved in maintaining self tolerance and regulating immune responses. This T cell maturation process appears to be heavily influenced by sensory neuronal mediators. Neuropeptides, such as CGRP and VIP, can bias dendritic cells towards a Th2-type immunity and reduce Th1-type immunity by promoting the production of certain cytokines and inhibiting others, as well as by reducing or enhancing dendritic cell migration to local lymph nodes 8, 10, 43. Sensory neurons also contribute considerably to allergic (mainly Th2 driven) inflammation 17. In addition to regulating Th1 and Th2 cells, other neuropeptides, such as SP and Hemokinin-1, can drive the inflammatory response more toward Th17 or Treg 44, 45, which means that neurons may also be involved in regulating inflammatory resolution. In immunopathologies such as colitis and psoriasis, blockade of neuronal mediators like substance P may significantly dampen T cell and immune mediated damage 15–17, although antagonizing one mediator may by itself only have a limited effect on neurogenic inflammation.


    Considering that signaling molecules released from peripheral sensory nerve fibers regulate not only small blood vessels, but also the chemotaxis, homing, maturation, and activation of immune cells, it is becoming clear that neuro-immune interactions are much more intricate than previously thought (Fig. 2). Furthermore, it is quite conceivable that it is not individual neural mediators but rather specific combinations of signaling molecules released from nociceptors that influence different stages and types of immune responses.


    Autonomic Reflex Control of Immunity


    A role for a cholinergic autonomic nervous system “reflex” circuit in the regulation of peripheral immune responses also appears prominent 46. The vagus is the chief parasympathetic nerve connecting the brainstem with visceral organs. Work by Kevin Tracey and others point to potent generalized anti-inflammatory responses in septic shock and endotoxemia, triggered by an efferent vagal nerve activity leading to a suppression of peripheral macrophages 47–49. The vagus activates peripheral adrenergic celiac ganglion neurons innervating the spleen, leading to the downstream release of acetylcholine, which binds to alpha-7 nicotinic receptors on macrophages in the spleen and gastrointestinal tract. This induces activation of the JAK2/STAT3 SOCS3 signaling pathway, which powerfully suppresses TNF-alpha transcription 47. The adrenergic celiac ganglion also directly communicates with a subset of acetylcholine producing memory T cells, which suppress inflammatory macrophages 48.


    Invariant natural Killer T cells (iNKT) are a specialized subset of T cells that recognize microbial lipids in the context of CD1d instead of peptide antigens. NKT cells are a key lymphocyte population involved in the combat of infectious pathogens and regulation of systemic immunity. NKT cells reside and traffic mainly through the vasculature and sinusoids of the spleen and liver. Sympathetic beta-adrenergic nerves in the liver directly signal to modulate NKT cell activity 50. During a mouse model of stroke (MCAO), for example, liver NKT cell mobility was visibly suppressed, which was reversed by sympathetic denervation or beta-adrenergic antagonists. Furthermore, this immunosuppressive activity of noradrenergic neurons on NKT cells led to increases in systemic infection and lung injury. Therefore, efferent signals from autonomic neurons can mediate a potent immuno-suppression.



    Dr. Alex Jimenez’s Insight

    Neurogenic inflammation is a local inflammatory response generated by the nervous system. It is believed to play a fundamental role in the pathogenesis of a variety of health issues, including, migraine, psoriasis, asthma, fibromyalgia, eczema, rosacea, dystonia and multiple chemical sensitivity. Although neurogenic inflammation associated with the peripheral nervous system has been extensively researched, the concept of neurogenic inflammation within the central nervous system still needs further research. According to several research studies, however, magnesium deficiencies are believed to be the main cause for neurogenic inflammation. The following article demonstrates an overview of the mechanisms of neurogenic inflammation in the nervous system, which may help healthcare professionals determine the best treatment approach to care for a variety of health issues associated with the nervous system.




    What are the respective specific roles of the somatosensory and autonomic nervous systems in regulating inflammation and the immune system (Fig. 4)? Activation of nociceptors leads to local axon reflexes, which locally recruit and activate immune cells and is therefore, mainly pro-inflammatory and spatially confined. In contrast, autonomic stimulation leads to a systemic immunosuppression by affecting pools of immune cells in liver and spleen. The afferent signaling mechanisms in the periphery leading to the triggering of the immunosuppressive vagal cholinergic reflex circuit are poorly understood. However, 80–90% of vagal fibers are primary afferent sensory fibers, and therefore signals from the viscera, many potentially driven by immune cells, may lead to activation of interneurons in the brainstem and through them to an output in efferent vagal fibers 46.


    Figure 4 Sensory and Autonomic Nervous Systems | El Paso, TX Chiropractor
    Figure 4: Sensory and autonomic nervous systems modulate local and systemic immune responses respectively. Nociceptors innervating epithelial surfaces (e.g. skin and lung) induce localized inflammatory responses, activating mast cells and dendritic cells. In allergic airway inflammation, dermatitis and rheumatoid arthritis, nociceptor neurons play a role in driving inflammation. By contrast, autonomic circuits innervating the visceral organs (e.g. spleen and liver) regulate systemic immune responses by blocking macrophage and NKT cell activation. In stroke and septic endotoxemia, these neurons play an immunosuppressive role.


    Typically, the time course and nature of inflammation, whether during infection, allergic reactions, or auto-immune pathologies, is defined by the categories of immune cells involved. It will be important to know what different types of immune cells are regulated by sensory and autonomic signals. A systematic assessment of what mediators can be released from nociceptors and autonomic neurons and the expression of receptors for these by different innate and adaptive immune cells might help address this question.


    During evolution, similar danger detection molecular pathways have developed for both innate immunity and nociception even though the cells have completely different developmental lineages. While PRRs and noxious ligand-gated ion channels are studied separately by immunologists and neurobiologists, the line between these two fields is increasingly blurred. During tissue damage and pathogenic infection, release of danger signals are likely to lead to a coordinated activation of both peripheral neurons and immune cells with complex bidirectional communication, and an integrated host defense. The anatomical positioning of nociceptors at the interface with the environment, the speed of neural transduction and their ability to release potent cocktails of immune-acting mediators allows the peripheral nervous system to actively modulate the innate immune response and coordinate downstream adaptive immunity. Conversely, nociceptors are highly sensitive to immune mediators, which activate and sensitize the neurons. Neurogenic and immune-mediated inflammation are not, therefore, independent entities but act together as early warning devices. However, the peripheral nervous system also plays an important role in the pathophysiology, and perhaps etiology, of many immune diseases like asthma, psoriasis, or colitis because its capacity to activate the immune system can amplify pathological inflammation 15–17. Treatment for immune disorders may need to include, therefore, the targeting of nociceptors as well as of immune cells.




    We thank the NIH for support (2R37NS039518).


    In conclusion, understanding the role of neurogenic inflammation when it comes to host defense and immunopathology is essential towards determining the proper treatment approach for a variety of nervous system health issues. By looking at the interactions of the peripheral neurons with immune cells, healthcare professionals may advance therapeutic approaches to further help increase host defense as well as suppress immunopathology. The purpose of the article above is to help patients understand the clinical neurophysiology of neuropathy, among other nerve injury health issues. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news



    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



    The post The Role of Neurogenic Inflammation appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 Figure 1 Activation Triggers of the Peripheral Nervous System | El Paso, TX Chiropractor Figure 2 Neuronal Factors Released from Nociceptor Sensory Neurons | El Paso, TX Chiropractor Figure 3 Timeline of Advances in Neurogenic Inflammation | El Paso, TX Chiropractor Dr-Jimenez_White-Coat_01.png Figure 4 Sensory and Autonomic Nervous Systems | El Paso, TX Chiropractor Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17602
    Overview of the Pathophysiology of Neuropathic Pain Thu, 28 Jun 2018 23:14:01 +0000

    Neuropathic pain is a complex, chronic pain condition that is generally accompanied by soft tissue injury. Neuropathic pain is common in clinical practice and also poses a challenge to patients and clinicians alike. With neuropathic pain, the nerve fibers themselves may be either damaged, dysfunctional or injured. Neuropathic pain is the result of damage from trauma or disease to the peripheral or central nervous system, where the lesion may occur at any site. As a result, these damaged nerve fibers can send incorrect signals to other pain centers. The effect of a nerve fiber injury consists of a change in neural function, both at the region of the injury and also around the injury. Clinical signs of neuropathic pain normally include sensory phenomena, such as spontaneous pain, paresthesias and hyperalgesia.

    The post Overview of the Pathophysiology of Neuropathic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Neuropathic pain is a complex, chronic pain condition that is generally accompanied by soft tissue injury. Neuropathic pain is common in clinical practice and also poses a challenge to patients and clinicians alike. With neuropathic pain, the nerve fibers themselves may be either damaged, dysfunctional or injured. Neuropathic pain is the result of damage from trauma or disease to the peripheral or central nervous system, where the lesion may occur at any site. As a result, these damaged nerve fibers can send incorrect signals to other pain centers. The effect of a nerve fiber injury consists of a change in neural function, both at the region of the injury and also around the injury. Clinical signs of neuropathic pain normally include sensory phenomena, such as spontaneous pain, paresthesias and hyperalgesia.


    Neuropathic pain, as defined by the International Association of the Study of Pain or the IASP, is pain initiated or caused by a primary lesion or dysfunction of the nervous system. It could result from damage anywhere along the neuraxis: peripheral nervous system, spinal or supraspinal nervous system. Traits that distinguish neuropathic pain from other kinds of pain include pain and sensory signs lasting beyond the recovery period. It’s characterized in humans by spontaneous pain, allodynia, or the experience of non-noxious stimulation as painful, and causalgia, or persistent burning pain. Spontaneous pain includes sensations of “pins and needles”, burning, shooting, stabbing and paroxysmal pain, or electric-shock like pain, often associated with dysesthesias and paresthesias. These sensations not only alter the patient’s sensory apparatus, but also the patient’s well-being, mood, attention and thinking. Neuropathic pain is made up of both “negative” symptoms, such as sensory loss and tingling sensations, and “positive” symptoms, such as paresthesias, spontaneous pain and increased feeling of pain.


    Conditions frequently related to neuropathic pain can be classified into two major groups: pain due to damage in the central nervous system and pain because of damage to the peripheral nervous system. Cortical and sub-cortical strokes, traumatic spinal cord injuries, syringo-myelia and syringobulbia, trigeminal and glossopharyngeal neuralgias, neoplastic and other space-occupying lesions are clinical conditions that belong to the former group. Nerve compression or entrapment neuropathies, ischemic neuropathy, peripheral polyneuropathies, plexopathies, nerve root compression, post-amputation stump and phantom limb pain, postherpetic neuralgia and cancer-related neuropathies are clinical conditions that belong to the latter group.


    Pathophysiology of Neuropathic Pain


    The pathophysiologic processes and concepts underlying neuropathic pain are multiple. Prior to covering these processes, a review of ordinary pain circuitry is critical. Regular pain circuitries involve activation of a nociceptor, also known as the pain receptor, in response to a painful stimulation. A wave of depolarization is delivered to the first-order neurons, together with sodium rushing in via sodium channels and potassium rushing out. Neurons end in the brain stem in the trigeminal nucleus or in the dorsal horn of the spinal cord. It is here where the sign opens voltage-gated calcium channels in the pre-synaptic terminal, allowing calcium to enter. Calcium allows glutamate, an excitatory neurotransmitter, to be released into the synaptic area. Glutamate binds to NMDA receptors on the second-order neurons, causing depolarization.


    These neurons cross through the spinal cord and travel until the thalamus, where they synapse with third-order neurons. These then connect to the limbic system and cerebral cortex. There is also an inhibitory pathway that prevents pain signal transmission from the dorsal horn. Anti-nociceptive neurons originate in the brain stem and travel down the spinal cord where they synapse with short interneurons in the dorsal horn by releasing dopamine and norepinephrine. The interneurons modulate the synapse between the first-order neuron as well as the second-order neuron by releasing gamma amino butyric acid, or GABA, an inhibitory neurotransmitter. Consequently, pain cessation is the result of inhibition of synapses between first and second order neurons, while pain enhancement might be the result of suppression of inhibitory synaptic connections.


    Pathophysiology of Neuropathic Pain Diagram | El Paso, TX Chiropractor


    The mechanism underlying neuropathic pain, however, aren’t as clear. Several animal studies have revealed that lots of mechanisms may be involved. However, one has to remember that what applies to creatures may not always apply to people. First order neurons may increase their firing if they’re partially damaged and increase the amount of sodium channels. Ectopic discharges are a consequence of enhanced depolarization at certain sites in the fiber, resulting in spontaneous pain and movement-related pain. Inhibitory circuits might be diminished in the level of the dorsal horn or brain stem cells, as well as both, allowing pain impulses to travel unopposed.


    In addition, there might be alterations in the central processing of pain when, because of chronic pain and the use of some drug and/or medications, second- and third-order neurons can create a “memory” of pain and become sensitized. There’s then heightened sensitivity of spinal neurons and reduced activation thresholds. Another theory demonstrates the concept of sympathetically-maintained neuropathic pain. This notion was demonstrated by analgesia following sympathectomy from animals and people. However, a mix of mechanics can be involved in many chronic neuropathic or mixed somatic and neuropathic pain conditions. Among those challenges in the pain field, and much more so as it pertains to neuropathic pain, is the capability to check it. There is a dual component to this: first, assessing quality, intensity and advancement; and second, correctly diagnosing neuropathic pain.


    There are, however, some diagnostic tools that may assist clinicians in evaluating neuropathic pain. For starters, nerve conduction studies and sensory-evoked potentials may identify and quantify the extent of damage to sensory, but not nociceptive, pathways by monitoring neurophysiological responses to electrical stimuli. Additionally, quantitative sensory testing steps perception in reaction to external stimuli of varying intensities by applying stimulation to the skin. Mechanical sensitivity to tactile stimuli is measured with specialized tools, such as von Frey hairs, pinprick with interlocking needles, as well as vibration sensitivity together with vibrameters and thermal pain with thermodes.


    It is also extremely important to perform a comprehensive neurological evaluation to identify motor, sensory and autonomic dysfunctions. Ultimately, there are numerous questionnaires used to distinguish neuropathic pain in nociceptive pain. Some of them include only interview queries (e.g., the Neuropathic Questionnaire and ID Pain), while others contain both interview questions and physical tests (e.g., the Leeds Assessment of Neuropathic Symptoms and Signs scale) and the exact novel tool, the Standardized Evaluation of Pain, which combines six interview questions and ten physiological evaluations.


    Neuropathic Pain Diagram | El Paso, TX Chiropractor


    Treatment Modalities for Neuropathic Pain


    Pharmacological regimens aim at the mechanisms of neuropathic pain. However, both pharmacologic and non-pharmacologic treatments deliver complete or partial relief in just about half of patients. Many evidence-based testimonials suggest using mixtures of drugs and/or medications to function for as many mechanisms as possible. The majority of studies have researched mostly post-herpetic neuralgia and painful diabetic neuropathies but the results may not apply to all neuropathic pain conditions.




    Antidepressants increase synaptic serotonin and norepinephrine levels, thereby enhancing the effect of the descending analgesic system associated with neuropathic pain. They’ve been the mainstay of neuropathic pain therapy. Analgesic actions might be attributable to nor-adrenaline and dopamine reuptake blockade, which presumably enhance descending inhibition, NMDA-receptor antagonism and sodium-channel blockade. Tricyclic antidepressants, such as TCAs; e.g., amitriptyline, imipramine, nortriptyline and doxepine, are powerful against continuous aching or burning pain along with spontaneous pain.


    Tricyclic antidepressants have been proven significantly more effective for neuropathic pain than the specific serotonin reuptake inhibitors, or SSRIs, such as fluoxetine, paroxetine, sertraline and citalopram. The reason may be that they inhibit reuptake of serotonin and nor-epinephrine, while SSRIs only inhibit serotonin reuptake. Tricyclic antidepressants can have unpleasant side effects, including nausea, confusion, cardiac conduction blocks, tachycardia and ventricular arrhythmias. They can also cause weight gain, a reduced seizure threshold and orthostatic hypotension. Tricyclics have to be used with care in the elderly, who are particularly vulnerable to their acute side effects. The drug concentration in the blood should be monitored to avoid toxicity in patients who are slow medication metabolizers.


