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s Objective To review past literature regarding exercise-induced hypoalgesia and pain reduction following blood flow restriction interventions, and to discuss potential mechanisms as well as future considerations towards the efficacy of blood flow restriction in pain reduction following exercise. Methods To be eligible for inclusion, studies had to include acute exercise, or long-term training interventions, with blood flow restriction, along with including pre and post intervention pain measurements. Results A total of 13 studies met the inclusion criteria. Among these 13 studies, 3 studies examined exercise-induced hypoalgesia after an acute bout of resistance exercise with blood flow restriction, and 10 studies investigated pain reduction following long-term blood flow restriction training. Conclusions Existing literature suggests that low load resistance exercise with blood flow restriction may serve as an effective pain management method for those who are unable or unwilling to train with high loads. Several potential mechanisms have been suggested, however, the roles of these mechanisms are still unclear and require further clarification. Future research should consider implementing different methods of blood flow restriction application, and research study design to clarify the utility and efficacy of blood flow restriction as a pain management tool, by itself or in combination with exercise.

Introduction Pain-inducing massage results in greater pain inhibition than pain free massage, suggesting a mechanism dependent on conditioned pain modulation (CPM). The purpose of this study was to test the hypothesis that pain inducing massage produces similar magnitude of reduction in pain sensitivity as a cold pressor task and that baseline conditioned pain modulation efficiency predicts pain inducing massage related hypoalgesia. Methods Sixty healthy participants were randomly assigned to receive either pain inducing massage to the neck, cold pressor task to the hand, or pain free massage to the neck. Participants also underwent pre and immediate post-intervention quantitative sensory testing. A repeated measures ANCOVA determined between group differences in pain sensitivity changes. Results Pain inducing massage used as a conditioning stimulus resulted in comparable experimental pain sensitivity changes as a cold pressor task (p > 0.05). Pain intensity during the intervention demonstrated a weak correlation (r = 0.20, p = 0.12) with changes in pain sensitivity at a remote site. Individuals with an efficient CPM at baseline who received the pain inducing massage displayed greater increases in pressure pain threshold compared to individuals with a less efficient CPM indicating the potential benefit of treatment stratification by mechanism. Conclusion Although pain inducing massage resulted in less self-reported pain than a cold pressor task, both resulted in similar magnitude of the CPM response, suggesting shared underlying mechanisms. Understanding mechanisms of interventions can move us closer to mechanistic based treatments for pain which is consistent with a personalized medicine approach to care.

Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg−/−) mice were examined. The gcg−/− mice showed tactile allodynia and thermal hyperalgesia at 12–18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg−/− mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.

OBJECTIVES: The aim of this study was to compare the acute effects of isometric versus dynamic resistance exercise on pain during a pain-provoking activity, and exercise-induced hypoalgesia in participants with patellar tendinopathy.DESIGN: This study was a pre-registered randomised crossover study. Participants were blinded to the study hypothesis.METHODS: Participants (N = 21) performed a single session of high load isometric resistance exercise or dynamic resistance exercise, in a randomised order separated by a 7-day washout period. Outcomes were assessed before, immediately after, and 45 min post-exercise. The primary outcome was pain intensity scored on a numeric pain rating scale (NRS; 0-10) during a pain-provoking single leg decline squat (SLDS). Secondary outcomes were pressure pain thresholds (PPTs) locally, distally and remotely, as well as tendon thickness.RESULTS: There was a significant decrease in pain NRS scores (mean reduction 0.9, NRS 95%CI 0.1-1.7; p = 0.028), and increase in PPTs at the tibialis anterior muscle (mean increase 34 kPa 95%CI 9.5-58.5; p = 0.009) immediately post-exercise. These were not sustained 45 min post-exercise for pain (NRS) or PPTs (p > 0.05). There were no differences between exercise on any outcome.CONCLUSIONS: While patients with patellar tendinopathy decreased pain during SLDS in response to resistance training, but the magnitude was small. Contraction mode may not be the most important factor in determining the magnitude of pain relieving effects. Similarly, there were only small increases in PPTs at the tibialis anterior which were not superior for isometric exercise.

Regular physical exercise has been described as a good strategy for prevention or reduction of musculoskeletal pain. The Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) has been investigated as a promising target for the control of inflammatory pain. Therefore, the aim of this study was to evaluate whether activation of PPARγ receptors is involved in the reduction of acute muscle pain by chronic exercise and, in this case, whether this process is modulated by inflammatory cytokines. To this end, Wistar rats were submitted to swimming physical training for a period of 10 weeks, 5 days per week, 40 min/day, in an intensity of 4% of the body mass. Muscle hyperalgesia was measured by Randall Selitto test and pro-inflammatory cytokines were quantified by ELISA. The results showed that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia and the increase in muscle levels of Cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by carrageenan into gastrocnemius muscle. In addition, local pre-treatment with the selective PPARγ receptors antagonist GW9662 reversed the mechanical muscle hypoalgesia and the modulation of CINC-1 levels induced by swimming physical training. These data suggest that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia by a mechanism dependent of PPARγ receptors, which seems to contribute to this process by modulation of the pro-inflammatory cytokine CINC-1, and highlight the potential of PPARγ receptors as a target to control musculoskeletal pain and to potentiate the reduction of musculoskeletal pain induced by exercise.

