Endogenous Pain Inhibition Research Articles

Lean mass predicts conditioned pain modulation in adolescents across weight status.

There is a wide continuum of conditioned pain modulation (CPM) in adults with older adults experiencing an attenuated CPM response compared with younger adults. Less is known for adolescents and the role of anthropometrics. Fifty-six adolescents (15.1±1.8years; 32 normal weight and 24 overweight/obese; 27 boys) completed in a CPM session that included anthropometric testing. Pressure pain thresholds were measured at the nailbed and deltoid muscle (test stimuli) with the foot submerged in a cool or ice water bath (conditioning stimulus). Weight status, body composition (Dual-energy X-ray absorptiometry scan), physical activity levels and clinical pain were also evaluated. The CPM response in adolescents was similar across sites (nailbed vs. deltoid), weight status (normal vs. overweight/obese) and sex. CPM measured at the deltoid muscle was positively associated with left arm lean mass but not fat mass; lean mass of the arm uniquely predicted 10% of the CPM magnitude. CPM measured at the nailbed was positively correlated with physical activity levels. These results suggest that lean mass and physical activity levels may contribute to endogenous pain inhibition in adolescents across weight status.

Mechanism of Action of Spinal Mobilizations: A Systematic Review.

Systematic review. To review the evidence regarding the mechanism of action of mobilizations. Spinal mobilizations-low velocity passive oscillatory movements-reduce spinal pain in some patient subgroups. Identifying patients likely to respond remains a challenge since mobilizations' mechanism(s) of action are unclear. Medline, Web of Science, Cinahl, Embase, and Scopus databases were searched for relevant studies. Reference lists of included studies were hand searched. Studies were included if the intervention was passive spinal mobilizations, participants were symptomatic, and outcomes evaluated possible mechanisms of action. Methodological quality was independently assessed by two assessors using a modified Cochrane Back Review Group tool. Twenty-four studies were included in the review. Four were classified high risk, 14 moderate risk, and four low risk of bias. Commonest methodological limitations were lack of participant blinding, adequate randomization and allocation concealment, and sample size calculation. Evidence suggests that spinal mobilizations cause neurophysiological effects resulting in hypoalgesia (local and/or distal to mobilization site), sympathoexcitation, and improved muscle function. Mobilizations have no effect on temperature pain threshold. Three of four studies reported reduction in spinal stiffness, heterogeneous in location and timing. There is limited evidence (one study in each case) to suggest that mobilizations produce increased nociceptive flexion reflex threshold, improved posture, decreased concentration of substance P in saliva, and improved sway index measured in cervical extension. Evidence does not support an effect on segmental vertebral movement. Two studies investigated correlations between hypoalgesia and mechanism: one found a correlation with sympathoexcitatory changes, whereas the other found no correlation with change in stiffness. These findings suggest involvement of an endogenous pain inhibition system mediated by the central nervous system, although this is yet to be investigated directly. There is limited evidence regarding other possible mechanisms. 3.

The influence of offset analgesia on the onset and offset of pain in patients with fibromyalgia.

Offset analgesia (OA) is a form of endogenous pain inhibition characterized by a disproportionately large reduction in pain perception after a small decrease in temperature during noxious thermal stimulation. In this study, the presence of OA was evaluated in patients with fibromyalgia and compared with healthy age-matched and sex-matched controls. Offset analgesia was induced by noxious thermal stimulation on the arm, causing a visual analog score (VAS) of about 50 mm, followed by a 1°C temperature decrease. The OA response is defined by the reduction in VAS induced by the 1°C stimulus decrease. To assess whether the OA response could be enhanced, 2 tests were applied: repetition of the OA paradigm and 1°C temperature downward steps after an initial OA test (downward step test). To assess whether OA affects onset of pain, OA steps at increasing temperatures (upward OA step test) were applied. Patients with fibromyalgia had reduced OA responses with a reduction in VAS of 65.3 ± 4.5% (mean ± SD) vs controls 97.8 ± 4.6% (P < 0.001). Decreased OA responses were not enhanced or restored by repeating the OA paradigm or by the downward step test. Defective engagement of OA had a significant effect on pain onset, as observed from the upward OA step test, with less tolerability to noxious pain stimulation in patients with fibromyalgia. In conclusion, patients with fibromyalgia showed less pain inhibition as measured by the OA paradigm, which influenced both the onset and offset of pain.