    Serotonin-norepinephrine reuptake inhibitors, or SNRIs, are a new class of antidepressants. Like TCAs, they seem to be more effective than SSRIs for treating neuropathic pain because they also inhibit reuptake of both nor-epinephrine and dopamine. Venlafaxine is as effective against debilitating polyneuropathies, such as painful diabetic neuropathy, as imipramine, in the mention of TCA, and the two are significantly greater than placebo. Like the TCAs, the SNRIs seem to confer benefits independent of their antidepressant effects. Side effects include sedation, confusion, hypertension and withdrawal syndrome.


    Antiepileptic Drugs


    Antiepileptic drugs can be utilized as first-line treatment especially for certain types of neuropathic pain. They act by modulating voltage-gated calcium and sodium channels, by improving the inhibitory effects of GABA and by inhibiting excitatory glutaminergic transmission. Anti-epileptic medications have not been demonstrated to be effective for acute pain. In chronic pain cases, antiepileptic drugs seem to be effective only in trigeminal neuralgia. Carbamazepine is routinely employed for this condition. Gabapentin, which functions by inhibiting calcium channel function through agonist actions at the alpha-2 delta subunit of the calcium channel, is also known to be effective for neuropathic pain. However, gabapentin acts centrally and it might cause fatigue, confusion and somnolence.


    Non-Opioid Analgesics


    There is a lack of strong data supporting using non-steroidal anti inflammatory medications, or NSAIDs, in the relief of neuropathic pain. This may be due to the lack of an inflammatory component in relieving pain. But they have been utilized interchangeably with opioids as adjuvants in treating cancer pain. There have been reported complications, though, especially in severely debilitated patients.


    Opioid Analgesics


    Opioid analgesics are a subject of much debate in relieving neuropathic pain. They act by inhibiting central ascending pain impulses. Traditionally, neuropathic pain has been previously observed to be opioid-resistant, in which opioids are more suitable methods for coronary and somatic nociceptive types of pain. Many doctors prevent using opioids to treat neuropathic pain, in large part because of concerns about drug abuse, addiction and regulatory issues. But, there are many trials that have found opioid analgesics to succeed. Oxycodone was superior to placebo for relieving pain, allodynia, improving sleep and handicap. Controlled-release opioids, according to a scheduled basis, are recommended for patients with constant pain to encourage constant levels of analgesia, prevent fluctuations in blood glucose and prevent adverse events associated with higher dosing. Most commonly, oral preparations are used because of their greater ease of use and cost-effectiveness. Trans-dermal, parenteral and rectal preparations are generally used in patients who cannot tolerate oral drugs.


    Local Anesthetics


    Nearby acting anesthetics are appealing because, thanks to their regional action, they have minimal side effects. They act by stabilizing sodium channels at the axons of peripheral first-order neurons. They work best if there is only partial nerve injury and excess sodium channels have collected. Topical lidocaine is the best-studied representative of the course for neuropathic pain. Specifically, the use of this 5 percent lidocaine patch for post-herpetic neuralgia has caused its approval by the FDA. The patch seems to work best when there is damaged, but maintained, peripheral nervous system nociceptor function from the involved dermatome demonstrating as allodynia. It needs to be set directly on the symptomatic area for 12 hours and eliminated for another 12 hours and may be used for years this way. Besides local skin reactions, it is often well tolerated by many patients with neuropathic pain.


    Miscellaneous Drugs


    Clonidine, an alpha-2-agonist, was shown to be effective in a subset of patients with diabetic peripheral neuropathy. Cannabinoids have been found to play a role in experimental pain modulation in animal models and evidence of the efficacy is accumulating. CB2-selective agonists suppress hyperalgesia and allodynia and normalize nociceptive thresholds without inducing analgesia.


    Interventional Pain Management


    Invasive treatments might be considered for patients who have intractable neuropathic pain. These treatments include epidural or perineural injections of local anesthetics or corticosteroids, implantation of epidural and intrathecal drug delivery methods and insertion of spinal cord stimulators. These approaches are reserved for patients with intractable chronic neuropathic pain who have failed conservative medical management and also have experienced thorough psychological evaluation. In a study by Kim et al, it was shown that a spinal cord stimulator was effective in treating neuropathic pain of nerve root origin.



    Dr. Alex Jimenez’s Insight

    With neuropathic pain, chronic pain symptoms occur due to the nerve fibers themselves being damaged, dysfunctional or injured, generally accompanied by tissue damage or injury. As a result, these nerve fibers can begin to send incorrect pain signals to other areas of the body. The effects of neuropathic pain caused by nerve fiber injuries includes modifications in nerve function both at the site of injury and at areas around the injury. Understanding the pathophysiology of neuropathic pain has been a goal for many healthcare professionals, in order to effectively determine the best treatment approach to help manage and improve its symptoms. From the use of drugs and/or medications, to chiropractic care, exercise, physical activity and nutrition, a variety of treatment approaches may be used to help ease neuropathic pain for each individual’s needs.


    Additional Interventions for Neuropathic Pain


    Lots of patients with neuropathic pain pursue complementary and alternative treatment options to treat neuropathic pain. Other well-known regimens used to treat neuropathic pain include acupuncture, percutaneous electrical nerve stimulation, transcutaneous electrical nerve stimulation, cognitive behavioral treatment, graded motor imagery and supportive treatment, and exercise. Among these however, chiropractic care is a well-known alternative treatment approach commonly utilized to help treat neuropathic pain. Chiropractic care, along with physical therapy, exercise, nutrition and lifestyle modifications can ultimately offer relief for neuropathic pain symptoms.


    Chiropractic Care


    What is known is that a comprehensive management application is crucial to combat the effects of neuropathic pain. In this manner, chiropractic care is a holistic treatment program that could be effective in preventing health issues associated with nerve damage. Chiropractic care provides assistance to patients with many different conditions, including those with neuropathic pain. Sufferers of neuropathic pain often utilize non-steroidal-anti-inflammatory medications, or NSAIDs, such as ibuprofen, or heavy prescription painkillers to help ease neuropathic pain. These may provide a temporary fix but need constant use to manage the pain. This invariably contributes to harmful side effects and in extreme situations, prescription drug dependence.


    Chiropractic care can help improve symptoms of neuropathic pain and enhance stability without these downsides. An approach such as chiropractic care offers an individualized program designed to pinpoint the root cause of the issue. Through the use of spinal adjustments and manual manipulations, a chiropractor can carefully correct any spinal misalignments, or subluxations, found along the length of the spine, which could lower the consequences of nerve wracking via the realigning of the backbone. Restoring spinal integrity is essential to keeping a high-functioning central nervous system.


    A chiropractor can also be a long-term treatment towards enhancing your overall well-being. Besides spinal adjustments and manual manipulations, a chiropractor may offer nutritional advice, such as prescribing a diet rich in antioxidants, or they may design a physical therapy or exercise program to fight nerve pain flair-ups. A long-term condition demands a long-term remedy, and in this capacity, a healthcare professional who specializes in injuries and/or conditions affecting the musculoskeletal and nervous system, such as a doctor of chiropractic or chiropractor, may be invaluable as they work to gauge favorable change over time.


    Physical therapy, exercise and movement representation techniques have been demonstrated to be beneficial for neuropathic pain treatment. Chiropractic care also offers other treatment modalities which may be helpful towards the management or improvement of neuropathic pain. Low level laser therapy, or LLLT, for instance, has gained tremendous prominence as a treatment for neuropathic pain. According to a variety of research studies, it was concluded that LLLT had positive effects on the control of analgesia for neuropathic pain, however, further research studies are required to define treatment protocols that summarize the effects of low level laser therapy in neuropathic pain treatments.


    Chiropractic care also includes nutritional advice, which can help control symptoms associated with diabetic neuropathy. During a research study, a low fat plant-based diet was demonstrated to improve glycemic control in patients with type 2 diabetes. After about 20 weeks of the pilot study, the individuals involved reported changes in their body weight and electrochemical skin conductance in the foot was reported to have improved with the intervention. The research study suggested a potential value in the low-fat plant-based diet intervention for diabetic neuropathy. Moreover, clinical studies found that the oral application of magnesium L-threonate is capable of preventing as well as restoring memory deficits associated with neuropathic pain.


    Chiropractic care can also offer additional treatment strategies to promote nerve regeneration. By way of instance, enhancing the regeneration of axons has been suggested to help improve functional recovery after peripheral nerve injury. Electrical stimulation, together with exercise or physical activities, was found to promote nerve regeneration after delayed nerve repair in humans and rats, according to recent research studies. Both electrical stimulation and exercise were ultimately determined to be promising experimental treatments for peripheral nerve injury which seem ready to be transferred to clinical use. Further research studies may be needed to fully determine the effects of these in patients with neuropathic pain.




    Neuropathic pain is a multifaceted entity with no particular guidelines to take care of. It’s best managed using a multidisciplinary approach. Pain management requires ongoing evaluation, patient education, ensuring patient follow-up and reassurance. Neuropathic pain is a chronic condition that makes the option for the best treatment challenging. Individualizing treatment involves consideration of the impact of the pain on the individual’s well-being, depression and disabilities together with continuing education and evaluation. Neuropathic pain studies, both on the molecular level and in animal models, is relatively new but very promising. Many improvements are anticipated in the basic and clinical fields of neuropathic pain hence opening the doorways to improved or new treatment modalities for this disabling condition. The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez




    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




    blog picture of cartoon paperboy big news


    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



    The post Overview of the Pathophysiology of Neuropathic Pain appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 Pathophysiology of Neuropathic Pain Diagram | El Paso, TX Chiropractor Neuropathic Pain Diagram | El Paso, TX Chiropractor Dr-Jimenez_White-Coat_01.png Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17574
    What is Neuropathic Pain? Wed, 27 Jun 2018 22:02:32 +0000

    When the sensory system is affected by injury or disease, the nerves within that system can't work properly to transmit sensations and feelings into the brain. This frequently contributes to a feeling of numbness, or lack of sensation. However, in certain cases, when this system is damaged, people may experience pain in the affected area.


    Neuropathic pain does not start abruptly or resolve quickly; it's a chronic pain condition which leads to persistent pain symptoms. For most individuals, the intensity of their symptoms may wax and wane throughout the day. Although neuropathic pain is supposed to be related to peripheral nerve health issues, like neuropathy caused by diabetes or spinal stenosis, injuries to the brain or spinal cord may also lead to chronic neuropathic pain. Neuropathic pain is a

    The post What is Neuropathic Pain? appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    When the sensory system is affected by injury or disease, the nerves within that system can’t work properly to transmit sensations and feelings into the brain. This frequently contributes to a feeling of numbness, or lack of sensation. However, in certain cases, when this system is damaged, people may experience pain in the affected area.


    Neuropathic pain does not start abruptly or resolve quickly; it’s a chronic pain condition which leads to persistent pain symptoms. For most individuals, the intensity of their symptoms may wax and wane throughout the day. Although neuropathic pain is supposed to be related to peripheral nerve health issues, like neuropathy caused by diabetes or spinal stenosis, injuries to the brain or spinal cord may also lead to chronic neuropathic pain. Neuropathic pain is also referred to as nerve pain.


    Neuropathic pain may be contrasted to nociceptive pain. Neuropathic pain does not develop to any specific circumstance or outside stimulus, but rather, the symptoms occur simply because the nervous system may not be working accordingly. As a matter of fact, individuals can also experience neuropathic pain even when the aching or injured body part is not actually there. This condition is called phantom limb pain, which may occur in people after they’ve had an amputation.


    Nociceptive pain is generally acute and develops in response to a specific circumstance, such as when someone experiences a sudden injury, like hammering a finger with a hammer or stubbing a toe when walking barefoot. Moreover, nociceptive pain tends to go away once the affected site heals. The body contains specialized nerve cells, known as nociceptors, which detect noxious stimuli that could damage the body, such as extreme heat or cold, pressure, pinching, and exposure to chemicals. These warning signals are then passed along the nervous system to the brain, resulting in nociceptive pain.


    Neuropathic Pain vs Nociceptive Pain Diagram | El Paso, TX Chiropractor


    What are the Risk Factors for Neuropathic Pain?


    Anything that contributes to a lack of function within the sensory nervous system can lead to neuropathic pain. As such, nerve health issues from carpal tunnel syndrome, or similar conditions, can ultimately trigger neuropathic pain. Trauma, resulting in nerve injury, may lead to neuropathic pain. Other conditions which could predispose individuals to developing neuropathic pain include: diabetes, vitamin deficiencies, cancer, HIV, stroke, multiple sclerosis, shingles, and even some cancer treatments.


    What are the Causes of Neuropathic Pain?


    There are many causes from which individuals may develop neuropathic pain. But on a cellular level, one explanation is an increased release of certain receptors that indicate pain, together with a diminished ability of the nerves to modulate these signals, leads to the sensation of pain originating from the affected region. Additionally, in the spinal cord, the region which exerts painful signs is rearranged with corresponding changes in hormones and loss of normally-functioning mobile bodies. Those alterations result in the perception of pain in the absence of external stimulation. In the brain, the ability to block pain can be affected following an injury, such as stroke or trauma from an injury. As time passes, additional cell damage happens and the feeling of pain continues. Neuropathic pain is also related to diabetes, chronic alcohol intake, certain cancers, vitamin B deficiency, diseases, other nerve-related diseases, toxins, and specific drugs.


    What are the Symptoms of Neuropathic Pain?


    Contrary to other neurological conditions, identification of neuropathic pain can be challenging. However, several, if any, objective signals may be present. Healthcare professionals have to decipher and translate an assortment of words which patients use to describe their pain. Patients may describe their symptoms as sharp, dull, hot, cold, sensitive, itchy, deep, stinging, burning, among a variety of other descriptive terms. Additionally, some patients may experience pain through light touch or pressure.


    In an effort to help identify how much pain patients could be undergoing, different scales are often used. Patients are asked to rate their pain according to a visual scale or numerical graph. Many examples of pain scales exist, such as the one demonstrated below. Often, pictures of faces depicting a variety of levels of pain may be helpful when individuals have a difficult time describing the quantity of pain they are experiencing.


    VAS Scale for Pain Diagram | El Paso, TX Chiropractor


    Chronic Pain and Mental Health


    For many, the impact of chronic pain may not be limited to the pain ; it may also negatively influence their mental state. New research studies conducted by scientists at the Northwestern University in Chicago can explain why individuals who have chronic pain also suffer with seemingly unrelated health issues, such as depression, stress, lack of sleep and difficulty concentrating.


    The evaluation demonstrated that people with chronic pain show different regions of the brain which are always active, most specifically, the area associated with mood and attention. This continuous action rewires nerve connections from the brain and leaves chronic pain sufferers at greater risk for psychological problems. Researchers suggested that getting pain signals constantly could result in mental rewiring that adversely affects the mind. The rewiring compels their brains to devote mental resources differently to deal with everyday tasks, from mathematics, to recalling a shopping list, to feeling happy.


    The pain-brain connection has been well recorded, at least anecdotally, and lots of healthcare professionals say they’ve seen first-hand the way the patient’s mental state can go downhill when they endure chronic pain. Misconceptions about the pain-brain connection may have emerged from a lack of evidence that pain has a measurable, lasting influence on the brain. Researchers expect that with additional research into the mechanisms of how chronic pain makes people more susceptible to mood disorders, people are going to have the ability to better manage their overall well-being.


    Culture and Chronic Pain


    Many things contribute to the way we experience and express pain, however, it has also been recently suggested by researchers that culture relates directly into the expression of pain. Our upbringing and societal values affect how we express pain and also its own nature, intensity and length. However, these variables aren’t as obvious as socio-psychological values, such as age and sex.


    Research states that chronic pain is a multifaceted process and the concurrent interplay between pathophysiology, cognitive, affective, behavioral and sociocultural factors summate to what is referred to as the chronic pain experience. It’s emerged that chronic pain is experienced differently among patients of varied cultures and ethnicities.


    Some cultures encourage the expression of pain, particularly in the southern Mediterranean and Middle East. Other individuals suppress it, as in the many lessons to our kids about behaving bravely and not crying. Pain is recognized as part of the human experience. We are apt to assume that communication about pain will seamlessly cross cultural boundaries. But people in pain are subject to the manners their civilizations have trained them to experience and express pain.


    Both individuals in pain and healthcare professionals experience difficulties communicating pain across ethnic borders. In a matter like pain, where effective communication can have far-reaching implications for medical care, quality of life and potentially survival, the role of culture in pain communicating remains under-evaluated. Persistent pain is a multidimensional, a composite encounter formed by interweaving and co-influencing biological and psychosocial factors. Knowing the culmination of these factors is critical to understanding the differences of its manifestation and management.


    How is Neuropathic Pain Diagnosed?