Introduction Neural mobilization can be performed in a way that facilitates movement through a stretching technique (tensioning) or in a way that maximizes the gliding of peripheral nerves in relation to adjacent structures (gliding). Evidence on how these techniques compare in terms of effects are scarce. The aim of this study is to compare the effects of neural gliding and neural tensioning targeting the median nerve on heat and cold temperature threshold, heat pain threshold, pressure pain thresholds and hand grip strength in asymptomatic participants. Methods Participants received 4 series of 10 repetitions of either neural gliding (n = 30) or neural tensioning (n = 30) and were assessed for heat and cold temperature threshold, heat pain threshold, pressure pain threshold, and hand grip strength at baseline, immediately after the intervention, and 30 min post-intervention. Results A significant main interaction between time and intervention was found for the PPT at the forearm (F(2,55) = 5.98; p = 0.004), favouring the tensioning neural mobilization. No significant differences were found for the other variables. Conclusions Four series of 10 repetitions of neural tensioning targeting the median nerve in asymptomatic subjects seem to be enough to induce hypoalgesia and have no negative effects on A-delta and C mediated sensory function and on hand grip strength production.

How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.

Background sympathoexcitation observed with passive cervical mobilisations may imply activation of an endogenous pain inhibition system resulting in hypoalgesia. However, research is mostly in asymptomatic participants and there is very limited evidence of a relationship between sympathoexcitation and symptomatic improvement in people with clinical pain. Objective to investigate the effects of cervical mobilisations on the sympathetic nervous system in participants with neck pain, and to explore the relationship between symptomatic improvement and sympathoexcitation. Design double-blind randomised controlled trial. Method 40 participants with neck pain (aged 20–69 years, 25 female) were randomly allocated to either cervical mobilisations or motionless placebo. Skin conductance was measured before, during, and after intervention. After interventions were completed, their credibility was assessed. Participants were classified as responders or non-responders according to global symptom change. Results participants receiving mobilisations were more likely to be classified as responders (odds ratio: 4.33, p = 0.03) and demonstrated greater change in most outcome measures of sympathoexcitation from baseline to during the intervention but not from during to after the intervention. There was no association between sympathoexcitation and symptomatic improvement. Mobilisations and placebo were equally credible. Conclusions These findings suggest sympathoexcitatory changes may be caused by an orienting response unrelated to the activation of an endogenous pain inhibition system Alternatively, the observed lack of an association may be explained by the existence of various mechanisms for pain relief. This study used single outcome measures of sympathoexcitation and symptomatic improvement and other measures may reveal different things. ClinicalTrials.gov number M10/2016/095.

Importance Cryotherapy is one of the simplest and oldest therapeutic methods used to alleviate acute soft tissue trauma and muscle soreness. However, inconsistent outcomes have been reported due to inconsistent protocols. Objective To determine if various cryotherapy methods lead to enhanced recovery in athletes and identify optimal methods and protocol for short-term recovery in athletes. Evidence review PubMed/MEDLINE and SPORTDiscus databases were searched from 1 April 1950 to 31 December 2018. The search algorithm used was: (Icing OR Ice Therapy OR Cryotherapy) AND (Athlete OR Sports) NOT (Case Reports). Inclusion criteria was human clinical studies with level 1–4 evidence, a cohort of at least 20 athletes, who were followed to determine the effect cryotherapy had on performance, pain and/or recovery were included. Abstracts, reviews, case reports and conference proceedings were excluded. Seven studies investigating the effect cryotherapy recovery were included. Manual extraction and compilation of demographic, methodology, functional and biochemical outcomes from the studies were completed. Non-randomised trials were assessed using the Methodological Index for Non-Randomised Studies and the randomised were assessed using Oxford quality scoring system. Findings Decreased pain or muscle soreness was seen with cold water immersion(CWI) when compared with passive recovery. Other outcome variables assessed (biomarkers, functional tests) did not reveal consistent findings. Longer icing times (>10 min) were associated with detrimental effects in muscle power and activity. Conclusions and relevance Duration is the critical variable in conventional cryotherapy, with prolonged icing leading to immediate detriment in muscle power and activity. Thus, we recommend using ice cryotherapy following exercise for no longer than 10 min for pure hypoalgesia. CWI had a greater benefit on recovery than passive recovery. Furthermore, CWI has a more beneficial effect on recovery in the first 24 hours following exercise versus immediately postrecovery. We recommend using a protocol to include immersion times of 11–15 min in 11°C–15°C (52°F–59°F) water. Level of evidence Level III.