Psychosocial, Physical, and Neurophysiological Risk Factors for Chronic Neck Pain: A Prospective Inception Cohort Study

The purpose of this investigation was to identify modifiable risk factors for the development of first-onset chronic neck pain among an inception cohort of healthy individuals working in a high-risk occupation. Candidate risk factors identified from previous studies were categorized into psychosocial, physical, and neurophysiological domains, which were assessed concurrently in a baseline evaluation of 171 office workers within the first 3 months of hire. Participants completed monthly online surveys over the subsequent year to identify the presence of chronic interfering neck pain, defined as a Neck Disability Index score ≥5 points for 3 or more months. Data were analyzed using backward logistic regression to identify significant predictors within each domain, which were then entered into a multivariate regression model adjusted for age, sex, and body mass index. Development of chronic interfering neck pain was predicted by depressed mood (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 1.10–10.31, P = .03), cervical extensor endurance (OR = .92, 95% CI, .87–.97, P = .001), and diffuse noxious inhibitory control (OR = .90, 95% CI, .83–.98, P = .02) at baseline. These findings provide the first evidence that individuals with preexisting impairments in mood and descending pain modulation may be at greater risk for developing chronic neck pain when exposed to peripheral nociceptive stimuli such as that produced during muscle fatigue. PerspectiveDepressed mood, poor muscle endurance, and impaired endogenous pain inhibition are predisposing factors for the development of new-onset chronic neck pain of nonspecific origin in office workers. These findings may assist with primary prevention by allowing clinicians to screen for individuals at risk of developing chronic neck pain.

Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter

Background: In addition to the frequently reported pain complaints, performance-based cognitive capabilities in patients with chronic fatigue syndrome (CFS) with and without comorbid fibromyalgia (FM) are significantly worse than those of healthy controls. In various chronic pain populations, cognitive impairments are known to be related to pain severity. However, to the best of our knowledge, the association between cognitive performance and experimental pain measurements has never been examined in CFS patients. Objectives: This study aimed to examine the association between cognitive performance and self-reported as well as experimental pain measurements in CFS patients with and without FM. Study Design: Observational study. Setting: The present study took place at the Vrije Universiteit Brussel and the University of Antwerp. Methods: Forty-eight (18 CFS-only and 30 CFS+FM) patients and 30 healthy controls were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, experimental pain measurements (pressure pain thresholds [PPT], temporal summation [TS], and conditioned pain modulation [CPM]) took place and participants were asked to fill out 3 questionnaires to assess self-reported pain, fatigue, and depressive symptoms. Results: In the CFS+FM group, the capacity of pain inhibition was significantly associated with cognitive inhibition. Self-reported pain was significantly associated with simple reaction time in CFS-only patients. The CFS+FM but not the CFS-only group showed a significantly lower PPT and enhanced TS compared with controls. Limitations: The cross-sectional nature of this study does not allow for inferences of causation. Conclusions: The results underline disease heterogeneity in CFS by indicating that a measure of endogenous pain inhibition might be a significant predictor of cognitive functioning in CFS patients with FM, while self-reported pain appears more appropriate to predict cognitive functioning in CFS patients without FM. Key words: Chronic fatigue syndrome, cognitive function, cognitive inhibition, chronic pain, fibromyalgia, pain inhibition, pain-related cognitive impairment, working memory

LPS increases pain sensitivity by decreased pain inhibition and increased insular activation

We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders.