    The diagnosis of neuropathic pain relies upon additional evaluation of an individual’s history. If underlying nerve damage is suspected, then analysis of the nerves together with testing may be justified. The most common means to assess whether or not a nerve is injured is using electrodiagnostic medicine. This medical subspecialty utilizes techniques of nerve conduction studies with electromyelography (NCS/EMG). Clinical evaluation may show evidence of loss of work, and can include evaluation of light touch, the capacity to differentiate sharp out of dull pain and the ability to discern temperature, as well as the evaluation of vibration.


    After a thorough clinical examination is completed, the electrodiagnostic analysis could be planned. These studies are conducted by specially trained neurologist and physiatrists. If neuropathy is suspected, a hunt for reversible causes ought to be accomplished. This can include blood function for vitamin deficiencies or thyroid problems, and imaging studies to exclude a structural lesion affecting the spinal cord. Depending on the results of this testing, there might be a means to decrease the intensity of the neuropathy and possibly reduce the pain that a patient is undergoing.


    Regrettably, in many conditions, even good control of the underlying cause of the neuropathy can’t reverse the neuropathic pain. This is commonly seen in patients with diabetic neuropathy. In rare instances, there may be signs of changes in the skin and hair growth pattern in an affected region. These alterations may be associated with changes in perspiration. If present, these changes can help identify the likely presence of neuropathic pain related to a condition known as complex regional pain syndrome.



    Dr. Alex Jimenez’s Insight

    Neuropathic pain is a chronic pain condition which is generally associated with direct damage or injury to the nervous system or nerves. This type of pain is different from nociceptive pain, or the typical sensation of pain. Nociceptive pain is an acute or sudden sensation of pain which causes the nervous system to send signals of pain immediately after the trauma occurred. With neuropathic pain, however, patients may experience shooting, burning pain without any direct damage or injury. Understanding the possible causes of the patient’s neuropathic pain versus any other type of pain, can help healthcare professionals find better ways to treat chronic pain conditions.


    What is the Treatment for Neuropathic Pain?


    Various medicines are used in an attempt to treat neuropathic pain. The majority of these drugs are utilized off-label, which means that the medicine was approved by the FDA to treat different conditions and was then recognized as being advantageous to treat neuropathic pain. Tricyclic antidepressants, such as amitriptyline, nortriptyline and desipramine, have been prescribed for management of neuropathic pain for several years.


    Some individuals find that these may be very effective in giving them relief. Other kinds of antidepressants have been shown to offer some relief. Selective serotonin reuptake inhibitors, or SSRIs, such as paroxetine and citalopram, and other antidepressants , such as venlafaxine and bupropion, have been utilized in certain patients. Another frequent treatment of neuropathic pain incorporates antiseizure medications, including carbamazepine, phenytoin, gabapentin, lamotrigine, and others.


    In acute cases of painful neuropathy which don’t respond to first-line brokers, drugs typically utilized to treat heart arrhythmias may be of some benefit; however, these can lead to significant side effects and often have to be monitored closely. Medications applied directly to the skin can offer modest to perceptible benefit for some patients. The forms commonly used include lidocaine (in patch or gel type) or capsaicin.


    Treating neuropathic pain is dependent on the underlying cause. If the cause is reversible, then the peripheral nerves can regenerate and the pain will abate; nonetheless, this reduction in pain may take several months to years. Several other alternative treatment options, including chiropractic care and physical therapy, may also be utilized in order to help relieve tension and stress along the nerves, ultimately helping to improve painful symptoms.


    What is the Prognosis for Neuropathic Pain?


    Many individuals with neuropathic pain are able to get some measure of aid, even when their pain persists. Although neuropathic pain isn’t dangerous to a patient, the presence of chronic pain can negatively affect quality of life. Patients with chronic nerve pain might suffer from sleep deprivation or mood disorders, including depression, anxiety and stress, as previously mentioned above. Because of the inherent alopecia and lack of sensory feedback, patients are at risk of developing injury or infection or unknowingly causing an escalation of a present injury. Therefore, it’s essential to seek immediate medical attention and follow specific guidelines directed by a healthcare professional for safety and caution.


    Can Neuropathic Pain be Prevented?


    The best way to prevent neuropathic pain is to avoid the development or progression of neuropathy. Monitoring and changing lifestyle options, including restricting the use of alcohol and tobacco; keeping a healthy weight to lower the chance of diabetes, degenerative joint disease, or stroke; and having great ergonomic form at work or when practicing hobbies to lower the risk of repetitive stress injury are strategies to decrease the probability of developing neuropathy and potential neuropathic pain. Make sure to seek immediate medical attention in the case of any symptoms associated with neuropathic pain in order to proceed with the most appropriate treatment approach. The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez




    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



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    Structural and Functional Mechanisms of Mechanoreceptors Mon, 25 Jun 2018 21:37:15 +0000

    We were all taught as children that there are 5 senses: sight, taste, sound, smell, and touch. The initial four senses utilize clear, distinct organs, such as the eyes, taste buds, ears, and nose, but just how does the body sense touch exactly? Touch is experienced over the entire body, both inside and outside. There is not one distinct organ that is responsible for sensing touch. Rather, there are tiny receptors, or nerve endings, around the entire body which sense touch where it occurs and sends signals to the brain with information regarding the type of touch that occurred. As a taste bud on the tongue detects flavor, mechanoreceptors are glands within the skin and on other organs that detect sensations of touch. They're known as mechanoreceptors because they're designed to detect mechanical

    The post Structural and Functional Mechanisms of Mechanoreceptors appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    We were all taught as children that there are 5 senses: sight, taste, sound, smell, and touch. The initial four senses utilize clear, distinct organs, such as the eyes, taste buds, ears, and nose, but just how does the body sense touch exactly? Touch is experienced over the entire body, both inside and outside. There is not one distinct organ that is responsible for sensing touch. Rather, there are tiny receptors, or nerve endings, around the entire body which sense touch where it occurs and sends signals to the brain with information regarding the type of touch that occurred. As a taste bud on the tongue detects flavor, mechanoreceptors are glands within the skin and on other organs that detect sensations of touch. They’re known as mechanoreceptors because they’re designed to detect mechanical sensations or differences in pressure.


    Role of Mechanoreceptors


    A person understands that they have experienced a sensation once the organ responsible for discovering that specific sense sends a message to the brain, which is the primary organ that processes and arranges all of the information. Messages are sent from all areas of the body to the brain through wires referred to as neurons. There are thousands of small neurons that branch out to all areas of the human body, and on the endings of many of these neurons are mechanoreceptors. To demonstrate what happens when you touch an object, we will use an example.


    Envision a mosquito lands on your arm. The strain of this insect, so light, stimulates mechanoreceptors in that particular area of the arm. Those mechanoreceptors send a message along the neuron they are connected to. The neuron connects all the way to the brain, which receives the message that something is touching your body in the exact location of the specific mechanoreceptor that sent the message. The brain will act with this advice. Maybe it will tell the eyes to look at the region of the arm that detected the signature. And when the eyes tell the brain that there’s a mosquito on the arm, the brain may tell the hand to quickly flick it away. That’s how mechanoreceptors work. The purpose of the article below is to demonstrate as well as discuss in detail the functional organization and molecular determinants of mechanoreceptors.


    Touch Sense: Functional Organization and Molecular Determinants of Mechanosensitive Receptors




    Cutaneous mechanoreceptors are localized in the various layers of the skin where they detect a wide range of mechanical stimuli, including light brush, stretch, vibration and noxious pressure. This variety of stimuli is matched by a diverse array of specialized mechanoreceptors that respond to cutaneous deformation in a specific way and relay these stimuli to higher brain structures. Studies across mechanoreceptors and genetically tractable sensory nerve endings are beginning to uncover touch sensation mechanisms. Work in this field has provided researchers with a more thorough understanding of the circuit organization underlying the perception of touch. Novel ion channels have emerged as candidates for transduction molecules and properties of mechanically gated currents improved our understanding of the mechanisms of adaptation to tactile stimuli. This review highlights the progress made in characterizing functional properties of mechanoreceptors in hairy and glabrous skin and ion channels that detect mechanical inputs and shape mechanoreceptor adaptation.


    Keywords: mechanoreceptor, mechanosensitive channel, pain, skin, somatosensory system, touch




    Touch is the detection of mechanical stimulus impacting the skin, including innocuous and noxious mechanical stimuli. It is an essential sense for the survival and the development of mammals and human. Contact of solid objects and fluids with the skin gives necessary information to the central nervous system that allows exploration and recognition of the environment and initiates locomotion or planned hand movement. Touch is also very important for apprenticeship, social contacts and sexuality. Sense of touch is the least vulnerable sense, although it can be distorted (hyperesthesia, hypoesthesia) in many pathological conditions.1-3


    Touch responses involve a very precise coding of mechanical information. Cutaneous mechanoreceptors are localized in the various layers of the skin where they detect a wide range of mechanical stimuli, including light brush, stretch, vibration, deflection of hair and noxious pressure. This variety of stimuli is matched by a diverse array of specialized mechanoreceptors that respond to cutaneous deformation in a specific way and relay these stimuli to higher brain structures. Somatosensory neurones of the skin fall into two groups: low-threshold mechanoreceptors (LTMRs) that react to benign pressure and high-threshold mechanoreceptors (HTMRs) that respond to harmful mechanical stimulation. LTMR and HTMR cell bodies reside within dorsal root ganglia (DRG) and cranial sensory ganglia (trigeminal ganglia). Nerve fibers associated with LTMRs and HTMRs are classified as Aβ-, Aδ- or C-fibers based on their action potential conduction velocities. C fibers are unmyelinated and have the slowest conduction velocities (~2 m/s), whereas Aδ and Aβ fibers are lightly and heavily myelinated, exhibiting intermediate (~12 m/s) and rapid (~20 m/s) conduction velocities, respectively. LTMRs are also classified as slowly, or rapidly adapting responses (SA- and RA-LTMRs) according to their rates of adaptation to sustained mechanical stimulus. They are further distinguished by the cutaneous end organs they innervate and their preferred stimuli.


    Ability of mechanoreceptors to detect mechanical cues relies on the presence of mechanotransducer ion channels that rapidly transform mechanical forces into electrical signals and depolarise the receptive field. This local depolarisation, called receptor potential, can generate action potentials that propagate toward the central nervous system. However, properties of molecules that mediate mechanotransduction and adaptation to mechanical forces remain unclear.


    In this review, we provide an overview of mammalian mechanoreceptor properties in innocuous and noxious touch in the hairy and glabrous skin. We also consider the recent knowledge about the properties of mechanically-gated currents in an attempt to explain the mechanism of mechanoreceptor’s adaptation. Finally, we review recent progress made in identifying ion channels and associated proteins responsible for the generation of mechano-gated currents.


    Innocuous Touch


    Hair Follicle-Associated LTMRs


    The hair follicles represent hair shaft-producing mini-organs that detect light touch. Fibers associated with hair follicles respond to hair motion and its direction by firing trains of action potentials at the onset and removal of the stimulus. They are rapidly adapting receptors.


    Cat and rabbit. In cat and rabbit coat, hair follicles can be divided in three hair follicle types, the Down hair, the Guard hair and the Tylotrichs. The Down hairs (underhair, wool, vellus)4 are the most numerous, the shortest and finest hairs of the coat. They are wavy, colorless and emerged in groups of two to four hairs from a common orifice in the skin. The Guard hairs (monotrichs, overhears, tophair)4 are slightly curved, either pigmented or unpigmented, and emerged singly from the mouths of their follicles. The tylotrichs are the least numerous, the longest and thickest hairs.5,6 They are pigmented or unpigmented, sometimes both and emerged singly from a follicle which is surrounded by a loop of capillary blood vessels. The sensory fibers supply to a hair follicle is located below the sebaceous gland and are attributed to Aβ or Aδ-LTMR fibers.7


    In close apposition to the down hair shaft, just below the level of the sebaceous gland is the ring of lanceolate pilo-Ruffini endings. These sensory nerve endings are positioned in a spiral course around the hair shaft within the connective tissue forming the hair follicle. Within the hair follicle, there are also free nerve endings, some of them forming mechanoreceptors. Frequently, touch corpuscles (see glabrous skin) are surrounding the neck region of tylotrich follicle.


    Properties of myelinated nerve endings in cat and rabbit hairy skin have been explored intensively in the 1930–1970 period (review in Hamann, 1995).8 Remarkably, Brown and Iggo, studying 772 units with myelinated afferent nerve fibers in the saphenous nerves from cat and rabbit, have classified responses in three receptor types corresponding to the movements of Down hairs (type D receptors), Guard hair (type G receptors) and Tylotrich hair (type T receptor).9 All the afferent nerve fiber responses have been brought together in the Rapidly Adapting receptor of type I (RA I) by opposition to the Pacinian receptor named RA II. RA I mechanoreceptors detect velocity of mechanical stimulus and have sharp border. They do not detect thermal variations. Burgess et al. also described a rapidly adapting field receptor that responds optimally to stroking of the skin or movement of several hairs, which was attributed to stimulation of pilo-Ruffini endings. None of the hair follicle response was attributed to C fiber activity.10


    Mice. In the dorsal hairy skin of mice, three major types of hair follicles have been described: zigzag (around 72%), awl/auchene (around 23%) and guard or tylotrich (around 5%).11-14 Zigzag and Awl/auchenne hair follicles produce the thinner and shorter hair shafts and are associated with one sebaceous gland. Guard or tylotrich hairs are the longest of the hair follicle types. They are characterized by a large hair bulb associated with two sebaceous glands. Guard and awl/auchene hairs are arranged in an iterative, regularly spaced pattern whereas zigzag hairs densely populate skin areas surrounding the two larger hair follicle types [Fig. 1 (A1, A2 and A3)].


    Figure 1 Organization and Projections of Cutaneous Mechanoreceptors | El Paso, TX Chiropractor
    Figure 1. Organization and projections of cutaneous mechanoreceptors. In hairy skin, light brush and touch are mainly detected by the innervation around the hair follicles: awl/auchenne (A1), zigzag (A2) and guard (A3). Awl/auchene hairs are triply innervated by C-LTMR lanceolate endings (A4), Aδ-LTMR and Aβ rapidly adapting-LTMR (A6). Zigzag hair follicles are the shorter hair shafts and are innervated by both C-LTMR (A4) and Aδ -LTMR lanceolate endings (A5). The longest guard hair follicles are innervated by Aβ rapidly adapting-LTMR longitudinal lanceolate endings (A6) and are associated with Aβ slowly adapting-LTMR of touch dome endings (A7). The central projections of all these fibers terminate in distinct, but partially overlapping laminae of the spinal cord dorsal horn (C-LTMR in lamina II, Aδ-LTMR in lamina III and Aβ-LTMR in lamina IV and V). The projections of LTMR that innervate the same or adjacent hair follicles are aligned to form a narrow column in the spinal cord dorsal horn (B1 in gray). Only in hairy skin, a subpopulation of C-fibers free ending innervates the epidermis and responds to pleasant touch (A8). These C-touch fibers don’t respond to noxious touch and their pathway travel is not yet known (B2). In glabrous skin, innocuous touch is mediated by four types of LTMRs. The Merkel cell-neurite complex is in the basal layer of the epidermis (C1). This mechanoreceptor consists of an arrangement between many Merkel cells and an enlarged nerve terminal from a single Aβ fiber. Merkel cells exhibits finger like processes contacting keratinocytes (C2). The Ruffini ending is localized in the dermis. It is a thin cigar-shaped encapsulated sensory endings connected to Aβ fiber (C3). The Meissner corpuscle connected to Aβ nerve ending and is located in the dermal papillae. This encapsulated mechanoreceptor consists of packed down supportive cells arranged as horizontal lamellae surrounded by connective tissue (C4). Pacinian corpuscle is the deeper mechanoreceptor. One single Aβ unmyelinated nerve ending terminates in the center of this large ovoid corpuscle made of concentric lamellae. Projections of these Aβ-LTMR fibers in the spinal cord are divided in two branches. The principal central branch (B3) ascends in the spinal cord in the ipsilateral dorsal forming cuneate or gracile fascicles (B5) upon medulla level where the primary afferents make their first synapse (B6). The secondary neurons make a sensory decussation (B7) to form a tract on the medial lemniscus which ascends through the brainstem to the midbrain, specifically in the thalamus. Secondary branche of LTMR terminates in the dorsal horn in the lamina II, IV, V and interfere with the pain transmission (B4). Noxious touch is detected by the free nerve ending in the epidermis of both hairy (A9) and glabrous skin (C7). These mechanoreceptors are the ending of Aδ-HTMR and C-HTMR in close contact with neighboring keratinocytes (C6). Aδ-hTMR terminate in the lamina I and V; C-HTMR terminate in the lamina I and II (B8). At spinal cord dorsal horn level, primary afferents HTMRs make synapses with secondary neurons which cross the midline and climb to the higher brain structure in the anterolateral fascicle (B9, B10). LTMR, low threshold mechanoreceptor; HTMR, high threshold mechanoreceptor.