Over the last 20 years a large number of transgenic mouse models have been produced showing different degrees of congenital hypoalgesia; some of these models mimic known human conditions while others seemingly have no human counterpart. However, very little significant contributions to our understanding of pain neurobiology were obtained from this multitude of animal models; in most cases the study of these animals was limited to the characterization of its pain perception without addressing the long term consequences of their hypoalgesic condition. In this review we discuss the untapped potential that these animal models of congenital hypoalgesia hold for future studies addressing brain plasticity during permanent conditions of reduced pain perception, and that may result in important insights on the interplay between pain, emotion, and cognition. Revisiting hypoalgesia using modern techniques of functional neurophysiology in awake animals may complement the recent literature of functional clinical and preclinical studies that improve our understanding of the central malplasticity caused by pain.

Pain control in opioid-dependent individuals is a clinical complication. The present study investigated the effects of different doses of amitriptyline in the three stages of the formalin test in morphine-dependent rats (MDRs). Morphine dependency was induced using the oral method, and then, amitriptyline-induced antinociceptive effects were measured at 4 doses (2.5, 5, 10, and 20 mg/kg) and compared with the control group in a formalin-based model of pain. There was no observed antinociceptive effect in the MDRs and morphine-naive rats (MNRs) in phase I. In the interphase, amitriptyline induced pain suppression at doses of 5 and 20 mg/kg. In phase II, at doses of 5, 10, and 20 mg/kg, the hypoalgesic effect on pain-related behaviors was seen in the MNRs. In MDRs, amitriptyline at doses of 2.5 and 5 mg/kg caused the hyperalgesic effect, whereas at 10 and 20 mg/kg doses, it induced a hypoalgesic effect. A significant attenuation was observed in the latency to fall from the accelerating rotarod at doses of 10 and 20 mg/kg in the MDRs, and at a dose of 20 mg/kg in the MNRs. Data showed that amitriptyline dose-dependently induced paradoxical hypo- and hyper-algesic effects in MDRs.

Placebo and nocebo effects are present within every treatment and intervention, and can be purposefully enhanced and reduced, respectively, in order to improve patients’ clinical outcomes. A plethora of research has been conducted on the mechanisms of placebo hypoalgesia and nocebo hyperalgesia in experimental and clinical settings. However, its implications in particular clinical settings such as orthodontic pain management remain underexplored. We conducted a search of the literature regarding placebo analgesia, orthodontic pain management, and orofacial and dental pain. Articles were qualitatively assessed and selected based on the scope of this narrative review. Although no studies investigating the extent of the implications of the placebo and nocebo phenomena in the orthodontic clinical setting were found, we herein present a comprehensive review on the influences of placebo and nocebo effects in experimental and clinical pain management, as well as on the potential for engaging placebo-related endogenous pain modulation for orthodontic pain management. Ethical considerations for the clinical application of placebos are discussed, and future research directions are presented.

Existing literature concerning the effect of experimentally-induced diabetes on pain thresholds in rodent models remains controversial. In this work, we describe a phenotypical switch from streptozotocin-induced pinprick hypoalgesia to hyperalgesia observed in the same laboratory, in the same strain of rats, obtained from the same vendor, and measured by the same technique carried out by the investigators. This switch was observed around January 2015, at the time when there was a change in the diet of rats at the Radley North Carolina Charles River facility. These data support the contention that diet may significantly modify disease progression, including progression of signs of diabetic neuropathy.

The purpose of this study was to compare the immediate change in temporal summation of heat pain (TSP) between spinal manipulation (SMT) and spinal mobilization (MOB) in healthy volunteers. Ninety-two volunteers (24 male; 23.8 ± 5.3 years) were randomized to receive SMT, MOB, or no treatment (REST) for 1 session. Primary outcomes were changes in TSP, measured at the hand and foot, immediately after the session. A planned subgroup analysis investigated effects across empirically derived TSP clusters. For the primary outcome there were no differences in the immediate change in TSP measured at the foot between SMT and MOB, however, both treatments were superior to the REST condition. In the subgroup analysis the response to a standard TSP protocol was best characterized by 3 clusters: 52% no change (n = 48, 52%); facilitatory response (n = 24, 26%), and inhibitory response (n = 20, 22%). There was a significant Time × Treatment group × Cluster interaction for TSP measured at the foot. The inhibitory cluster showed the greatest attenuation of TSP after SMT and MOB compared with REST. These data suggest lumbar manual therapies of different velocities produce a similar localized attenuation of TSP, compared with no treatment. Attenuation of localized pain facilitatory processes by manual therapies was greatest in pain-free individuals who show an inhibitory TSP response. Perspective The attenuation of pain facilitatory measures may serve an important underlying role in the therapeutic response to manual therapies. Identifying patients in pain who still have an inhibitory capacity (ie, an inhibitory response subgroup) may be useful clinically in identifying the elusive “manual therapy” responder.