Intranasal Oxytocin Administration is Associated With Enhanced Endogenous Pain Inhibition and Reduced Negative Mood States

This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. A total of 30 pain-free, young adults each completed 3 laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States. CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; nondominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory and then self-administered a single (40 IU/1 mL) dose of intranasal oxytocin or placebo in a randomized counterbalanced order. Thirty minutes postadministration, participants again completed the State-Trait Anxiety Inventory and repeated assessments of ischemic pain sensitivity and CPM followed by the Profile of Mood States. Findings demonstrated that ischemic pain sensitivity did not significantly differ across the 3 study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety.

Influence of Dopaminergic Medication on Conditioned Pain Modulation in Parkinson's Disease Patients.

BackgroundPain is highly prevalent in patients with Parkinson’s disease (PD), but little is known about the underlying pathophysiological mechanisms. The susceptibility to pain is known to depend on ascending and descending pathways. Because parts of the descending pain inhibitory system involve dopaminergic pathways, dysregulations in dopaminergic transmission might contribute to altered pain processing in PD. Deficits in endogenous pain inhibition can be assessed using conditioned pain modulation (CPM) paradigms.MethodsApplying such a paradigm, we investigated i) whether CPM responses differ between PD patients and healthy controls, ii) whether they are influenced by dopaminergic medication and iii) whether there are effects of disease-specific factors. 25 patients with idiopathic PD and 30 healthy age- and gender-matched controls underwent an established CPM paradigm combining heat pain test stimuli at the forearm and the cold pressor task on the contralateral foot as the conditioning stimulus. PD patients were tested under dopaminergic medication and after at least 12 hours of medication withdrawal.ResultsNo significant differences between CPM responses of PD patients and healthy controls or between PD patients “on” and “off” medication were found. These findings suggest (i) that CPM is insensitive to dopaminergic modulations and (ii) that PD is not related to general deficits in descending pain inhibition beyond the known age-related decline. However, at a trend level, we found differences between PD subtypes (akinetic-rigid, tremor-dominant, mixed) with the strongest impairment of pain inhibition in the akinetic-rigid subtype.ConclusionsThere were no significant differences between CPM responses of patients compared to healthy controls or between patients “on” and “off” medication. Differences between PD subtypes at a trend level point towards different pathophysiological mechanisms underlying the three PD subtypes which warrant further investigation and potentially differential therapeutic strategies in the future.

V31. Learned control over spinal nociception in chronic back pain patients

Question The descending pain inhibition is a top-down system exerting powerful endogenous pain inhibition. It originates in the brainstem and sends serotonergic and noradrenergic pathways to the spinal dorsal horn, where they inhibit spinal nociceptive transmission and therefore reduce nociceptive input to the brain. The brainstem centers at the origin of descending inhibition are targeted by cortical regions like the prefrontal cortex and the anterior cingulate cortex, and are susceptible to cognitive-emotional modulation ( Bingel and Tracey, 2008 ). A method to measure spinal nociceptive transmission and quantify the effects of the descending pain inhibition is the spinal withdrawal (RIII) reflex. Young healthy subjects can learn to use cognitive-emotional processes to suppress their spinal nociception to 66% when receiving feedback on the size of their RIII reflex, likely by learning to deliberately activate their descending pain inhibition ( n = 15; Ruscheweyh et al., in press ). Here, we investigated if chronic pain patients are also able to learn using cognitive-emotional strategies to suppress their spinal nociception under feedback of the RIII reflex. If this is the case, this approach may be used to improve descending pain inhibition in chronic pain patients. Methods The RIII reflex was evoked by painful electrical stimulation of the sural nerve at the ankle and recorded from the biceps femoris muscle. Subjects were in one of three groups: (1) chronic back pain patients receiving true feedback of their RIII, (2) chronic back pain patients receiving sham feedback of their RIII and (3) healthy control subjects receiving true feedback of their RIII. Subjects were trained in three sessions. The RIII reflex was recorded every 8–12 s, and subjects received immediate true and sham feedback, respectively, on their RIII reflex size. During a defined time window, subjects had the task to use cognitive-emotional strategies to reduce the RIII reflex size. Additionally, we documented the subjective pain sensation. To date, 10 patients with true feedback, 5 patients with sham feedback and 4 healthy controls with feedback have been trained to reduce their RIII reflex. Results In three sessions, the patients with true feedback achieved a significant ( p n = 10), patients with sham feedback reached a suppression to 93 ± 8% ( n = 5) and controls to 47 ± 33% ( n = 4). Simultaneously, the pain perception was significantly reduced to 83 ± 8% in patients with sham feedback ( p Discussion Consequently, this feedback training might be a useful approach to enhance endogenous pain inhibition in chronic pain patients. It remains to be determined if the feedback training has an effect on the patients’ clinical pain and on supraspinal measures of nociception (somatosensory evoked potentials).