    Recently, Ginty and collaborators used a combination of molecular-genetic labeling and somatotopic retrograde tracing approaches to visualize the organization of peripheral and central axonal endings of the LTMRs in mice.15 Their findings support a model in which individual features of a complex tactile stimulus are extracted by the three hair follicle types and conveyed via the activities of unique combinations of Aβ-, Aδ- and C- fibers to dorsal horn.


    They showed that the genetic labeling of tyrosine hydroxylase positive (TH+) DRG neurones characterize a population of nonpeptidergic, small-diameter sensory neurones and allow for visualization of C-LTMR peripheral endings in the skin. Surprisingly, the axoneal branches of individual C-LTMRs were found to arborise and form longitudinal lanceolate endings that are intimately associated with zigzag (80% of endings) and awl/auchene (20% of endings), but not tylotrich hair follicles [Fig. 1 (A4)]. Longitudinal lanceolate endings have been long thought to belong exclusively to Aβ-LTMRs and therefore it was unexpected that the endings of C-LTMRs would form longitudinal lanceolate endings.15 These C-LTMRs have an intermediate adaptation in comparison with the slowly and rapidly adapting myelinated mechanoreceptors [Fig. 2 (C1)].


    Figure 2 Tactile Receptors in Mammals | El Paso, TX Chiropractor
    Figure 2. Tactile receptors in mammals: Cutaneous tactile receptors differentiate into innocuous touch supported by multiple receptors with low mechanical threshold (LTMRs) in glabrous and hairy skin and noxious touch supported by high mechanical threshold receptor (HTMRs). They make up nerve free endings that terminate mainly in epidermis. (A) Glabrous skin. A1: Meissner corpuscles detect skin motion and slipping of object in the hand. They are important for handing object and dexterity. Receptors rapidly adapt to stimulus, are connected to Aβ fibers and sparsely to C fibers and have large receptor field. A2: Ruffini corpuscles detect skin stretch and are important to detect finger position and handing object. Receptor slowly adapt to stimulus and maintained activity as long as the stimulus was applied. Receptors are connected to Aβ fibers and have large receptive field. A3: Pacinian corpuscles are deeper in the dermis and detect vibration. Receptors are connected to Aβ fibers; they rapidly adapt to stimulus and have the largest receptive field. (B) Whole skin. B1: Merkel-cell complexes are present in both glabrous skin and around hair. They are densely expressed in the hand and are important for texture perception and finest discrimination between two points. They are responsible for finger precision. Receptors are connected to Aβ fibers; they slowly adapt to stimulus and have short receptive field. B2: Noxious touch HTMRs with very slow adaptation to the stimulus, i.e., active as long as the nociceptive stimulus is applied. They are formed by the free nerve ending of Aδ and C-fibers associated to keratinocytes. (C) Hairy skin. C1: Hair follicles are associated with the different hair types. In mice Guard hairs are the longer and sparsely expressed one, awl/auchenne are of medium size and zigzag are the smallest and the most densely expressed hair. They are connected to Aβ fibers but also to Aδ and C-LTMRs fibers for awl/auchenne and zizag hair. They detect hair movement including pleasant touch during caress. They adapt rapidly or with intermediate kinetic to stimulus. C2: C-touch nerve endings correspond to a subtype of C fibers terminus with free ending characterized by a low mechanical threshold. They are supposed to encode for pleasant sensation induced by caress. They moderately adapt to stimulus and have short receptive field. Putative mechanosensitive (MS) ion channels expressed in the different tactile receptors are indicated accordingly to preliminary data and summarize present hypothesis under evaluation.


    A second major population identified concerns the Aδ-LTMR endings in Awl/Auchenne and zigzag follicles to be compared with the Down hair follicle extensively studied in cat and rabbit. Ginty and collaborators showed that TrkB is expressed at high levels in a subset of medium-diametre DRG neurones. Intracellular recordings using the ex vivo skin-nerve preparation of labeled fibers revealed that they exhibit the physiological properties of fibers previously studied in cat and rabbit: exquisite mechanical sensitivity (Von Frey threshold < 0.07 mN), rapidly adapting responses to suprathreshold stimuli, intermediate conduction velocities (5.8 ± 0.9 m/s) and narrow uninflected soma spikes.15 These Aδ-LTMRs form longitudinal lanceolate endings associated with virtually every zigzag and awl/auchene hair follicle of the trunk [Fig. 1 (A5)].


    Finally, they showed that the peripheral endings of rapidly adapting Aβ LTMRs form longitudinal lanceolate endings associated with guard (or tylotrich) and awl/auchene hair follicles [Fig. 1 (A6)].15 In addition, Guard hairs are also associated with a Merkel cell complex forming a touch dome connected to Aβ slowly adapting LTMR [Fig. 1 (A7)].


    In summary, virtually all zigzag hair follicles are innervated by both C-LTMR and Aδ-LTMR lanceolate endings; awl/auchene hairs are triply innervated by Aβ rapidly adapting-LTMR, Aδ-LTMR and C-LTMR lanceolate endings; Guard hair follicles are innervated by Aβ rapidly adapting-LTMR longitudinal lanceolate endings and interact with Aβ slowly adapting-LTMR of touch dome endings. Thus, each mouse hair follicle receives unique and invariant combinations of LTMR endings corresponding to neurophysiologically distinct mechanosensory end organs. Considering the iterative arrangement of these three hair types, Ginty and collaborators propose that hairy skin consists of iterative repeat of peripheral unit containing, (1) one or two centrally located guard hairs, (2) ~20 surrounding awl/auchenne hairs and (3) ~80 interspersed zigzag hairs [Fig. 2 (C1)].


    Spinal cord projection. The central projections of Aβ rapidly adapting-LTMRs, Aδ-LTMRs and C-LTMRs terminate in distinct, but partially overlapping laminae (II, III, IV) of the spinal cord dorsal horn. In addition, the central terminals of LTMRs that innervate the same or adjacent hair follicles within a peripheral LTMR unit are aligned to form a narrow LTMR column in the spinal cord dorsal horn [Fig. 1 (B1)]. Thus, it appears likely that a wedge, or column of somatotopically organized primary sensory afferent endings in the dorsal horn represents the alignment of the central projections of Aβ-, Aδ- and C-LTMRs that innervate the same peripheral unit and detect mechanical stimuli acting upon the same small group of hairs follicles. Based on the numbers of guard, awl/ auchene and zigzag hairs of the trunk and limbs and the numbers of each LTMR subtype, Ginty and collaborators estimate that the mouse dorsal horn contains 2,000–4,000 LTMR columns, which corresponds to the approximate number of peripheral LTMR units.15


    Furthermore, axones of LTMR subtypes are closely associated with one another, having entwined projections and interdigitated lanceolate endings that innervate the same hair follicle. In addition, because the three hair follicle types exhibit different shapes, sizes and cellular compositions, they are likely to have distinct deflectional or vibrational tuning properties. These findings are consistent with classic neurophysiological measurements in the cat and rabbit indicating that Aβ RA-LTMRs and Aδ-LTMRs can be differentially activated by deflection of distinct hair follicle types.16,17


    In conclusion, touch in hairy skin is the combination of: (1) the relative numbers, unique spatial distributions and distinct morphological and deflectional properties of the three types of hair follicles; (2) the unique combinations of LTMR subtype endings associated with each of the three hair follicle types; and (3) distinct sensitivities, conduction velocities, spike train patterns and adaptation properties of the four main classes of hair-follicle-associated LTMRs that enable the hairy skin mechanosensory system to extract and convey to the CNS the complex combinations of qualities that define a touch.


    Free-Nerve Endings LTMRs


    Generally, C-fibers free endings in the skin are HTMRs, but a subpopulation of C-fibers doesn’t respond to noxious touch. This subset of tactile C-fiber (CT) afferents represents a distinct type of unmyelinated, low-threshold mechanoreceptive units existing in the hairy but not glabrous skin of humans and mammals [Fig. 1 (A8)].18,19 CTs are generally associated with the perception of pleasant tactile stimulation in body contact.20,21


    CT afferents respond to indentation forces in the range 0.3–2.5 mN and are thus as sensitive to skin deformation as many of the Aβ afferents.19 The adaptation characteristics of CT afferents are thus intermediate in comparison with the slowly and rapidly adapting myelinated mechanoreceptors. The receptive fields of human CT afferents are roughly round or oval in shape. The field consists of one to nine small responsive spots distributed over an area up to 35 mm2.22 The mouse homolog receptors are organized in a pattern of discontinuous patches covering about 50–60% of the area in the hairy skin [Fig. 2 (C2)].23


    Evidence from patients lacking myelinated tactile afferents indicates that signaling in CT fibers activate the insular cortex. Since this system is poor in encoding discriminative aspects of touch, but well-suited to encoding slow, gentle touch, CT fibers in hairy skin may be part of a system for processing pleasant and socially relevant aspects of touch.24 CT fiber activation may also have a role in pain inhibition and it has recently been proposed that inflammation or trauma may change the sensation conveyed by C-fiber LTMRs from pleasant touch to pain.25,26


    Which pathway CT-afferents travel is not yet known [Fig. 1 (B2)], but low-threshold tactile inputs to spinothalamic projection cells have been documented,27 lending credence to reports of subtle, contralateral deficits of touch detection in human patients following destruction of these pathways after chordotomy procedures.28


    LTMRs in Glabrous Skin


    Merkel cell-neurite complexes and touch dome. Merkel (1875) was the first to give a histological description of clusters of epidermal cells with large lobulated nuclei, making contact with presumed afferent nerve fibers. He assumed that they subserved sense of touch by calling them Tastzellen (tactile cells). In humans, Merkel cell–neurite complexes are enriched in touch sensitive areas of the skin, they are found in the basal layer of the epidermis in fingers, lips and genitals. They also exist in hairy skin at lower density. The Merkel cell–neurite complex consists of a Merkel cell in close apposition to an enlarged nerve terminal from a single myelinated Aβ fiber [Fig. 1 (C1)] (review in Halata and collaborators).29 At the epidermal side Merkel cell exhibits finger-like processes extending between neighboring keratinocytes [Fig. 1 (C2)]. Merkel cells are keratinocyte-derived epidermal cells.30,31 The term of touch dome was introduced to name the large concentration of Merkel cell complexes in the hairy skin of cat forepaw. A touch dome could have up to 150 Merkel cells innervated by a single Aβ-fiber and in humans besides Aβ-fibers, Aδ and C-fibers were also regularly present.32-34


    Stimulation of Merkel cell–neurite complexes results in slowly-adapting Type I (SA I) responses, which originate from punctuate receptive fields with sharp borders. There is no spontaneous discharge. These complexes respond to indentation depth of the skin and have the highest spatial resolution (0.5 mm) of the cutaneous mechanoreceptors. They transmit a precise spatial image of tactile stimuli and are proposed to be responsible for shape and texture discrimination [Fig. 2 (B1)]. Mice devoid of Merkel cells cannot detect textured surfaces with their feet while they do so using their whiskers.35


    Whether the Merkel cell, the sensory neuron or both are sites of mechanotransduction is still a matter of debate. In rats, phototoxic destruction of Merkel cells abolishes SA I response.36 In mice with genetically suppressed-Merkel cells, the SA I response recorded in ex vivo skin/nerve preparation completely disappeared, demonstrating that Merkel cells are required for the proper encoding of Merkel receptor responses.37 However, the mechanical stimulation of isolated Merkel cells in culture by motor driven pressure does not generate mechanically-gated currents.38,39 Keratinocytes may play an important role in the normal functioning of the Merkel cell–neurite complex. The Merkel cell finger-like processes can move with skin deformation and epidermis cell movement, and this may be the first step of mechanical transduction. Clearly, the conditions required to study mechano-sensitivity of Merkel cells have yet to be established.


    Ruffini endings. Ruffini endings are thin cigar-shaped encapsulated sensory endings connected to Aβ nerve endings. Ruffini endings are small connective tissue cylinders arranged along dermal collagen strands which are supplied by one to three myelinated nerve fibers of 4–6 µm diametre. Up to three cylinders of different orientation in the dermis may merge to form one receptor [Fig. 1 (C3)]. Structurally, Ruffini endings are similar to Golgi tendon organs. They are broadly expressed in the dermis and have been identified as the slowly adapting type II (SA II) cutaneous mechanoreceptors. Against the background of spontaneous nervous activity, a slowly-adapting regular discharge is elicited by perpendicular low force maintained mechanical stimulation or more effectively by dermal stretch. SA II response originates from large receptive fields with obscure borders. Ruffini receptors contribute to the perception of the direction of object motion through the pattern of skin stretch [Fig. 2 (A2)].


    In mice, SA I and SA II responses can be separated electrophysiologically in ex-vivo nerve-skin preparation.40 Nandasena and collaborators reported the immunolocalization of aquaporin 1 (AQP1) in the periodontal Ruffini endings of the rat incisors suggesting that AQP1 is involved in the maintenance of the dental osmotic balance necessary for the mechanotransduction.41 The periodontal Ruffini endings also expressed the putative mechanosensitive ion channel ASIC3.42


    Meissner corpuscles. Meissner corpuscles are localized in the dermal papillae of the glabrous skin, mainly in hand palms and foot soles but also in lips, in tongue, in face, in nipples and in genitals. Anatomically, they consist of an encapsulated nerve ending, the capsule being made of flattened supportive cells arranged as horizontal lamellae embedded in connective tissue. There is one single nerve fiber Aβ afferents connected per corpuscle [Fig. 1 (C4)]. Any physical deformation of the corpuscle triggers a volley of action potentials that quickly ceases, i.e., they are rapidly adapting receptors. When the stimulus is removed, the corpuscle regains its shape and while doing so produces another volley of action potentials. Due to their superficial location in the dermis, these corpuscles selectively respond to skin motion, tactile detection of slip and vibrations (20–40 Hz). They are sensitive to dynamic skin – for example, between the skin and an object that is being handled [Fig. 2 (A1)].


    Pacinian corpuscles. Pacinian corpuscles are the deeper mechanoreceptors of the skin and are the most sensitive encapsulated cutaneous mechanoreceptor of skin motion. These large ovoid corpuscles (1 mm in length) made of concentric lamellae of fibrous connective tissue and fibroblasts lined by flat modified Schwann cells are expressed in the deep dermis.43 In the center of the corpuscle, in a fluid-filled cavity called inner bulb, terminates one single Aβ afferent unmyelinated nerve ending [Fig. 1 (C5)]. They have a large receptive field on the skin’s surface with a particularly sensitive center. The development and function of several rapidly adapting mechanoreceptor types are disrupted in c-Maf mutant mice. In particular, Pacinian corpuscles are severely atrophied.44


    Pacinian corpuscles display very rapid adaptation in response to the indentation of the skin, the rapidly-adapting II (RA II) nervous discharge that are capable of following high frequency of vibratory stimuli, and allow perception of distant events through transmitted vibrations.45 Pacinian corpuscle afferents respond to sustained indentation with transient activity at the onset and offset of the stimulus. They are also called acceleration detectors because they can detect changes in the strength of the stimulus and, if the rate of change in the stimulus is altered (as happens in vibrations), their response becomes proportional to this change. Pacinian corpuscles sense gross pressure changes and most of all vibrations (150–300 Hz), which they can detect even centimeters away [Fig. 2 (A3)].


    Tonic response was observed in decapsulated Pacinian corpuscle.46 In addition, intact Pacinian corpuscles respond with sustained activity during constant indentation stimuli, without altering mechanical thresholds or response frequency when GABA-mediated signaling is blocked between lamellate glia and a nerve ending.47 Thus, the non-neuronal components of the Pacinian corpuscle may have dual roles in filtering the mechanical stimulus as well as in modulating the response properties of the sensory neurone.