The mechanisms through which acute exercise reduces pain (ie, exercise-induced hypoalgesia [EIH]) are poorly understood. This study aimed to determine if education about EIH affected pain responses after acute exercise in healthy adults. Participants received 15 minutes of education either about EIH (intervention, n = 20) or more general education about exercise and pain (control, n = 20). After this, the participants’ knowledge and beliefs about exercise and pain were assessed. Pressure pain thresholds were then measured before and after 20 minutes of cycle ergometer exercise. Compared with the control group, the intervention group believed more strongly that pain could be reduced by a single session of exercise (P = .005) and that the information they had just received had changed what they thought about the effect of exercise on pain (P = .045). After exercise, pressure pain threshold increased in both groups, but the median increase was greater in the intervention group compared with the control group (intervention = .78 kg/cm2, control = .24 kg/cm2, P = .002, effect size [r] of difference = .49). These results suggest that cognitive processes in the appraisal of pain can be manipulated to influence EIH in healthy adults. Perspective This study shows that preceding a bout of exercise with pain education can alter pain responses after exercise. This finding has potential clinical implications for exercise prescription for people with chronic pain whereby pain education before exercise could be used to improve pain responses to that exercise.

We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes.

Repetitive trunk flexion can damage spinal tissues, however its association with low back pain in the workplace may be confounded by factors related to pain sensitivity. Muscle fatigue, exercise-induced hypoalgesia, and creep-induced neuromuscular changes following repetitive trunk flexion may all affect this assumed exposure-pain relationship. This study’s purpose was to determine how mechanical pain sensitivity in the low back is affected by a repetitive trunk flexion exposure and identify factors associated with changes in low back pain sensitivity. Pressure pain thresholds, perceptions of sub-threshold stimuli, and muscle fatigue in the trunk and tibia, as well as lumbar spine creep were tracked in 37 young healthy adults before and up to 40 min after a 10-min repetitive trunk flexion exposure. Pressure pain thresholds (p = 0.033), but not perceptions of sub-threshold stimuli (p > 0.102) were associated with approximately a 12.5% reduction in pain sensitivity 10 min after completing the exposure, while creep and local muscle fatigue effects were only observed immediately following the exposure. Creep and fatigue interactions and the corresponding tibial measure co-varied with individual low back pressure pain thresholds. The net hypoalgesic effects of repetitive trunk flexion have the potential to partially mask possibly injurious loads, which could contribute to the severity or incidence of lower back injuries related to these exposures.

It has been proposed that the post-ictal state is associated with the expression of hypoalgesia. It is clear that the projections among the periaqueductal gray matter (PAG), dorsal raphe nucleus (DRN) and locus coeruleus (LC) play a role in pain management. These mesencephalic structures have direct reciprocal opioid and monoaminergic projections to the LC that can possibly modulate post-ictal hypoalgesia. The goal of this study was to examine if LC-opioid and serotonergic/noradrenergic mechanisms signal the post-ictal hypoalgesic responses to tonic–clonic seizures produced by intraperitoneal administration of pentylenetetrazole (PTZ at 64 mg/kg), causing an ionophore γ-aminobutyric acid (GABA)-mediated Cl− influx antagonism. The rodents’ nociceptive threshold was measured by the tail-flick test. Intra-LC cobalt chloride (1.0 nM/0.2 μL) microinjections produced intermittent local synaptic inhibition and were able to reduce post-ictal hypoalgesia. Central administration of naltrexone (a non-selective antagonist for opioid receptors), naloxonazine (a selective antagonist for μ1-opioid-receptors), methysergide (a non-selective antagonist for serotonergic receptors) or ketanserin (an antagonist for both α1-noradrenergic and 5-Hydroxytryptamine(HT)2A/2C receptors) at 5.0 μg/0.2 μL, R-96544 (a 5-HT2A receptor selective antagonist) at 10 nM/0.2 μL, or RS-102221 (a 5-HT2C receptor selective antagonist) at 0.15 μg/0.2 μL into the LC also decreased post-ictal hypoalgesia. The data presented here suggest that the post-ictal antinociception mechanism involves the μ1-opiod, 5-HT2A- and 5-HT2C-serotonergic, and α1-noradrenergic receptors in the LC.