Doubling Your Payoff: Winning Pain Relief Engages Endogenous Pain Inhibition

When in pain, pain relief is much sought after, particularly for individuals with chronic pain. In analogy to augmentation of the hedonic experience (“liking”) of a reward by the motivation to obtain a reward (“wanting”), the seeking of pain relief in a motivated state might increase the experience of pain relief when obtained. We tested this hypothesis in a psychophysical experiment in healthy human subjects, by assessing potential pain-inhibitory effects of pain relief “won” in a wheel of fortune game compared with pain relief without winning, exploiting the fact that the mere chance of winning induces a motivated state. The results show pain-inhibitory effects of pain relief obtained by winning in behaviorally assessed pain perception and ratings of pain intensity. Further, the higher participants scored on the personality trait novelty seeking, the more pain inhibition was induced. These results provide evidence that pain relief, when obtained in a motivated state, engages endogenous pain-inhibitory systems beyond the pain reduction that underlies the relief in the first place. Consequently, such pain relief might be used to improve behavioral pain therapy, inducing a positive, perhaps self-amplifying feedback loop of reduced pain and improved functionality.

Sex differences in experimental measures of pain sensitivity and endogenous pain inhibition.

It has been suggested that increased pain sensitivity and disruption of endogenous pain inhibitory processes may account, at least in part, for the greater prevalence and severity of chronic pain in women compared to men. However, previous studies addressing this topic have produced mixed findings. This study examined sex differences in pain sensitivity and inhibition using quantitative sensory testing (QST), while also considering the influence of other important factors such as depressive symptoms and sleep quality. Healthy men (n=24) and women (n=24) each completed a QST battery. This battery included an ischemic pain task (IPT) that used a submaximal effort tourniquet procedure as well as a conditioned pain modulation (CPM) procedure for the assessment of endogenous pain inhibition. Prior to QST, participants completed the Center for Epidemiologic Studies Depression Scale and the Pittsburgh Sleep Quality Index. Analyses revealed significant sex differences for the ischemic pain task and the conditioned pain modulation procedure, such that women tolerated the ischemic pain for a shorter amount of time and demonstrated less pain inhibition compared with men. This remained true even when accounting for sex differences in depressive symptoms and sleep quality. The results of this study suggest that women may be more pain sensitive and possess less-efficient endogenous pain inhibitory capacity compared with men. Whether interventions that decrease pain sensitivity and enhance pain inhibition in women ultimately improve their clinical pain outcomes is an area of research that deserves additional attention in the future.

Central sensitization and changes in conditioned pain modulation in people with chronic nonspecific low back pain: a case-control study.