    Spinal cord projections. Projections of the Aβ-LTMRs in the spinal cord are divided in two branches. The principal central branch ascends in the spinal cord in the ipsilateral dorsal columns to the cervical level [Fig. 1 (B3)]. Secondary branches terminate in the dorsal horn in the laminae IV and interfere with the pain transmission, for example. This may attenuate pain as a part of the gate control [Fig. 1 (B4)].48


    At cervical levels, axones of the principal branch separate in two tracts: the midline tract comprises the gracile fascicle conveying information from the lower half of the body (legs and trunk), and the outer tract comprises the cuneate fascicle conveying information from the upper half of the body (arms and trunk) [Fig. 1 (B5)].


    Primary tactile afferents make their first synapse with second order neurones at the medulla where fibers from each tract synapse in a nucleus of the same name: the gracile fasciculus axones synapse in the gracile nucleus and the cuneate axones synapse in the cuneate nucleus [Fig. 1 (B6)]. Neurones receiving the synapse provide the secondary afferents and cross the midline immediately to form a tract on the contralateral side of the brainstem—the medial lemniscus—which ascends through the brainstem to the next relay station in the midbrain, specifically, in the thalamus [Fig. 1 (B7)].


    Molecular specification of LTMRs. Molecular mechanisms controlling the early diversification of LTMRs have been recently partly elucidated. Bourane and collaborators have shown that the neuronal populations expressing the Ret tyrosine kinase receptor (Ret) and its co-receptor GFRα2 in E11–13 embryonic mice DRG selectively coexpress the transcription factor Mafa.49,50 These authors demonstrate that the Mafa/Ret/GFRα2 neurones destined to become three specific types of LTRMs at birth: the SA1 neurones innervating Merkel-cell complexes, the rapidly adapting neurones innervating Meissner corpuscles and the rapidly adapting afferents (RA I) forming lanceolate endings around hair follicles. Ginty and collaborators also report that DRG neurones expressing early-Ret are rapidly adapting mechanoreceptors from Meissner corpuscles, Pacinian corpuscles and lanceolate endings around hair follicles.51 They innervate discrete target zones within the gracile and cuneate nuclei, revealing a modality-specific pattern of mechanosensory neurone axonal projections within the brainstem.


    Exploration of human skin mechanoreceptors. The technique of “microneurography” described by Hagbarth and Vallbo in 1968 has been applied to study the discharge behavior of single human mechanosensitive endings supplying muscle, joint and skin (see for review Macefield, 2005).52,53 The majority of human skin microneurography studies have characterized the physiology of tactile afferents in the glabrous skin of the hand. Microelectrode recordings from the median and ulnar nerves in human subjects have revealed touch sensation generated by the four classes of LTMRs: Meissner afferents are particularly sensitive to light stroking across the skin, responding to local shear forces and incipient or overt slips within the receptive field. Pacinian afferents are exquisitively sensitive to brisk mechanical transients. Afferents respond vigorously to blowing over the receptive field. A Pacinian corpuscle located in a digit will usually respond to tapping the table supporting the arm. Merkel afferents characteristically have a high dynamic sensitivity to indentation stimuli applied to a discrete area and often respond with an off-discharge during release. Although the Ruffini afferents do respond to forces applied normally to the skin, a unique feature of SA II afferents is their capacity to respond also to lateral skin stretch. Finally, hair units in the forearm have large ovoid or irregular receptive fields composed of multiple sensitive spots that corresponded to individual hairs (each afferent supply ~20 hairs).


    Mechanical Sensitivity of Keratinocytes


    Any mechanical stimulus on the skin must be transmitted through keratinocytes that form the epidermis. These ubiquitous cells may perform signaling functions in addition to their supportive or protective roles. For example, keratinocytes secrete ATP, an important sensory signaling molecule, in response to mechanical and osmotic stimuli.54,55 The release of ATP induces intracellular calcium increase by autocrine stimulation of purinergic receptors.55 Furthermore, there is evidence that hypotonicity activates the Rho-kinase signaling pathway and the subsequent F-actin stress fiber formation suggesting that the mechanical deformation of the keratinocytes may mechanically interfere with the neighbor cells such as Merkel cells for innocuous touch and C-fiber free endings for noxious touch [Fig. 1 (C6)].56,57


    Noxious Touch


    High threshold mechanoreceptors (HTMRs) are epidermal C- and Aδ free nerve-endings. They are not associated with specialized structures and are observed in both hairy skin [Fig. 1 (A9)] and glabrous skin [Fig. 1(C7)]. However, the term of free nerve-ending has to be considered prudently since nerve endings are always in close apposition with keratinocyte or Langherans’ cell or melanocytes. Ultrastructural analysis of nerve endings reveals the presence of rough endoplasmic reticulum, abundant mitochondria and dense-core vesicle. Adjacent membranes of epidermal cells are thickened and resembling post-synaptic membrane in nervous tissues. Note that the interactions between nerve endings and epidermal cells may be bidirectional since epidermal cells may release mediators as ATP, interleukine (IL6, IL10) and bradykinin and conversely peptidergic nerve endings may release peptides such as CGRP or substance P acting on epidermal cells. HTMRs comprise mechano-nociceptors excited only by noxious mechanical stimuli and polymodal nociceptors that also respond to noxious heat and exogenous chemical [Fig. 2 (B2)].58


    HTMR afferent fibers terminate on projection neurones in the dorsal horn of the spinal cord. Aδ-HTMRs contact second order neurones predominantly in the lamina I and V, whereas C-HTMRs terminate in the lamina II [Fig. 1 (B8)]. Second order nociceptive neurones project to the controlateral side of the spinal cord and ascend in the white matter, forming the anterolateral system. These neurones terminate mainly in the thalamus [Fig. 1 (B9 and B10)].


    Mechano-Currents in Somatosensory Neurones


    The mechanisms of slow or rapid adaptation of mechanoreceptors are not yet elucidated. It is not clear to what extent mechanoreceptor adaptation is provided by the cellular environment of the sensory nerve ending, the intrinsic properties of the mechanically-gated channels and the properties of the axonal voltage-gated ion channels in sensory neurones (Fig. 2). However, recent progress in the characterization of mechanically-gated currents has demonstrated that different classes of mechanosensitive channels exist in DRG neurones and may explain some aspects of the adaptation of mechanoreceptors.


    In vitro recording in rodents has shown that the soma of DRG neurons is intrinsically mechanosensitive and express cationic mechano-gated currents.59-64 Gadolinium and ruthenium red fully block mechanosensitive currents, whereas external calcium and magnesium, at physiological concentrations, as well as amiloride and benzamil, cause partial block.60,62,63 FM1-43 acts as a lasting blocker, and the injection of FM1-43 into the hind paw of mice decreases pain sensitivity in the Randall–Selitto test and increases the paw withdrawal threshold assessed with von Frey hairs.65


    In response to sustained mechanical stimulation, mechanosensitive currents decline through closure. Based on the time constants of current decay, four distinct types of mechanosensitive currents have been distinguished: rapidly adapting currents (~3–6 ms), intermediately adapting currents (~15–30 ms), slowly adapting currents (~200–300 ms) and ultra-slowly adapting currents (~1000 ms).64 All these currents are present with variable incidence in rat DRG neurones innervating the glabrous skin of the hindpaw.64


    The mechanical sensitivity of mechanosensitive currents can be determined by applying a series of incremental mechanical stimuli, allowing for relatively detailed stimulus-current analysis.66 The stimulus–current relationship is typically sigmoidal, and the maximum amplitude of the current is determined by the number of channels that are simultaneously open.64,67 Interestingly, the rapidly adapting mechanosensitive current has been reported to display low mechanical threshold and half-activation midpoint compared with the ultra-slowly adapting mechanosensitive current.63,65


    Sensory neurones with non-nociceptive phenotypes preferentially express rapidly adapting mechanosensitive currents with lower mechanical threshold.60,61,63,64,68 Conversely, slowly and ultra-slowly adapting mechanosensitive currents are occasionally reported in putative non-nociceptive cells.64,68 This prompted suggestion that these currents might contribute to the different mechanical thresholds seen in LTMRs and HTMRs in vivo. Although these in vitro experiments should be taken with caution, support for the presence in the soma of the DRG neurones of low- and high-threshold mechanotransducers was also provided by radial stretch-based stimulation of cultured mouse sensory neurones.69 This paradigm revealed two main populations of stretch-sensitive neurones, one that responds to low stimulus amplitude and another one that selectively responds to high stimulus amplitude.


    These results have important, yet speculative, mechanistic implications: the mechanical threshold of sensory neurones might have little to do with the cellular organization of the mechanoreceptor but may lie in the properties of the mechanically-gated ion channels.


    The mechanisms that underlie desensitization of mechanosensitive cation currents in rat DRG neurones have been recently unraveled.64,67 It results from two concurrent mechanisms that affect channel properties: adaptation and inactivation. Adaptation was first reported in auditory hair cell studies. It can be described operationally as a simple translation of the transducer channel’s activation curve along the mechanical stimulus axis.70-72 Adaptation allows sensory receptors to maintain their sensitivity to new stimuli in the presence of an existing stimulus. However, a substantial fraction of mechanosensitive currents in DRG neurones cannot be reactivated following conditioning mechanical stimulation, indicating inactivation of some transducer channels.64,67 Therefore, both inactivation and adaptation act in tandem to regulate mechanosensitive currents. These two mechanisms are common to all mechanosensitive currents identified in rat DRG neurones, suggesting that related physicochemical elements determine the kinetics of these channels.64


    In conclusion, determining the properties of endogenous mechanosensitive currents in vitro is crucial in the quest to identify transduction mechanisms at the molecular level. The variability observed in the mechanical threshold and the adapting kinetics of the different mechanically-gated currents in DRG neurones suggest that intrinsic properties of ion channels may explain, at least in part, mechanical threshold and adaptation kinetics of the mechanoreceptors described in the decades 1960–80 using ex vivo preparations.


    Putative Mechanosensitive Proteins


    Mechanosensitive ion currents in somatosensory neurones are well characterized, by contrast, little is known about the identity of molecules that mediate mechanotransduction in mammals. Genetic screens in Drosophila and C. elegans have identified candidate mechanotransduction molecules, including the TRP and degenerin/epithelial Na+ channel (Deg/ENaC) families.73 Recent attempts to elucidate the molecular basis of mechanotransduction in mammals have largely focused on homologs of these candidates. Additionally, many of these candidates are present in cutaneous mechanoreceptors and somatosensory neurones (Fig. 2).


    Acid-Sensing Ion Channels


    ASICs belong to a proton-gated subgroup of the degenerin–epithelial Na+ channel family.74 Three members of the ASIC family (ASIC1, ASIC2 and ASIC3) are expressed in mechanoreceptors and nociceptors. The role of ASIC channels has been investigated in behavioral studies using mice with targeted deletion of ASIC channel genes. Deletion of ASIC1 does not alter the function of cutaneous mechanoreceptors but increases mechanical sensitivity of afferents innervating the gut.75 ASIC2 knockout mice exhibit a decreased sensitivity of rapidly adapting cutaneous LTMRs.76 However, subsequent studies reported a lack of effects of knocking out ASIC2 on both visceral mechano-nociception and cutaneous mechanosensation.77 ASIC3 disruption decreases mechano sensitivity of visceral afferents and reduces responses of cutaneous HTMRs to noxious stimuli.76


    The Transient Receptor Channel


    THE TRP superfamily is subdivided into six subfamilies in mammals.78 Nearly all TRP subfamilies have members linked to mechanosensation in a variety of cell systems.79 In mammalian sensory neurones, however, TRP channels are best known for sensing thermal information and mediating neurogenic inflammation, and only two TRP channels, TRPV4 and TRPA1, have been implicated in touch responsiveness. Disrupting TRPV4 expression in mice has only modest effects on acute mechanosensory thresholds, but strongly reduces sensitivity to noxious mechanical stimuli.80,81 TRPV4 is a crucial determinant in shaping the response of nociceptive neurones to osmotic stress and to mechanical hyperalgesia during inflammation.82,83 TRPA1 seems to have a role in mechanical hyperalgesia. TRPA1-deficient mice exhibit pain hypersensitivity. TRPA1 contributes to the transduction of mechanical, cold and chemical stimuli in nociceptor sensory neurones but it appears that is not essential for hair-cell transduction.84,85


    There is no clear evidence indicating that TRP channels and ASICs channels expressed in mammals are mechanically gated. None of these channels expressed heterologously recapitulates the electrical signature of mechanosensitive currents observed in their native environment. This does not rule out the possibility that ASICs and TRPs channels are mechanotransducers, given the uncertainty of whether a mechanotransduction channel may function outside of its cellular context (see section on SLP3).


    Piezo Proteins


    Piezo protiens have been recently identified like as promising candidates for mechanosensing proteins by Coste and collaborators.86,87 Vertebrates have two Piezo members, Piezo 1 and Piezo 2, previously known as FAM38A and FAM38B, respectively, which are well conserved throughout multi cellular eukaryotes. Piezo 2 is abundant in DRGs, whereas Piezo 1 is barely detectable. Piezo-induced mechanosensitive currents are prevented inhibited by gadolinium, ruthenium red and GsMTx4 (a toxin from the tarantula Grammostola spatulata).88 Expression of Piezo 1 or Piezo 2 in heterologous systems produces mechanosensitive currents, the kinetics of inactivation of Piezo 2 current being faster than Piezo 1. Similar to endogenous mechanosensitive currents, Piezo-dependent currents have reversal potentials around 0 mV and are cation no selective, with Na+, K+, Ca2+ and Mg2+ all permeating the underlying channel. Likewise, piezo-dependent currents are regulated by membrane potential, with a marked slowing of current kinetics at depolarized potentials.86


    Piezo proteins are undoubtedly mechanosensing proteins and share many properties of rapidly adapting mechanosensitive currents in sensory neurones. Treatment of cultured DRG neurones with Piezo 2 short interfering RNA decreased the proportion of neurones with rapidly adapting current and decreased the percentage of mechanosensitive neurones.86 Transmembrane domains are located throughout the piezo proteins but no obvious pore-containing motifs or ion channel signatures have been identified. However, mouse Piezo 1 protein purified and reconstituted into asymmetric lipid bilayers and liposome forms ion channels sensitive to ruthenium red.87 An essential step in validating mechanotransduction through Piezo channels is to use in vivo approaches to determine the functional importance in touch signaling. Information was given in Drosophila where deletion of the single Piezo member reduced mechanical response to noxious stimuli, without affecting normal touch.89 Although their structure remains to be determined, this novel family of mechanosensitive proteins is a promising subject for future research, beyond the border of touch sensation. For exemple, a recent study on patients with anemia (hereditary xerocytosis) shows the role of Piezo 1 in maintaining erythrocyte volume homeostasis.90


    Transmembrane Channel-Like (TMC)


    A recent study indicates that two proteins, TMC1 and TMC2, are necessary for hair cell mechanotransduction.91 Hereditary deafness due to TMC1 gene mutation was reported in human and mice.92,93 Presence of these channels had not yet been shown in the somatosensory system, but it seems to be a good lead to investigate.


    Stomatin-Like Protein 3 (SLP3)


    Additionally to the transduction channels, some accessory proteins linked to the channel have been shown to play a role in touch sensivity. SLP3 is expressed in mammalian DRG neurones. Studies using mutant mice lacking SLP3 had shown change in mechanosensation and mechanosentive currents.94,95 SLP3 precise function remains unknown. It may be a linker between the mechanosensitive channel and the underlying microtubules, as proposed for its C. elegans homolog MEC2.96 Recently GR. Lewin lab has suggested that a tether is synthesized by DRG sensory neurones and links mechanosensitive ion channel to the extracellular matrix.97 Disrupting the link abolishes the RA-mechanosensitive current suggesting that some ion channels are mechanosensitive only when tethered. RA-mechanosensitive currents are also inhibited by laminin-332, a matrix protein produced by keratinocytes, reinforcing the hypothesis of a modulation of the mechanosensitive current by extracellular proteins.98


    K+ Channel Subfamily


    In parallel to cationic depolarizing mechanosensitive currents, the presence of repolarizing mechanosensitive K+ currents is under investigation. K+ channels in mechanosensitive cells can step in the current balance and contribute to define the mechanical threshold and the time course of adaptation of mechanoreceptors.