Exercise acutely reduces pain sensitivity, termed exercise-induced hypoalgesia (EIH). The mechanisms underlying EIH remain unclear. Caffeine, a non-specific adenosine receptor antagonist has been shown to attenuate EIH in animals-suggesting the involvement of the adenosinergic system. This pilot study investigated the effects of caffeine on pain sensitivity following cycling exercise in college-aged men. Pressure pain threshold (PPT) and thermal pain threshold (TPT) were assessed in thirteen low caffeine consuming men prior to ingestion of a counter-balanced 5mg·kg(-1) dose of caffeine or a placebo (Pre), 60min following ingestion (Post-In), and then following a 15min bout of cycling exercise (Post-Ex) at an intensity eliciting a quadriceps muscle pain rating of 3 out of 10. Nine of the men completed follow-up testing which was identical except that the exercise consisted of 10min of cycling eliciting a pain rating of 5 out of 10. Caffeine had no effect compared to placebo on PPT (p≥0.15) or TPT (p≥0.41) 60min following ingestion and following exercise. PPT increased from 599±176kPa to 648±202kPa (p=0.009) and from 578±217kPa to 666±278kPa (p=0.01) following 15 and 10min of cycling, respectively. TPT increased from 46.2±2.9°C to 46.8±2.6°C (p=0.008) following the 15min exercise bout, but did not change (46.4±3.6°C vs. 46.8±3.3°C; p=0.24) following the shorter, higher intensity exercise bout. The results from this study indicate cycling exercise reduces pain sensitivity, especially to pressure stimuli. Caffeine ingestion did not alter the EIH response-suggesting adenosine may not play a prominent role in the EIH response in humans.

Copulatory behavior has been reported to raise the pain threshold in male rats. In this study, we examined the effect of copulatory behavior with or without ejaculation on pain threshold measured by electrical shock via an electrode attached to the tail. It was demonstrated that ejaculation is not necessary to raise the pain threshold in male rats. In addition, we examined whether oxytocin, a hypothalamic neuropeptide, was involved in copulation-induced hypoalgesia. Sexually experienced males were subjected to stereotaxic implantation of a guide cannula targeting the lateral ventricle. After the recovery period, half of the males were intracerebroventricularly treated with an oxytocin antagonist (OTA, 100 ng d(CH2)51,Tyr(Me)2,Thr4, Orn8,Tyr-NH29]-vasotocin/1 μL saline) and the remaining half were administered saline without anesthesia. Fifteen minutes later, half of each group were given sexual behavior with receptive females. We found no effect of OTA on sexual activity. Immediately after ejaculation, pain threshold was measured. While raised pain threshold was observed after sexual behavior in saline-treated males, no change in pain threshold was found in OTA-treated males even after copulation. The results suggest that central oxytocin mediates copulation-induced hypoalgesia in male rats.

Purpose Spinal epidural hematoma is a rare but important disease as it can be a stroke mimic. Our aim was to investigate the clinical characteristics of patients with an activated stroke code and spinal epidural hematoma. Methods Patients with an activated stroke code were examined retrospectively. Patients with spinal epidural hematoma were evaluated with further neurological examinations and neuroimaging. Results Of 2866 patients with an activated stroke code, spinal epidural hematoma was detected in 5 (0.2%, 63–79 years, 2 men). In all 5 cases, hematoma was located in the unilateral dorsal region of the spinal canal and spread to 5–9 vertebral segments at the C1–T3 level. None of the patients had a medical history of head or neck injury, coagulopathy, or use of anti-thrombotic agents. All of the patients had occipital, neck, and/or back pain, and their hemiparesis occurred simultaneously or within 1 h after the onset of pain. Hyperalgesia ipsilateral to the hematoma was observed in 1 patient, hypoalgesia contralateral to the hematoma was observed in 1, and quadriparesis and bilateral hypoalgesia were observed in 1. The hematomas spontaneously decreased in size in 4 patients, and cervical laminectomy was performed in the other patient. In the 1860 patients with an activated stroke code and spontaneous eye opening, the sensitivity of pain as a predictor of spinal epidural hematoma was 100%, with a specificity of 88.7%, and positive predictive value of 2.3%. Conclusion Patients with spinal epidural hematoma could present with clinical characteristics mimicking ischemic stroke. Spinal epidural hematoma should be differentiated in patients treated under stroke code activation.

Background People with LBP who experience rapid improvement in symptoms after spinal manipulative therapy (SMT) are more likely to experience better longer-term outcomes compared to those who don't improve rapidly. It is unknown if short-term hypoalgesia after SMT could be a relevant finding in rapid responders. Objectives We aimed to explore whether rapid responders had different short-term pressure pain threshold (PPT) and temporal summation (TS) outcomes after SMT and sham compared to non-rapid responders. Methods This was a planned secondary analysis of a randomised controlled trial that recruited 80 adults with LBP (42 females, mean age 37 yrs). PPT at the calf, lumbar spine, and shoulder and TS at the hands and feet were measured before and three times over 30 min after a lumbar SMT or sham manipulation. Participants were classified as rapid responders or non-rapid responders based on self-reported change in LBP over the following 24 h. Results Shoulder PPT transiently increased more in the rapid responders than non-rapid responders immediately post-intervention only (between-group difference in change from baseline = 0.29 kg/cm2, 95% CI 0.02–0.56, p = .0497). There were no differences in calf PPT, lumbar PPT, hand TS, or foot TS based on responder status. Conclusions Hypoalgesia in shoulder PPT occurred transiently in the rapid responders compared to the non-rapid responders. This may or may not contribute to symptomatic improvement after SMT or sham in adults with LBP, and may be a spurious finding. Short-term changes in TS do not appear to be related to changes in LBP.