Quantitative sensory testing is widely used in human research to investigate the state of the peripheral and central nervous system contributions in pain processing. It is a valuable tool to help identify central sensitization and may be important in the treatment of low back pain. The aim of this study was to evaluate changes in local and segmental hypersensitivity and endogenous pain inhibition in people with chronic nonspecific low back pain. Thirty patients with chronic low back pain and thirty healthy subjects were studied. Pressure pain thresholds (PPTs) were measured from the lumbar region and over the tibialis anterior muscle (TA). A cold pressor test was used to assess the activation of conditioned pain modulation (CPM), and PPTs in the lumbar region were recorded 30s after immersion of participant's foot in a bucket with cold water. People with chronic low back pain have significantly lower PPT than controls at both the lumbar region [89.5kPa (mean difference) 95% CI 40.9-131.1kPa] and TA [59.45kPa (mean difference) 95% CI 13.49-105.42kPa]. During CPM, people with chronic low back pain have significantly lower PPT than controls in lumbar region [118.6kPa (mean difference) 95% CI 77.9-159.2kPa]. Women had significantly lower PPTs than men in both lumbar region [101.7kPa (mean difference) 95% CI 37.9-165.7kPa] and over the TA [189.7kPa (mean difference) 95% CI 14.2-145.2kPa]. There was no significant difference in PPTs in men between healthy controls and those with low back pain, suggesting the significant differences are mediated primarily by difference between women.

Associations between cognitive performance and pain in chronic fatigue syndrome: comorbidity with fibromyalgia does matter

In addition to the frequently reported pain complaints, performance-based cognitive capabilities in patients with chronic fatigue syndrome (CFS) with and without comorbid fibromyalgia (FM) are significantly worse than those of healthy controls. In various chronic pain populations, cognitive impairments are known to be related to pain severity. However, to the best of our knowledge, the association between cognitive performance and experimental pain measurements has never been examined in CFS patients.This study aimed to examine the association between cognitive performance and self-reported as well as experimental pain measurements in CFS patients with and without FM.Observational study.The present study took place at the Vrije Universiteit Brussel and the University of Antwerp.Forty-eight (18 CFS-only and 30 CFS+FM) patients and 30 healthy controls were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, experimental pain measurements (pressure pain thresholds [PPT], temporal summation [TS], and conditioned pain modulation [CPM]) took place and participants were asked to fill out 3 questionnaires to assess self-reported pain, fatigue, and depressive symptoms.In the CFS+FM group, the capacity of pain inhibition was significantly associated with cognitive inhibition. Self-reported pain was significantly associated with simple reaction time in CFS-only patients. The CFS+FM but not the CFS-only group showed a significantly lower PPT and enhanced TS compared with controls.The cross-sectional nature of this study does not allow for inferences of causation.The results underline disease heterogeneity in CFS by indicating that a measure of endogenous pain inhibition might be a significant predictor of cognitive functioning in CFS patients with FM, while self-reported pain appears more appropriate to predict cognitive functioning in CFS patients without FM.

(219) Dysfunction of endogenous pain inhibition following acute aerobic exercise in healthy older adults

Laboratory based studies show that acute aerobic exercise reduces sensitivity to painful stimuli in young healthy individuals, indicative of a hypoalgesic response. However, little is known regarding the effect of aging on exercise-induced hypoalgesia (EIH) following aerobic exercise. The current study tested for differences between healthy older and younger adults in the magnitude of exercise-induced hypoalgesia of pressure and heat pain following moderate and vigorous aerobic exercise. Healthy younger (N=25) and older adults (N=18) completed one training session and three testing sessions consisting of 25 minutes of either vigorous (VAE) or moderate (MAE) intensity stationary cycling or quiet rest (control).

(296) Dispositional optimism is not associated with conditioned pain modulation of electric pain

Dispositional optimism refers to a general belief in positive future outcomes. Conditioned pain modulation (CPM) is a way to examine endogenous pain inhibition and involves the use of a painful stimulus to inhibit pain at another body site. Past research has looked at the impact of a cold pressor paradigm on pressure pain thresholds in healthy individuals. The past study further examined the effect of CPM and its relationship to dispositional optimism. The results of this past study indicated that individuals who reported greater optimism had enhanced CPM-related inhibition.