    KCNK members belong to the two-pore domain K+ channel (K2P) family.99,100 The K2P display a remarkable range of regulation by cellular, physical and pharmacological agents, including pH changes, heat, stretch and membrane deformation. These K2P are active at resting membrane potential. Several KCNK subunits are expressed in somatosensory neurones.101 KCNK2 (TREK-1), KCNK4 (TRAAK) and TREK-2 channels are among the few channels for which a direct mechanical gating by membrane stretch has been shown.102,103


    Mice with a disrupted KCNK2 gene displayed an enhanced sensitivity to heat and mild mechanical stimuli but a normal withdrawal threshold to noxious mechanical pressure applied to the hindpaw using the Randall–Selitto test.104 KCNK2-deficient mice also displays increased thermal and mechanical hyperalgesia in inflammatory conditions. KCNK4 knockout mice were hypersensitive to mild mechanical stimulation, and this hypersensitivity was increased by additional inactivation of KCNK2.105 Increased mechanosensitivity of these knockout mice could mean that stretch normally activates both depolarizing and repolarizing mechanosensitive currents in a coordinated way, similarly to the unbalance of depolarizing and repolarizing voltage-gated currents.


    KCNK18 (TRESK) is a major contributor to the background K+ conductance that regulates the resting membrane potential of somatosensory neurones.106 Although it is not known if KCNK18 is directly sensitive to mechanical stimulation, it may play a role in mediating responses to light touch, as well as painful mechanical stimuli. KCNK18 and to a lesser extent KCNK3, are proposed to be the molecular target of hydroxy-α-sanshool, a compound found in Schezuan peppercorns that activates touch receptors and induces a tingling sensation in humans.107,108


    The voltage dependent K+ channel KCNQ4 (Kv7.4) is crucial for setting the velocity and frequency preference of a subpopulation of rapidly adapting mechanoreceptors in both mice and humans. Mutation of KCNQ4 has been initially associated with a form of hereditary deafness. Interestingly a recent study localizes KCNQ4 in the peripheral nerve endings of cutaneous rapidly adapting hair follicle and Meissner corpuscle. Accordingly, loss of KCNQ4 function leads to a selective enhancement of mechanoreceptor sensitivity to low-frequency vibration. Notably, people with late-onset hearing loss due to dominant mutations of the KCNQ4 gene show enhanced performance in detecting small-amplitude, low-frequency vibration.109



    Dr. Alex Jimenez’s Insight

    Touch is considered to be one of the most complex senses in the human body, particularly because there is no specific organ in charge of it. Instead, the sense of touch occurs through sensory receptors, known as mechanoreceptors, which are found across the skin and respond to mechanical pressure or distortion. There are four main types of mechanoreceptors in the glabrous, or hairless, skin of mammals: lamellar corpuscles, tactile corpuscles, Merkel nerve endings and bulbous corpuscles. Mechanoreceptors function in order to allow the detection of touch, in order to monitor the position of the muscles, bones and joints, known as proprioception, and even to detect sounds and the motion of the body. Understanding the mechanisms of structure and function of these mechanoreceptors is a fundamental element in the utilization of treatments and therapies for pain management.




    Touch is a complex sense because it represents different tactile qualities, namely, vibration, shape, texture, pleasure and pain, with different discriminative performances. Up to now, the correspondence between a touch-organ and the psychophysical sense was correlative and class-specific molecular markers are just emerging. The development of rodent tests matching the diversity of touch behavior is now required to facilitate future genomics identification. The use of mice that lack specific subsets of sensory afferent types will greatly facilitate identification of mechanoreceptors and sensory afferent fibers associated with a particular touch modality. Interestingly, a recent paper opens the important question of the genetic basis of mechanosensory traits in human and suggests that single gene mutation could negatively influence touch sensitivity.110 This underlines that the pathophysiology of the human touch deficit is in a large part unknown and would certainly progress by identifying precisely the subset of sensory neurones linked to a touch modality or a touch deficit.


    In return, progress has been made to define the biophysical properties of the mechano-gated currents.64 The development of new techniques in recent years, allowing monitoring of membrane tension changes, while recording mechano-gated current, has proved valuable experimental method to describe mechanosensitive currents with rapid, intermediate and slow adaptation (reviewed in Delmas and collaborators).66,111 The future will be to determine the role of the current properties in the mechanisms of adaptation of functionally diverse mechanoreceptors and the contribution of mechanosensitive K+ currents to the excitability of LTMRs and HTMRs.


    The molecular nature of mechano-gated currents in mammals is also a future promising research topic. Future research will progress in two perspectives, first to determine the role of accessory molecule that tether channels to the cytoskeleton and would be required to confer or regulate mechanosensitivity of ion channels of the like of TRP and ASIC/EnaC families. Second, to investigate the large and promising area of the contribution of the Piezo channels by answering key questions, relative to the permeation and gating mechanisms, the subset of sensory neurones and touch modalities involving Piezo and the role of Piezo in non neuronal cells associated with mechanosensation.


    The sense of touch, in comparison to that of sight, taste, sound and smell, which utilize specific organs to process these sensations, can occur all throughout the body through tiny receptors known as mechanoreceptors. Different types of mechanoreceptors can be found in various layers of the skin, where they can detect a wide array of mechanical stimulation. The article above describes specific highlights which demonstrate the progress of structural and functional mechanisms of mechanoreceptors associated with the sense of touch. Information referenced from the National Center for Biotechnology Information (NCBI). The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Back Pain


    Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.




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    EXTRA IMPORTANT TOPIC: Lower Back Pain Rehabilitation


    MORE TOPICS: EXTRA EXTRA: Chronic Pain Treatment



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    ]]> 0 Figure 1 Organization and Projections of Cutaneous Mechanoreceptors | El Paso, TX Chiropractor Figure 2 Tactile Receptors in Mammals | El Paso, TX Chiropractor Dr-Jimenez_White-Coat_01.png Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17506
    Understanding Abnormalities of the Pain System in El Paso, Tx Thu, 14 Jun 2018 21:45:28 +0000

    Why does localized damage or injury caused by trauma lead to chronic, intractable pain in certain patients? What's in charge of the translation of local injury with acute pain into a chronic pain condition? Why does some pain respond to anti-inflammatory drugs and/or medications, whereas other forms of pain require opiates?


    Pain is an intricate process involving both the peripheral nervous system (PNS) and the central nervous system (CNS). Tissue injury triggers the PNS, which transmits signals via the spinal cord into the brain, in which pain perception occurs. However, what causes the intense experience of pain to develop into an unremitting phenomenon? Can anything be done to prevent it? Evidence indicates that chronic pain results from a combination of mechanisms, such as neurological "memorie

    The post Understanding Abnormalities of the Pain System in El Paso, Tx appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Why does localized damage or injury caused by trauma lead to chronic, intractable pain in certain patients? What’s in charge of the translation of local injury with acute pain into a chronic pain condition? Why does some pain respond to anti-inflammatory drugs and/or medications, whereas other forms of pain require opiates?


    Pain is an intricate process involving both the peripheral nervous system (PNS) and the central nervous system (CNS). Tissue injury triggers the PNS, which transmits signals via the spinal cord into the brain, in which pain perception occurs. However, what causes the intense experience of pain to develop into an unremitting phenomenon? Can anything be done to prevent it? Evidence indicates that chronic pain results from a combination of mechanisms, such as neurological “memories” of preceding pain.


    Nociception: The Simplest Pathway


    Acute or nociceptive pain is characterized as the regular experience of discomfort which occurs in response to very basic damage or injury. It is protective, warning us to move away from the origin of the insult and take care of the trauma. The mechanisms that create nociceptive pain include transduction, which extends the external traumatic stimulation into electrical activity in specialized nociceptive primary afferent nerves. The afferent nerves then conduct the sensory information from the PNS to the CNS.


    In the CNS, the pain data is transmitted by the primary sensory neurons into central projection cells. After the information is transferred to all those areas of the brain which are responsible for our perception, the actual sensory experience happens. Nociceptive pain is a relatively simple reaction to a particularly simple, acute stimulus. But the mechanics in charge of nociceptive pain cannot identify phenomena, such as pain that persists despite removal or healing of the stimulation, such as in the instance of phantom limb pain.


    Pain and the Inflammatory Response


    In circumstances of more severe injury, such as surgical wounds, tissue damage may stimulate an inflammatory reaction. However, other conditions, especially arthritis, can also be characterized by continuing cases of inflammation associated with intense pain symptoms. The mechanisms for this type of pain related to tissue damage and an inflammatory response are different from early-warning nociceptive pain.


    Observing the incision or site of other damage or injury, a cascade of hyperexcitable events occur in the nervous system. This bodily “wind-up” phenomenon begins at the skin, where it is potentiated along the peripheral nerves, and culminates at a hypersensitivity response along the spinal cord (dorsal horn) and the brain. Inflammatory cells then surround the regions of tissue damage and also produce cytokines and chemokines, substances which are intended to mediate the process of healing and tissue regeneration. But, these agents may also be considered irritants and adjust the properties of the primary sensory neurons surrounding the area of trauma.


    Thus, the major factors which trigger inflammatory pain include damage to the high-threshold nociceptors, known as peripheral sensitization, changes and alterations of the neurons in the nervous system, and the amplification of the excitability of neurons within the CNS. This represents central sensitization and is accountable for hypersensitivity, where areas adjacent to those of the true injury will experience pain as if these were injured. These tissues can also react to stimulation which normally doesn’t create pain, such as a touch, wearing clothing, light pressure, or even brushing your own hair, as if they were truly painful, referred to as allodynia.


    Peripheral and Central Sensitization (Video)



    Other Mechanisms of Pain


    Neuropathic pain results from damage or injury to the nervous system, such as carpal tunnel syndrome, postherpetic neuralgia and diabetic neuropathy. Although some of the mechanisms which seem to cause neuropathic pain overlap with those responsible for inflammatory pain, many of them are different, and thus will need a different approach towards their management.


    The process of peripheral and central sensitization is maintained, at least theoretically and experimentally, during the excitatory neurotransmitter, glutamate, which is believed to be released when the N-methyl-D-aspartate (NMDA) receptor is activated.


    The nervous system is made up of either inhibitory or excitatory neurotransmitters. Most of what permits our nervous system to respond appropriately to damage or injury is the fine-tuning or inhibition of a variety of processes. The overexcitation of the nervous system is seen to be an issue in a number of different disorders. For instance, overactivation of an NMDA receptor can also be related to affective disorders, sympathetic abnormalities, and even opiate tolerance.


    Even ordinary nociceptive pain, to some degree, activates the NMDA receptor and is believed to lead to glutamate release. Nonetheless, in neuropathic pain, oversensitivity to the NMDA receptor is key.


    With other types of chronic pain, such as fibromyalgia and tension-type headaches, some of the mechanisms active in inflammatory and neuropathic pain may also create similar abnormalities in the pain system, including central sensitization, higher excitability of the somatosensory pathways, and reductions in central nervous system inhibitory mechanisms.


    Peripheral Sensitization


    Cyclo-oxygenase (COX) also plays an essential function in both peripheral and central sensitizations. COX-2 is one of the enzymes which are induced during the inflammatory process; COX-2 converts arachidonic acid into prostaglandins, which increase the sensitivity of peripheral nociceptor terminals. Virtually, peripheral inflammation also causes COX-2 to be produced from the CNS. Signals from peripheral nociceptors are partially responsible for this upregulation, but there also seems to be a humoral component to the transduction of the pain signals across the blood-brain barrier.


    For instance, in experimental models, COX-2 is generated from the CNS even if animals receive a sensory nerve block prior to peripheral inflammatory stimulation. The COX-2 that is expressed over the dorsal horn neurons of the spinal cord releases prostaglandins, which act on the central terminals, or the presynaptic terminals of nociceptive sensory fibers, to increase transmitter release. Additionally, they act postsynaptically on the dorsal horn neurons to produce direct depolarization. And finally, they inhibit the activity of glycine receptor, and this is an inhibitory transmitter. Therefore, the prostaglandins create an increase in excitability of central neurons.


    Peripheral and Central Sensitization | El Paso, TX Chiropractor


    Brain Plasticity and Central Sensitization


    Central sensitization describes changes which happen in the brain in reaction to repeated nerve stimulation. After repeated stimuli, amounts of hormones and brain electric signals change as neurons develop a “memory’ for reacting to those signs. Constant stimulation creates a more powerful brain memory, so the brain will respond more rapidly and effectively when undergoing the identical stimulation in the future. The consequent modifications in brain wiring and reaction are referred to as neural plasticity, which describe the capability of the brain to alter itself readily, or central sensitization. Therefore, the brain is activated or sensitized by previous or repeated stimuli to become more excitable.


    The fluctuations of central sensitization occur after repeated encounters with pain. Research in animals indicates that repeated exposure to a painful stimulation will change the animal’s pain threshold and lead to a stronger pain response. Researchers think that these modifications can explain the persistent pain that could occur even after successful back surgery. Although a herniated disc may be removed from a pinched nerve, pain may continue as a memory of the nerve compression. Newborns undergoing circumcision without anesthesia will react more profoundly to future painful stimulation, such as routine injections, vaccinations, and other painful processes. These children haven’t only a higher hemodynamic reaction, known as tachycardia and tachypnea, but they will also develop enhanced crying too.


    This neurological memory of pain was studied extensively. In a report on his previous research studies, Woolf noted that the improved reflex excitability following peripheral tissue damage or injury doesn’t rely on continuing peripheral input signals; rather, hours after a peripheral trauma, spinal dorsal horn neuron receptive fields continued to enlarge. Researchers also have documented the significance of the spinal NMDA receptor to the induction and maintenance of central sensitization.


    Mechanism of Central Sensitization | El Paso, TX Chiropractor


    Cortical Reorganization | El Paso, TX Chiropractor


    Significance for Pain Management


    Once central sensitization is established, bigger doses of analgesics are often required to suppress it. Preemptive analgesia, or therapy before pain progresses, may lower the effects of all of these stimulation on the CNS. Woolf demonstrated that the morphine dose required to stop central hyperexcitability, given before short noxious electrical stimulation in rats, was one tenth the dose required to abolish activity after it had grown. This translates to clinical practice.


    In a clinical trial of 60 patients undergoing abdominal hysterectomy, individuals who received 10 mg of morphine intravenously at the time of induction of anesthesia required significantly less morphine for postoperative pain control. Furthermore, pain sensitivity around the wound, referred to as secondary hyperalgesia, was also reduced in the morphine pretreated group. Preemptive analgesia was used with comparable success in an assortment of surgical settings, including prespinal operation and postorthopaedic operation.


    A single dose of 40 or 60 mg/kg of rectal acetaminophen has a clear morphine-sparing effect in day-case surgery in children, if administered in the induction of anesthesia. Furthermore, children with sufficient analgesia with acetaminophen experienced significantly less postoperative nausea and vomiting.


    NMDA receptor antagonists have imparted postoperative analgesia when administered preoperatively. Various reports exist in the literature supporting the use of ketamine and dextromethorphan in the preoperative period. In patients undergoing anterior cruciate ligament reconstruction, 24-hour patient-controlled analgesia opioid consumption was significantly less in the preoperative dextromethorphan category versus the placebo group.


    In double-blind, placebo-controlled research studies, gabapentin was indicated as a premedicant analgesic for patients undergoing mastectomy and hysterectomy. Preoperative oral gabapentin reduced pain scores and postoperative analgesic consumption without gap in side effects as compared with placebo.


    Preoperative administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has demonstrated a significant decrease in opioid use postoperatively. COX-2s are preferable due to their relative lack of platelet effects and significant gastrointestinal safety profile when compared with conventional NSAIDs. Celecoxib, rofecoxib, valdecoxib, and parecoxib, outside the United States, administered preoperatively reduce postoperative narcotic use by more than 40 percent, with many patients using less than half of the opioids compared with placebo.


    Blocking nerve conduction in the preoperative period appears to prevent the development of central sensitization. Phantom limb syndrome (PLS) has been attributed to a spinal wind-up phenomenon. Patients with amputation
    often have burning or tingling pain in the body part removed. One possible cause is that nerve fibers at the stump are stimulated and the brain interprets the signals as originating in the amputated portion. The other is the rearrangement within the cortical areas so that area say for the hand now responds to signals from other parts of the body but still interprets them as coming for the amputated hand.


    However, for patients undergoing lower-extremity amputation under epidural anesthesia, not one of the 11 patients who received lumbar epidural blockade with bupivacaine and morphine for 72 hours before operation developed PLS. For people who underwent general anesthesia without prior lumbar epidural blockade, 5 of 14 patients had PLS at 6 weeks and 3 continued to experience PLS at 1 year.


    Woolf and Chong have noted that perfect preoperative, intraoperative, and postoperative treatment comprises of “NSAIDs to reduce the activation/centralization of nociceptors, local anesthetics to block sensory inflow, and centrally acting drugs such as opiates.” Decreasing perioperative pain with preemptive techniques enhances satisfaction, hastens discharge, spares opioid use, along with diminished constipation, sedation, nausea, and urinary retention, and may even stop the development of chronic pain. Anesthesiologists and surgeons should consider integrating these techniques in their everyday practices.