Retrowalking (walking backwards) is often used clinically to address movement impairment. Whether retrowalking at a moderate intensity is sufficient to produce exercise-induced hypoalgesia (EIH) is unknown. This pilot study explored EIH following retrowalking in twenty healthy young adults (21.6 ± 2.9 yrs, 10 men). Pressure pain thresholds (PPTs) were assessed at bilateral quadriceps and left index finger nailbed utilizing a computerized pressure algometer (Medoc AlgoMed) pre/post 20 minutes quiet rest (session 1) and pre/post 20 minutes of retrowalking at 45-55% heart rate reserve (session 2). Participants pressed the indicator button when the applied pressure first became painful. The average of three trials at each site was used for PPT and site order was randomized between sessions. A significant trial x site interaction was identified. Post hoc testing revealed no significant trial effects after quiet rest at any site. After retrowalking, only the right quadriceps showed an increase in PPT (417.8 ± 146.3 vs 380.5 ± 122.8 kPa). Although baseline PPTs were significantly lower in the right quadriceps than the left in session 1 (362.9 ± 107.2 vs 395.1 ± 127.9 kPa), this difference did not reach significance in session 2 (380.5 ± 122.8 vs 417.4 ± 174 kPa). In both sessions, PPT of the right quadriceps increased to match that of the left (Quiet Rest: 383.8 ± 117.9 vs 382.7 ± 148.6 kPa; Retrowalking: 417.8 ± 146.3 vs 418.9 ± 167.8 kPa). Of the twenty participants, 18 reported right leg dominance, 1 left, and 1 failed to report. Our pilot data suggests that pain sensitivity and EIH response to retrowalking may vary based upon leg dominance; therefore, unilateral assessment of EIH with bilateral working muscles could produce spurious outcomes. Further investigation into the potential role of leg dominance on pain reports before and after this novel exercise task is warranted.

Posttraumatic stress disorder (PTSD) and chronic pain often co-occur and exacerbate each other. Elucidating the mechanism of this co-occurrence therefore has clinical importance. Previously, patients with PTSD with chronic pain were found to demonstrate a unique paradoxical pain profile: hyperresponsiveness together with hyposensitivity to pain. Our aim was to examine whether 2 seemingly paradoxical facets of PTSD (anxiety and dissociation) underlie this paradoxical profile. Patients with PTSD (n = 32) and healthy control individuals (n = 43) underwent psychophysical testing and completed questionnaires. Patients with PTSD had higher pain thresholds and higher pain ratings to suprathreshold stimuli than control individuals. Pain thresholds were positively associated with dissociation levels and negatively associated with anxiety sensitivity levels. Experimental pain ratings were positively associated with anxiety sensitivity and negatively related to dissociation levels. Chronic pain intensity was associated with anxiety, anxiety sensitivity, and pain catastrophizing. It appears that reduced conscious attention toward incoming stimuli, resulting from dissociation, causes delayed response in pain threshold measurement, whereas biases toward threatening stimuli and decreased inhibition, possibly caused by increased anxiety, are responsible for the intensification of experimental and chronic pain. The paradoxical facets of PTSD and their particular influences over pain perception seem to reinforce the coexistence of PTSD and chronic pain, and should be considered when treating traumatized individuals. Perspective This article provides new information regarding the underlying mechanism of the coexistence of PTSD and chronic pain. This knowledge could help to provide better management of PTSD and chronic pain among individuals in the aftermath of trauma.

The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 years) completed 3 sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds and pressure pain ratings before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated that circulating concentrations of 2 endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, as well as related lipids oleoylethanolamide, palmitoylethanolamide, N-docosahexaenoylethanolamine, and 2-oleoylglycerol, increased significantly (P.05) following exercise. Pressure pain thresholds increased significantly (P.05), whereas pressure pain ratings decreased significantly (P.05) following exercise. Also, temporal summation ratings were significantly lower (P.05) following exercise. These changes in pain responses did not differ between the placebo and naltrexone conditions (P.05). A significant association was found between EIH and docosahexaenoylethanolamine. These results suggest involvement of a nonopioid mechanism in EIH following isometric exercise.Currently, the mechanisms responsible for EIH are unknown. This study provides support for a potential endocannabinoid mechanism of EIH following isometric exercise.