Endogenous pain inhibition is unrelated to autonomic responses in acute whiplash-associated disorders

Patients with acute whiplash-associated disorder (WAD) demonstrate an inefficient endogenous pain inhibition and may experience a dysfunction in autonomic nervous system reactivity to pain. This study compared the autonomic response to painful stimuli between patients with acute and chronic WAD and healthy controls. In addition, the role of the autonomic nervous system for explaining inefficient endogenous pain inhibition was examined in acute WAD. Seventeen patients with acute WAD, 30 patients with chronic WAD, and 31 healthy controls participated in an experiment evaluating the autonomic nervous system at rest and during painful stimuli. Skin conductance and heart rate variability (HRV) parameters were monitored continuously during conditioned pain modulation. A significant autonomic response to pain was present for skin conductance and two HRV parameters in all experimental groups. There was an interaction effect in the skin conductance response to pain but not in HRV responses in any of the groups. In patients with acute WAD, no significant correlations were present between pain, pressure pain thresholds, pain inhibition, and any of the autonomic parameters. This study refutes autonomic dysfunction at rest and in response to pain in acute WAD. The dysfunctional conditioned pain modulation appears unrelated to autonomic responses to pain.

Modality and sex differences in pain sensitivity during human endotoxemia.

Systemic inflammation can induce pain hypersensitivity in animal and human experimental models, and has been proposed to be central in clinical pain conditions. Women are overrepresented in many chronic pain conditions, but experimental studies on sex differences in pain regulation during systemic inflammation are still scarce. In two randomized and double blind placebo controlled experiments, we used low doses of lipopolysaccharide (LPS) as an experimental model of systemic inflammation. The first study employed 0.8ng/kg LPS in a within-subject design of 8 individuals (1 woman), and the second study 0.6ng/kg LPS in a between-subject design of 52 participants (29 women). We investigated the effect on (a) pressure, heat, and cold pain thresholds, (b) suprathreshold noxious heat and cold sensitivity, and (c) conditioned pain modulation (CPM), and differences between men and women. LPS induced significantly lower pressure pain thresholds as compared to placebo (mean change with the 0.8ng/kg dose being -64±30kPa P=.04; with the 0.6ng/kg dose -58±55kPa, P<.01, compared to before injection), whereas heat and cold pain thresholds remained unaffected (P's>.70). Suprathreshold noxious pain was not affected by LPS in men (P's⩾.15). However, LPS made women rated suprathreshold noxious heat stimuli as more painful (P=.01), and showed a tendency to rate noxious cold pain as more painful (P=.06) as compared to placebo. Furthermore, LPS impaired conditioned pain modulation, a measure of endogenous pain inhibition, but this effect was also restricted to women (P<.01, for men P=.27). Pain sensitivity correlated positively with plasma IL-6 and IL-8 levels. The results show that inflammation more strongly affects deep pain, rather than cutaneous pain, and suggest that women's pain perception and modulation is more sensitive to immune activation than men's.

Effects of stress and relaxation on pain perception in subjects with pain-free occlusional disharmony compared with healthy controls.

The significance of occlusal disharmony for the development of painful temporomandibular disorder (TMD) is controversial. The ongoing biomechanical strain caused by occlusal disharmony might lead to sensitization processes in the nociceptive system. Understanding these processes might be an important step toward understanding the possible relationship between occlusal disharmony and TMD. In this study, we therefore investigated whether subjects with occlusal disharmony (n=22) differ from healthy controls (n=26) in their pain perception and pain modulation by stress and relaxation. Trigeminal and extratrigeminal experimental pain perception (pinprick, heat, and pressure pain) was assessed before and after stress (mental arithmetic) and relaxation (viewing of low-arousal pictures). There were no group differences in pain perception at baseline or during the stress task. Compared with controls, the occlusal disharmony group exhibited an inadequate reduction in pain perception during relaxation, which was significant for the extratrigeminal site (P<0.01) and reached a trend for significance at the trigeminal site (P=0.1). These results suggest that subjects with occlusal disharmony show signs of disturbed endogenous pain inhibition during relaxation. There is evidence for the presence of sensitization of the nociceptive system in subjects with occlusal disharmony. Possibly, deficient inhibition of extratrigeminal and trigeminal pain perception by relaxation might contribute to the development of TMD or other chronic pain disorders.