    When pain occurs as a result of damage or injury in consequence of surgery, the spinal cord can attain a hyperexcitable state wherein excessive pain reactions occur that may persist for days, weeks or even years.


    Why does localized injury resulting from trauma result in chronic, intractable pain in some patients? Tissue injury leads to a constellation of changes in spinal excitability, including elevated spontaneous firing, greater response amplitude and length, decreased threshold, enhanced discharge to repeated stimulation, and expanded receptive fields. The persistence of these changes, which are collectively termed central sensitization, appears to be fundamental to the prolonged enhancement of pain sensitivity which defines chronic pain. Numerous drugs and/or medications as well as local anesthetic neural blockade may limit the magnitude of the central nervous system (CNS) windup, as evidenced by diminished pain and diminished opioid consumption in the preemptive analgesic models.



    Dr. Alex Jimenez’s Insight

    Chiropractic care is an alternate treatment option which utilizes spinal adjustments and manual manipulations to safely and effectively restore as well as maintain the proper alignment of the spine. Research studies have determined that spinal misalignments, or subluxations, can lead to chronic pain. Chiropractic care is commonly utilized for pain management, even if the symptoms are not associated to an injury and/or condition in the musculoskeletal and nervous system. By carefully re-aligning the spine, a chiropractor can help reduce stress and pressure from the structures surrounding the main component of out body’s foundation, ultimately providing pain relief.


    Enteric Nervous System Function and Pain


    When it comes to the diminished use of drugs and/or medications, including opioids, in order to prevent side-effects like gastrointestinal health issues, the proper function of the enteric nervous system may be at play.


    The enteric nervous system (ENS) or intrinsic nervous system is one of the key branches of the autonomic nervous system (ANS) and consists of a mesh-like system of nerves which modulates the role of the gastrointestinal tract. It’s capable of acting independently of the sympathetic and parasympathetic nervous systems, even though it might be affected by them. The ENS can also be called the second brain. It is derived from neural crest cells.


    The enteric nervous system in humans is made up of some 500 million neurons, including the numerous types of Dogiel cells, approximately one two-hundredth of the amount of neurons in the brain. The enteric nervous system is inserted into the lining of the gastrointestinal system, beginning at the esophagus and extending down to the anus. Dogiel cells, also known as cells of Dogiel, refers to some kind of multipolar adrenal tissues within the prevertebral sympathetic ganglia.


    Cells of Dogiel | El Paso, TX Chiropractor


    The ENS is capable of autonomous functions, such as the coordination of reflexes; even though it receives considerable innervation in the autonomic nervous system, it does and can operate independently of the brain and the spinal cord. The enteric nervous system has been described as the “second brain” for a number of reasons. The enteric nervous system may operate autonomously. It normally communicates with the central nervous system (CNS) via the parasympathetic, or via the vagus nerve, and the sympathetic, that is through the prevertebral ganglia, nervous systems. However, vertebrate studies reveal that when the vagus nerve is severed, the enteric nervous system continues to function.


    In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, all of which make the enteric nervous system capable of carrying reflexes and acting as an integrating center in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. The enteric nervous system has the ability to change its response based on such factors as nutrient and bulk composition. In addition, ENS contains support cells that are much like astroglia of the brain and a diffusion barrier around the capillaries surrounding ganglia that’s like the blood-brain barrier of blood vessels.


    The enteric nervous system (ENS) plays a pivotal role in inflammatory and nociceptive processes. Drugs and/or medications that interact with the ENS have recently raised considerable interest because of their capacity to regulate numerous aspects of the gut physiology and pathophysiology. In particular, experiments in animals have demonstrated that proteinase-activated receptors (PARs) may be essential to neurogenic inflammation in the intestine. Moreover, PAR2 agonists seem to induce intestinal hypersensitivity and hyperalgesic states, suggesting a role for this receptor in visceral pain perception.


    Furthermore, PARs, together with the proteinases that activate them, represent exciting new targets for therapeutic intervention on the ENS. The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez




    Additional Topics: Sciatica

    Sciatica is medically referred to as a collection of symptoms, rather than a single injury and/or condition. Symptoms of sciatic nerve pain, or sciatica, can vary in frequency and intensity, however, it is most commonly described as a sudden, sharp (knife-like) or electrical pain that radiates from the low back down the buttocks, hips, thighs and legs into the foot. Other symptoms of sciatica may include, tingling or burning sensations, numbness and weakness along the length of the sciatic nerve. Sciatica most frequently affects individuals between the ages of 30 and 50 years. It may often develop as a result of the degeneration of the spine due to age, however, the compression and irritation of the sciatic nerve caused by a bulging or herniated disc, among other spinal health issues, may also cause sciatic nerve pain.




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    ]]> 0 Understanding Abnormalities of the Pain System in El Paso, Tx | PushAsRx Athletic Training Centers El Paso, TX Abnormalities of the pain system, such as peripheral and central sensitization, have shown a significance in the development of chronic pain. abnormalities,chiropractic,clinical neurophysiology,dralexjimenez,health,pain system,treatment,wellness,pain Peripheral and Central Sensitization | El Paso, TX Chiropractor Mechanism of Central Sensitization | El Paso, TX Chiropractor Cortical Reorganization | El Paso, TX Chiropractor Dr-Jimenez_White-Coat_01.png Cells of Dogiel | El Paso, TX Chiropractor Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17429
    Pain Modulation Pathway Mechanisms in El Paso, TX Wed, 13 Jun 2018 21:37:19 +0000

    Most, if not all, ailments of the body trigger pain. Pain is interpreted and sensed in the brain. Pain is modulated by two key types of drugs which operate on the brain: analgesics and anesthetics. The term analgesic refers to a medication that relieves pain without loss of consciousness. The expression central anesthesia refers to a medication that depresses the CNS. It's distinguished by the lack of all perception of sensory modalities, for instance, loss of consciousness without loss of critical functions.


    Opiate Analgesia (OA)


    The most successful clinically used drugs for producing temporary analgesia and relief from pain are the opioid family, which includes morphine, and heroin. There are currently no additional powerful pain therapeutic options to opiates. Several side effects caused by opiate use include tolerance and drug dependence or addiction. In general, these dru

    The post Pain Modulation Pathway Mechanisms in El Paso, TX appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Most, if not all, ailments of the body trigger pain. Pain is interpreted and sensed in the brain. Pain is modulated by two key types of drugs which operate on the brain: analgesics and anesthetics. The term analgesic refers to a medication that relieves pain without loss of consciousness. The expression central anesthesia refers to a medication that depresses the CNS. It’s distinguished by the lack of all perception of sensory modalities, for instance, loss of consciousness without loss of critical functions.


    Opiate Analgesia (OA)


    The most successful clinically used drugs for producing temporary analgesia and relief from pain are the opioid family, which includes morphine, and heroin. There are currently no additional powerful pain therapeutic options to opiates. Several side effects caused by opiate use include tolerance and drug dependence or addiction. In general, these drugs modulate the incoming pain information in the spine and central nervous system, in addition to relieve pain temporarily, and can also be called opiate producing analgesia (OA). Opiate antagonist is a drug that antagonizes the opioid effects, such as naloxone or maltroxone, etc.. They are competitive antagonists of opiate receptors. However, the brain has a neuronal circuit and endogenous substances which modulate pain.


    Endogenous Opioids


    Opioidergic neurotransmission is located throughout the brain and spinal cord and is believed to influence many functions of the central nervous system, or CNS, such as nociception, cardiovascular functions, thermoregulation, respiration, neuroendocrine functions, neuroimmune functions, food consumption, sexual activity, competitive locomotor behaviour as well as memory and learning. Opioids exert marked effects on mood and motivation and produce a sense of euphoria.


    Three classes of opioid receptors are identified: μ-mu, δ-delta and κ-kappa. All 3 classes are widely dispersed in the brain. The genes encoding each one of these have been cloned and found to function as members of the G protein receptors. Moreover, three major types of endogenous opioid peptides that interact with the above opiate receptors have been recognized in the central nervous system, including, β-endorphins, enkephalins and the dynorphins. These 3 opioid peptides are derived from a large protein receptor by three different genes, such as the proopiomelanocortin, or POMC, gene, the proenkephalin gene and the prodynorphin gene. The opioid peptides modulate nociceptive input in two ways: first, they block neurotransmitter release by inhibiting Ca2+ influx into the presynaptic terminal, or second, they open potassium channels, which hyperpolarizes neurons and inhibits spike activity. They act on various receptors within the brain and spinal cord.


    Enkephalins are considered the putative ligands for the δ receptors, β endorphins for its μ-receptors, and dynorphins for the κ receptors. The various types of opioid receptors are distributed differently within the peripheral and central nervous system, or CNS. There’s evidence for functional differences in these receptors in various structures. This explains why many undesirable side effects occur after opiate treatments. For instance, mu (μ) receptors are widespread in the brain stem parabrachial nuclei, where a respiratory center and inhibition of these neurons may cause what’s known as respiratory depression.


    Endogenous Opioids Diagram 4 | El Paso, TX Chiropractor


    Central or peripheral terminals of nociceptive afferent fibers feature opiate receptors in which exogenous and endogenous opioids could act to modulate the capability to transmit nociceptive information. Additionally, high densities of opiate receptors are found in periaqueductal gray, or PAG, nucleus raphe magnus, or NRM, and dorsal raphe, or DR, from the rostral ventral medulla, in the spinal cord, caudate nucleus, or CN, septal nucleus, hypothalamus, habenula and hippocampus. Systemically administered opioids at analgesic dosages activate spinal and supraspinal mechanisms via μ, δ, and κ type opioid receptors and regulate pain signals to modulate symptoms.


    Neuronal Circuits and Pain Modulation


    For many decades it was suggested that somewhere in the central nervous system there is a circuit which can modulate incoming pain details. The gate control theory and the ascending/descending pain transmission system are two suggestions of such a circuit. Below, we will discuss both in further detail.


    Gate Control Theory


    The initial pain modulatory mechanism known as the gate control theory, has been proposed by Melzack and Wall in the mid 1960’s. The notion of the gate control theory is that non-painful input closes the gates to painful input, which results in avoidance of the pain sensation from travel into the CNS, for example, non-noxious input, or stimulation, suppresses pain.


    The theory implies that collaterals of the large sensory fibers carrying cutaneous sensory input activate inhibitory interneurons, which inhibit and regulate pain transmission data carried from the pain fibers. Non-noxious input inhibits pain, or sensory input, and closes the gate to noxious input. The gate control theory demonstrates that in the spinal cord level, non-noxious stimulation will create presynaptic inhibition on dorsal root nociceptor fibers that synapse on nociceptors spinal neurons (T). This presynaptic inhibition will also prevent incoming noxious information from reaching the CNS, for example, it will shut the gate to incoming toxic information.


    Gate Control Theory Diagram 1 | El Paso, TX Chiropractor


    The gate control theory was the rationale for the idea behind the production and utilization of the transcutaneous electrical nerve stimulation, or TENS, for pain relief. In order to be effective, the TENS unit generates two different present frequencies below the pain threshold that can be taken by the patient. This process has found a degree of achievement in chronic pain treatment.


    Pain Modulation: Gate Control Theory



    Stimulation Produced Analgesia (SPA)


    Evidence for an inherent analgesia system was found by intracranial electrical stimulation of certain discrete brain regions. These areas would be the periaqueductal gray, or PAG, and nucleus raphe magnus, or NRM, dorsal raphe, or DR, caudate nucleus, or CN, septal nucleus, or Spt, along with other nuclei. Such stimulation or sensory signals, inhibits pain, making analgesia without behavioral suppression, while the touch, temperature and pressure sensation stays intact. According to research studies, SPA, or stimulation produced analgesia, is more pronounced and continues for a longer period of time after stimulation in humans than in experimental animals. Additionally, during SPA, the subjects, however, still respond to nonpainful stimulation like temperature and touch within the circumscribed region of analgesia. The most effective CNS, or central nervous system regions for SPA to occur, would be in the PAG and the raphe nuclei, or RN.


    Electrical stimulation of PAG or NRM inhibits spinal thalamic cells, or spinal neurons that project monosynaptically to the thalamus, in laminae I, II and V to ensure the noxious information from the nociceptors which are ultimately modulated in the level of the spinal cord. Furthermore, PAG has neuronal connections to the nucleus raphe magnus, or NRM.


    The activity of the PAG most likely occurs by activation of the descending pathway from NRM and likely also by activation of ascending connections acting on greater subcortical levels of the CNS. In addition, electric stimulation of PAG or NRM produces behavioral analgesia, or stimulation produced analgesia. Stimulation produced analgesia, or SPA causes the release of endorphins which can be blocked by the opiate antagonist naloxone.


    During PAG and/or RN stimulation, serotonin, also medically referred to as 5-HT, can also be discharged from ascending and descending axons from subcortical nuclei, in spinal trigeminal nuclei and in the spinal cord. This release of 5-HT modulates and regulates pain transmission by inhibiting or blocking incoming neural action. Depletion of 5-HT by electrical lesion of the raphe nuclei or with a neurotoxic lesion made by local injection of a chemical agent such as parachlorophenylalanine, or PCPA, results in blocking the power of opiate, both intracranial and systemic, as well as that of electrical stimulation in order to produce analgesia.


    To confirm if the electric stimulation produced analgesia via the release of opiate and dopamine, then the region is locally microinjected with morphine or 5-HT. All these microinjections ultimately create analgesia. These processes also provide a way of identifying brain areas related to pain suppression and assist to produce a map of pain centers. The most effective way of producing opiate analgesia, or OA, is by intracerebral injection of morphine into the PAG.


    The PAG and RN as well as other brain structures in which analgesia is produced, are also rich in opiate receptors. Intracerebral opioid administration produced analgesia and SPA can be blocked by systemic or from local microinjections of naloxone, the morphine antagonist, into the PAG or RN. For that reason, it’s been suggested that the two, both OA and SPA, operate by a frequent mechanism.


    If OA and SPA behave through the same intrinsic system, then the hypothesis that opiates activate a pain-suppression mechanism is much more likely. As a matter of fact, current evidence suggests that microinjections of an opiate into the PAG activate an efferent brainstem system which inhibits pain transmission at segmental spinal cord levels. These observations imply that analgesia elicited from the periaqueductal gray, or PAG, demands a descending pathway into the spinal cord.



    Dr. Alex Jimenez’s Insight

    Pain modulation occurs through the process of electrical brain stimulation which occurs due to the activation of descending inhibitory fibers, which regulate or inhibit the input and output of certain neurons. What has been described as opioid and serotonergic antagonists, is believed to reverse both local opiate analgesia and brain-stimuli generated analgesia. The sensory signals or impulses in the central nervous system are ultimately controlled by both ascending and descending inhibitory systems, utilizing endogenous opioids or other endogenous substances, such as serotonin as inhibitory mediators. Pain is a complex perception which can also be influenced by a variety of other factors, including emotional state.


    Mechanisms of Pain Modulation


    Ascending and Descending Pain Suppression Mechanism


    The primary ascending pain fibers, such as the A δ and C fibers, reach the dorsal horn of the spinal cord from peripheral nerve areas in order to innervate the nociceptor neurons in Rexed laminae I & II. Cells from Rexed lamina II make synaptic connections in Rexed layers IV to VII. Cells, particularly within laminae I and VII of the dorsal horn, give rise to ascending spinothalamic tracts. In the spinal level, opiate receptors are located in the presynaptic endings of their nocineurons and in the interneural level layers IV to VII from the dorsal horn.


    Activation of opiate receptors at the interneuronal level produces hyperpolarization of the neurons, which lead to the the inhibition of activation as well as the release of substance P, a neurotransmitter involved in pain transmission, thus preventing pain transmission. The circuit which consists of the periaqueductal gray, or PAG, matter in the upper brain stem, the locus coeruleus, or LC, the nucleus raphe magnus, or the NRM, and the nucleus reticularis gigantocellularis, or Rgc,  leads to the descending pain suppression pathway, which inhibits incoming pain data at the spinal cord level.


    As stated before, opioids interact with the opiate receptors in distinct central nervous system levels. These opiate receptors are the normal target regions for hormones and endogenous opiates, such as the endorphins and enkephalins. Due to binding at the receptor in subcortical websites, secondary changes which result in some change in the electrophysiological properties of the neurons and regulation of their ascending pain information.