When the pain intensity of an impending stimulus is highly unpredictable, the uncertain expectation of pain may exacerbate the perceived pain intensity of the stimulus, compared to the same stimulus delivered with certain expectation. Here, we address how the perception of physically identical stimuli delivered with different predictability of the pain intensity is influenced by learning. We hypothesized that the difference in perceived pain intensity following high and low predictable cues could be explained by: (1) uncertainty-driven hyperalgesia associated with hippocampal activity; (2) certainty-driven hypoalgesia associated with activity in the periaqueductal gray (PAG) and the rostral anterior cingulate cortex (rACC); and (3) a mixed model of both. To test this hypothesis, two sessions of a delayed conditioning paradigm was employed in conjunction with event-related functional magnetic resonance imaging and trial-by-trial rating of the pain intensity. Participants had to simultaneously learn the outcome association of two cues. One cue was always delivered at the same intensity while the other cue was delivered either at a matched or a substantially higher intensity. As expected, the uncertain condition resulted in higher perceived pain intensity than the certain condition. However, this effect occurred only in the second session and was driven by decreased perceived pain in the certain condition. Furthermore, this effect was associated with decreased activity in the PAG but not the rACC. The changing pain ratings and PAG activity across sessions reflect a dynamic learning process that may mirror decreased perceived threat of and/or decreased attention to pain in the certain condition.

Despite the importance of the periaqueductal gray (PAG) in the modulation of nociception and pain, many aspects of the roles of the different columns of the PAG in descending controls: facilitation and inhibition, are not understood. Employing a tonic muscle pain model established by i.m. injection of 5.8% saline into the gastrocnemius muscle, we now report the results of investigations designed to explore any differences in Fos expression in the different functional columns of the PAG in male Sprague-Dawley rats. In a second series of experiments, effects of the PAG on descending control of spinally-organized nociception were assessed by measuring hind paw withdrawal reflexes to noxious mechanical and heat stimulation before and after electrolytic lesion of specific columns of the PAG. Our results show that Fos expression within different columns of the PAG increases significantly and differentially following i.m. injection of 5.8% saline. The mean number of Fos positive neurons in the dorsolateral (dl), lateral (l), dorsomedial (dm) PAG elicited by i.m. injection of 5.8% saline reached a peak at 4h with a gradual decrease over time, whereas the maximum number of Fos-positive neurons in the ventrolateral (vl) PAG was observed 8h after i.m. injection. Contralateral lesion of the dl PAG significantly depressed ipsilateral secondary mechanical hyperalgesia in intramuscularly induced (5.8% saline) nociception (P0.05), whereas heat hypoalgesia was not affected (P0.05). By contrast, contralateral lesion of the vl PAG completely blocked the occurrence of ipsilateral heat hypoalgesia (P0.05), while bilateral mechanical hyperalgesia was unaffected (P0.05). In conclusion, functions of specific columns of the PAG in the control of spinal nociceptive activities are not homogeneous. It is suggested that, in this muscle pain model, the dl PAG and vl PAG participate in descending facilitation and inhibition of nociception, respectively.

Small-fiber neuropathy was induced in young adult mice by intraperitoneal injection of resiniferatoxin (RTX), a TRPV1 agonist. At day 7, RTX induced significant thermal and mechanical hypoalgesia. At day 28, mechanical and thermal nociception were restored. No nerve degeneration in skin was observed and unmyelinated nerve fiber morphology and density in sciatic nerve were unchanged. At day 7, substance P (SP) was largely depleted in dorsal root ganglia (DRG) neurons, although calcitonin gene-related peptide (CGRP) was only moderately depleted. Three weeks after, SP and CGRP expression was restored in DRG neurons. At the same time, CGRP expression remained low in intraepidermal nerve fibers (IENFs) whereas SP expression had improved. In summary, RTX induced in our model a transient neuropeptide depletion in sensory neurons without nerve degeneration. We think this model is valuable as it brings the opportunity to study functional nerve changes in the very early phase of small fiber neuropathy. Moreover, it may represent a useful tool to study the mechanisms of action of therapeutic strategies to prevent sensory neuropathy of various origins.

Early noxious stimuli may alter the neurogenesis rate in the dentate gyrus and the behavioral repertoire of adult rats. This study evaluated the long-term effects of noxious stimulation, imposed in different phases of development, on nociceptive and anxiety-like behaviors, hippocampal activation, cell proliferation, hippocampal BDNF and plasma corticosterone levels in 40 day-old male and female adolescents. Noxious stimulation was induced by intra-plantar injection of Complete Freund's adjuvant (CFA), on postnatal days (P) 1 (group P1), 8 (P8) or 21 (P21). Control animals were not stimulated in any way. On P21 a subset of animals from each group received BrdU and was perfused on P40 for identification of proliferating cells in the granule cell layer of the dentate gyrus. Another subset of rats was subjected to behavioral testing on P40 and one week later, to magnetic resonance imaging (MRI) acquisition. Noxious stimulation evoked hypoalgesia in adolescents, mainly in females (P0.02), reflected by greater latency to withdraw the paw and less paw lickings in the hot plate test than controls (P0.001). It also resulted in more time spent in the open arms, e.g., less anxiety-like behavior than controls (P0.01), especially in females (P0.01, compared with males). Proliferative cell rate in the dentate gyrus was the highest in P8 males and females (P0.001), with males exhibiting more proliferation than females on P1 and P8, which was directly related to the hippocampal levels of BDNF and inversely related to plasma corticosterone. Sex differences were also detected in manganese-enhanced MRI signal, which was more prominent in P1 females than males (P0.01). This study represents the first step of investigation on the cellular basis of the sex-dependent long-term consequences of nociceptive stimuli in newborns.