Effect of Pain Induction or Pain Reduction on Conditioned Pain Modulation in Adults: A Systematic Review.

Pain facilitation as well as pain inhibition might be present in chronic pain patients. A decreased efficacy of pain inhibition can be measured by conditioned pain modulation (CPM). The use of the CPM paradigm in scientific research has boosted over the last few years and is recognized for its high clinical relevance in chronic pain patients. It is, however, unclear whether the presence of pain and possible modulations of pain influences the efficacy of endogenous pain inhibition, measured by CPM. This systematic literature study aimed to provide an overview of the effects of clinical pain and experimental pain induction or pain reduction on CPM in adults. A systematic literature search was conducted in the databases "Pubmed" and "Web of Science". Only full texts of original studies regarding the effect of clinical pain and experimentally induced pain and pain reduction on CPM in adults were included. The included articles were scored on methodological quality and through a CPM paradigm. Twelve articles of good to moderate quality were included in this review. Some pain inhibitory medication and oral contraceptives inhibit the CPM mechanism. Removing chronic pain by surgery results in an improved CPM response. This effect is not observed when removing acute pain. Analgesic medication and oral contraceptives might inhibit the CPM response, whereas there is limited evidence that pain-relieving surgery improves CPM in chronic pain patients. However, the results merely suggest that decreased CPM values (as in chronic pain patients) can improve after elimination of pain.

Antihyperalgesic effect of 5-HT7 receptor activation on the midbrain periaqueductal gray in a rat model of neuropathic pain

The 5-HT7 receptor is the most recently discovered receptor for 5-hydroxytryptamine (5-HT), and only little is known about the analgesic potential of this receptor. Adenosine triphosphate (ATP) modulates pain transmission by activating P2X/P2Y receptors, in which the P2X3 subtype is an important target for this effect. This study examined the antihyperalgesic effect of the 5-HT7 receptors in the ventrolateral midbrain periaqueductal gray (vlPAG), a crucial site for endogenous pain inhibition. This study also explored the importance of the interactions between the 5-HT7 and P2X3 receptors in this effect. To address this issue, neuropathic pain was induced through chronic constriction injury (CCI) of the sciatic nerve in Sprague–Dawley (SD) rats. The expression level and distribution of the 5-HT7 receptor were evaluated through Western blot and immunohistochemistry. The mechanical withdrawal threshold (MWT) was measured by using an electronic pressure meter test. Different doses (3, 6, and 12μmol) of AS-19, a selective agonist of the 5-HT7 receptor, were administered in the vlPAG of CCI rats. The effects of pretreatment with the selective 5-HT7 receptor antagonist SB-269970 or the selective P2X3 receptor antagonist A-317491 on the analgesic effect of AS-19 were observed. Results showed that CCI decreased the MWT values of the rats. The injury also increased the protein level of the 5-HT7 receptor in the vlPAG of neuropathic pain rats. AS-19 microinjection significantly elevated the MWT values in a dose-dependent manner, but SB-269970 pretreatment attenuated the antihyperalgesic effect of AS-19. Furthermore, the antihyperalgesic effect of the 5-HT7 receptor was partially but significantly blocked by A-317491 pretreatment. These data indicate that the 5-HT7 receptor in the vlPAG exerts an antihyperalgesic effect on rats with neuropathic pain. The 5-HT7 and P2X3 receptors interact in the vlPAG and exhibit an analgesic action through the enhanced function of the endogenous analgesic system.