    Ascending and Descending Pain Suppression Mechanism Diagram 2 | El Paso, TX Chiropractor


    Ascending and Descending Pain Suppression Mechanism Diagram 3 | El Paso, TX Chiropractor


    What activates the PAG to exert its consequences? It was discovered that noxious stimulation triggers neurons in the nucleus reticularis gigantocellularis, or RGC. The nucleus Rgc innervates both PAG and NRM. The PAG sends axons into the NRM, and nerves in the NRM send their axons to the spinal cord. Additionally, bilateral dorsolateral funiculus, or DLF, lesions, referred to as DLFX, block the analgesia produced by both electrical stimulation and by microinjection of opiates directly into the PAG and NRM, but they just attenuate the systemic analgesic effects of opiates. These observations support the hypothesis that discrete descending pathways from the DLF are necessary for both OA and SPA.


    The DLF is comprised of fibers originating from several brainstem nuclei, which can be serotonergic, or 5-HT, from nerves located inside the nucleus raphe magnus, or NRM; dopaminergic neurons originating from ventral tegmental area, or VTA, and adrenergic neurons originating from the locus coeruleus, or LC. These descending fibers suppress noxious input in the nociceptive spinal cord neurons in laminae I, II, and V.


    Opiate receptors have also been discovered in the dorsal horn of the spinal cord, chiefly in Rexed laminae I, II, and V, and such spinal opiate receptors mediate inhibitory effects on dorsal horn neurons transmitting nociceptive information. The action of morphine seems to be exerted equally in the spinal cord and brainstem nuclei, including the PAG and NRM. Systemic morphine acts on both brain stem and spinal cord opiate receptors to produce analgesia. Morphine binds the brainstem opiate receptors, which triggers the brainstem descending serotonergic pathway into the spinal cord as well as the DLF, and these have an opioid-mediated synapse at the level of the spinal cord.


    This observation demonstrates that noxious stimuli, instead of non-noxious stimulus, determine the gate control theory, which are critical for the activation of the descending pain modulation circuit where pain inhibits pain via the descending DLF pathway. In addition, there are ascending connections in the PAG and the raphe nuclei into the PF-CM complex. These thalamic regions are a part of the ascending pain modulation at the diencephalon degree.


    Stress Induced Analgesia (SIA)


    Analgesia may be produced in certain stressful circumstances. Exposure to many different stressful or painful events generates an analgesic response. This phenomenon is known as stress induced analgesia, or SIA. Stress induced analgesia has been believed to give insight into the physiological and psychological factors that trigger endogenous pain control and opiate systems. By way of instance, soldiers injured in battle or athletes hurt in sports sometimes report that they don’t feel pain or discomfort during the battle or game, nevertheless, they will go through the pain afterwards once the specific situation has stopped. It’s been demonstrated in animals that electrical shocks cause stress-induced analgesia. Based on these experiments, it is assumed that the pressure the soldiers and the athletes experienced suppressed the pain which they would later experience.


    It’s believed that endogenous opiates are produced in response to stress and inhibit pain by triggering the midbrain descending system. Furthermore, some SIA exhibited cross tolerance with opiate analgesia, which indicates that this SIA is mediated via opiate receptors. Experiments using different parameters of electrical shock stimulation demonstrate such stress induced analgesia and some of those anxieties that produce analgesia could be blocked by the opioid antagonist naloxone, whereas others were not blocked by naloxone. In conclusion, these observations lead to the decision that both opiate and non-opiate forms of SIA exist.


    Somatovisceral Reflex


    The somatovisceral reflex is a reflex in which visceral functions are activated or inhibited by somatic sensory stimulation. In experimental animals, both noxious and innocuous stimulation of somatic afferents are proven to evoke reflex changes in sympathetic efferent activity and, consequently, effector organ function. These phenomena have been shown in such regions as the gastrointestinal tract, urinary tract, adrenal medulla, lymphatic cells, heart and vessels of the brain and peripheral nerves.


    Most frequently, incisions are elicited experimentally by stimulation of cutaneous afferents, even though some work has also been conducted on muscle and articular afferents, including those of spinal cells. The ultimate responses will represent the integration of multiple tonic and reflex influences and might exhibit laterality and segmental trends as well as variable excitability in line with the afferents involved. Given the complexity and multiplicity of mechanisms involved in the last expression of the reflex response, attempts to extrapolate to clinical situations should most likely be conducted in favor of further systematic physiological studies.


    The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez




    Additional Topics: Sciatica

    Sciatica is medically referred to as a collection of symptoms, rather than a single injury and/or condition. Symptoms of sciatic nerve pain, or sciatica, can vary in frequency and intensity, however, it is most commonly described as a sudden, sharp (knife-like) or electrical pain that radiates from the low back down the buttocks, hips, thighs and legs into the foot. Other symptoms of sciatica may include, tingling or burning sensations, numbness and weakness along the length of the sciatic nerve. Sciatica most frequently affects individuals between the ages of 30 and 50 years. It may often develop as a result of the degeneration of the spine due to age, however, the compression and irritation of the sciatic nerve caused by a bulging or herniated disc, among other spinal health issues, may also cause sciatic nerve pain.




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    The post Pain Modulation Pathway Mechanisms in El Paso, TX appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 Pain Modulation Pathway Mechanisms in El Paso, TX | PushAsRx Athletic Training Centers El Paso, TX Pain modulation occurs through the process of electrical brain stimulation that occurs due to the activation of descending inhibitory fibers. chiropractic care,chronic pain,clinical neurophysiology,dralexjimenez,health,pain,pain modulation pathways,wellness,pain modulation Endogenous Opioids Diagram 4 | El Paso, TX Chiropractor Gate Control Theory Diagram 1 | El Paso, TX Chiropractor Dr-Jimenez_White-Coat_01.png Ascending and Descending Pain Suppression Mechanism Diagram 2 | El Paso, TX Chiropractor Ascending and Descending Pain Suppression Mechanism Diagram 3 | El Paso, TX Chiropractor Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17413
    What is Central Sensitization? | El Paso, TX Chiropractor Mon, 11 Jun 2018 22:04:19 +0000

    Central sensitization is a state of the nervous system that's related to the development and maintenance of chronic pain. When central sensitization occurs, the nervous system goes through a procedure known as wind-up and gets regulated in a constant condition of increased reactivity. This persistent, or regulated, state of reactivity decreases the threshold for what causes pain and subsequently learns to keep pain after the initial injury has healed. Central sensitization has two major characteristics. Both have an increased sensitivity to pain and to the feeling of touch. These are referred to as allodynia and hyperalgesia.


    Allodynia occurs when an individual experiences pain with circumstances that are normally not supposed to be painful. For instance, chronic pain patients

    The post What is Central Sensitization? | El Paso, TX Chiropractor appeared first on PushAsRx Athletic Training Centers El Paso, TX.


    Central sensitization is a state of the nervous system that’s related to the development and maintenance of chronic pain. When central sensitization occurs, the nervous system goes through a procedure known as wind-up and gets regulated in a constant condition of increased reactivity. This persistent, or regulated, state of reactivity decreases the threshold for what causes pain and subsequently learns to keep pain after the initial injury has healed. Central sensitization has two major characteristics. Both have an increased sensitivity to pain and to the feeling of touch. These are referred to as allodynia and hyperalgesia.


    Allodynia occurs when an individual experiences pain with circumstances that are normally not supposed to be painful. For instance, chronic pain patients often experience pain even with things as simple as touch or a massage. In these situations, nerves in the region which has been touched sends signals through the nervous system into the brain. Because the nervous system is in a constant condition of heightened reactivity, the brain doesn’t generate a mild feeling of touch as it should, given that the stimulus that initiated it was an easy touch or massage. Instead, the brain produces a feeling of pain and discomfort.


    Hyperalgesia occurs when a stimulus that’s usually considered to be somewhat painful is perceived as a much more debilitating pain than it ought to be. For instance, chronic pain patients that experience a simple bump, which generally would be mildly painful, will often feel intense pain. Again, once the nervous system is in a constant condition of high reactivity, it amplifies pain.


    Peripheral and Central Sensitization



    Chronic pain patients sometimes believe they might be suffering from a mental health issue because they understand from common sense that touch or simple bumps produce tremendous amounts of pain or discomfort. Other times, it’s not the patients themselves who feel this way, but their friends and family members. Individuals who don’t suffer with chronic pain may witness others who have central sensitization experience pain at the slightest touch or cry out at the simplest bump. However, because they don’t have the condition, it may be difficult for them to understand what someone who does is going through.


    In addition to allodynia and hyperalgesia, central sensitization has other well-known features, though they may occur less commonly. Central sensitization may lead to heightened sensitivities throughout all senses, not only the feeling of touch. Chronic pain patients can sometimes report sensitivities to light, smell and sound. As such, regular levels of light may seem overly bright or even the perfume aisle in the department shop can produce a headache. Central sensitization can also be associated with cognitive deficits, such as poor concentration and poor short-term memory. Central sensitization also interferes with increased levels of psychological distress, particularly fear and axiety. After all, the nervous system is responsible for not merely senses, like pain, but also emotions. If the nervous system is trapped in a constant condition of reactivity, patients are going to be nervous or anxious. Lastly, central sensitization is also correlated with sick role behaviors, such as resting and malaise, and pain behavior.


    Central sensitization has long been known as a potential consequence of stroke and spinal cord injury. However, it is increasingly believed that it plays a part in several different chronic pain disorders. It may happen with chronic low back pain, chronic neck pain, whiplash injuries, chronic tension headaches, migraine headaches, rheumatoid arthritis, osteoarthritis of the knee, endometriosis, injuries sustained in an automobile accident, and even following surgeries. Fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome, all appear to occur due to central sensitization as well.


    Central Sensitization and C Fibers



    What Causes Central Sensitization?


    Central sensitization involves specific changes to the nervous system. Changes in the dorsal horn of the spinal cord and in the brain occur, particularly at the cellular level, such as at the receptor sites. As mentioned previously, it has long been proven that fractures and spinal cord injuries can cause central sensitization. It stands to reason. Strokes and spinal cord injuries cause harm to the central nervous system, including the brain, in the event of strokes, and the spinal cord, in the case of spinal cord injuries. These injuries change the sections of the nervous system which are involved in central sensitization.


    However, what about the other, more prevalent, types of chronic pain disorders, recorded above, such as headaches, chronic back pain, or pain in the extremities? The accidents or conditions which lead to these kinds of chronic pain are not direct injuries to the brain or spinal cord. Rather, they include injuries or condition which affect the peripheral nervous system, particularly in that are of the nervous system which lies outside the spinal cord and brain. How can health issues associated with the peripheral nervous system contribute to modifications in the central nervous system and cause chronic pain in the isolated area of the initial injury? In summary, how can isolated migraine headaches eventually become chronic daily headaches? How can an acute low back lifting injury become chronic low back pain? How does an injury to the hand or foot turn into a complex regional pain syndrome?


    There are probably multiple factors that cause the development of central sensitization in these ‘peripheral’ chronic pain disorders. These variables may be divided into two classes:


    • Factors that are associated with the state of the central nervous system before onset of the initial pain or injury condition
    • Factors that are associated with the central nervous system following onset of the initial pain or injury condition


    The first group involves those factors that might predispose individuals to developing central sensitization once an accident occurs and the next group involves antecedent factors that boost central sensitization once pain begins.



    Dr. Alex Jimenez’s Insight

    Chronic pain can often modify the way the central nervous system itself functions, so much so that a patient may become more sensitive to pain with less provocation. This is what’s referred to as central sensitization and it generally involves changes in the central nervous system, or CNS, more specifically, in the brain and the spinal cord. Central sensitization has been associated with several common diseases and it’s even been reported to develop with something as simple as a muscle ache. Central sensitization has also been documented to persist and worsen even in the absence of obvious provocation. Several factors have also been attributed with the development of central sensitization, although the true cause is still unknown.


    Predisposing Factors for Central Sensitization


    There are probably biological, emotional, and environmental predisposing factors for central sensitization. Low and higher sensitivity to pain, or pain thresholds, are perhaps in part due to numerous genetic factors. While there’s absolutely no research as of yet to support a causal link between pre-existing pain thresholds and following development of central sensitization after an incident, it’s largely assumed that it will be eventually found.


    Psychophysiological factors, like the stress-response, are also apt to play a part in the development of central sensitization. Direct experimental evidence on animals and humans, as well as prospective studies on humans, have demonstrated a connection between stress and the decrease of pain thresholds. Similarly, different kinds of pre-existing anxiety about pain is consistently related to higher pain sensitivities. All these psychophysiological aspects suggest that the preexisting state of the nervous system is also an important determinant of creating central sensitization after the onset of pain. If the stress response has made the nervous system responsive prior to injury, then the nervous system might be more prone to become sensitized once onset of pain happens.


    There is considerable indirect evidence for this theory as well. A prior history of anxiety, physical and psychological trauma, and depression are predictive of onset of chronic pain later in life. The most common denominator between chronic pain, anxiety, nervousness, injury, and depression, is the nervous system. They’re all states of the nervous system, especially a persistently changed, or dysregulated, nervous system.


    It’s not that such pre-existing health issues make individuals more vulnerable to injury or the onset of illness, as injury or illness is apt to happen on a somewhat random basis across the populace. Instead, these pre-existing health issues are more inclined to make people prone to the development of chronic pain once an injury or disease occurs. The dysregulated nervous system, at the time of injury, for instance, may interfere with the normal trajectory of healing and thereby stop pain from subsiding once tissue damage is healed.


    Factors Resulting in Central Sensitization After Onset of Pain


    Predisposing factors may also be part of the development of central sensitization. The onset of pain is frequently associated with subsequent development of conditions, such as depression, fear-avoidance, nervousness or anxiety and other phobias. The stress of those responses can, in turn, further exacerbate the reactivity of the nervous system, leading to central sensitization. Inadequate sleep is also a frequent effect of living with chronic pain. It’s associated with increased sensitivity to pain as well. In what’s technically known as operant learning, interpersonal and environmental reinforcements have long been proven to lead to pain behaviors, however, it is also evident that such reinforcements may lead to the development of central sensitization.


    Mayo Clinic Discusses Central Sensitization



    Treatments of Central Sensitization


    Treatments for chronic pain syndromes that involve fundamental sensitization typically target the central nervous system or the inflammation which corresponds with central sensitization. All these often generally include antidepressants and anticonvulsant medications, and cognitive behavioral treatment. While usually not considered to target the central nervous system, regular mild aerobic exercise changes structures in the central nervous system and contributes to reductions in the pain of many ailments which are mediated by central sensitization. As such, moderate aerobic exercise is used to treat chronic pain syndromes marked by central sensitization. Non-steroidal anti-inflammatories are utilized for the inflammation associated with central sensitization.


    Finally, chronic pain rehabilitation programs are a standard, interdisciplinary treatment that employs each of the above-noted therapy strategies in a coordinated manner. They also make the most of the research on the role of operant learning from central sensitization and also have developed behavioral interventions to reduce the pain and discomfort associated with the health issue. Such applications are typically considered the most effective treatment option for chronic pain syndromes. The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .


    Curated by Dr. Alex Jimenez


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    Additional Topics: Sciatica

    Sciatica is medically referred to as a collection of symptoms, rather than a single injury and/or condition. Symptoms of sciatic nerve pain, or sciatica, can vary in frequency and intensity, however, it is most commonly described as a sudden, sharp (knife-like) or electrical pain that radiates from the low back down the buttocks, hips, thighs and legs into the foot. Other symptoms of sciatica may include, tingling or burning sensations, numbness and weakness along the length of the sciatic nerve. Sciatica most frequently affects individuals between the ages of 30 and 50 years. It may often develop as a result of the degeneration of the spine due to age, however, the compression and irritation of the sciatic nerve caused by a bulging or herniated disc, among other spinal health issues, may also cause sciatic nerve pain.




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    The post What is Central Sensitization? | El Paso, TX Chiropractor appeared first on PushAsRx Athletic Training Centers El Paso, TX.

    ]]> 0 What is Central Sensitization? | El Paso, TX Chiropractor | PushAsRx Athletic Training Centers El Paso, TX Chronic pain believed to cause a patient to become more sensitive to pain with less provocation, is known as central sensitization. central sensitization,chiropractic care,clinical neurophysiology,dralexjimenez,health,wellness,central sensitization Dr-Jimenez_White-Coat_01.png Green-Call-Now-Button-24H-150x150-2-3.png blog picture of cartoon paperboy big news 17378