The objectives of this study were to determine whether thermal quantitative sensory testing (QST) can be performed in client-owned dogs, is repeatable and whether QST differs between normal dogs and dogs with hind limb osteoarthritis (OA). This clinical, prospective, observational study used clinically normal dogs (n=23) and dogs with OA-associated hind limb pain (n=9). Thermal QST was performed in standing dogs using a high-powered light source delivered by a previously validated system. Dogs were tested on two occasions, 2 weeks apart. Five tests were performed on each hind limb at each time point. Repeated measures analysis of variance was used to evaluate the effects of leg, time point and OA/normal status on thermal threshold latencies (TTL). Additionally, paired t tests were used to compare the TTL of left and right limbs within groups and between time points. Thermal thresholds were successfully measured in 32 client-owned dogs without prior training. TTL were significantly different between normal and OA dogs (P=0.012). There was no difference between limbs (P=0.744) or time periods (P=0.572), when analyzed by repeated measures analysis of variance, and no interactions between group and limb, visit and limb, or visit and group. In conclusion, thermal thresholds can be measured in client owned dogs with no prior training and are repeatable from week to week. Further data are required to determine if OA results in thermal hypoalgesia as measured at the distal hind limb and whether this is an indication of central sensitization.

Exercise-induced hypoalgesia is characterised by a reduction in pain sensitivity following exercise. Recently, low intensity exercise performed with blood flow restriction has been shown to induce hypoalgesia. The purpose of this manuscript is to discuss the mechanisms of exercise-induced hypoalgesia and provide rationale as to why low intensity exercise performed with blood flow restriction may induce hypoalgesia. Research into exercise-induced hypoalgesia has identified several potential mechanisms, including opioid and endocannabinoid-mediated pain inhibition, conditioned pain modulation, recruitment of high threshold motor units, exercise-induced metabolite production and an interaction between cardiovascular and pain regulatory systems. We hypothesise that several mechanisms consistent with prolonged high intensity exercise may drive the hypoalgesia effect observed with blood flow restriction exercise. These are likely triggered by the high level of intramuscular stress in the exercising muscle generated by blood flow restriction including hypoxia, accumulation of metabolites, accelerated fatigue onset and ischemic pain. Therefore, blood flow restriction exercise may induce hypoalgesia through similar mechanisms to prolonged higher intensity exercise, but at lower intensities, by changing local tissue physiology, highlighting the importance of the blood flow restriction stimulus. The potential to use blood flow restriction exercise as a pain modulation tool has important implications following acute injury and surgery, and for several load compromised populations with chronic pain.

Trauma exposure, especially sexual assault (SA), is highly correlated with pain conditions, in that many chronic pain samples report trauma histories. However, our understanding of the mechanisms behind this relationship is limited. Previous findings from our lab suggest that SA disrupts descending pain modulation. However, to date, no study has used quantitative sensory testing (QST) to comprehensively assess the pain system in SA survivors. 41 healthy, pain-free SA survivors were matched to a group of 41 healthy, pain-free trauma exposed persons without SA (TE). These groups were compared to a group of healthy, pain-free persons with no trauma history (no-TE; N=62). QST included warm, cool, heat, cold, ischemia, and electric thresholds, and heat, cold, ischemia, and electric tolerances. The nociceptive flexion reflex (NFR) threshold was used to assess spinal nociception. Results suggested SA survivors had higher cool thresholds than the TE and no-TE groups. Moreover, SA survivors had lower cold thresholds, cold tolerances, and heat tolerances than no-TE. Surprisingly, SA survivors had higher ischemia tolerances than no-TE and TE groups. The TE group had lower heat and cold tolerances than the no-TE group. None of the other group differences were significant for any pain outcome. These findings suggest that SA is associated with greater sensitivity in A-delta fibers (cool thresholds) and hyperalgesia in response to thermal stimuli (heat, cold). However, hypoalgesia was noted in response to deep tissue pain (ischemia). By contrast, TE is primarily associated with reduced tolerance to heat and cold. These group differences are not likely due to spinal sensitization due to the lack of group differences in NFR. Future studies are needed to replicate these findings and determine whether QST responses can predict negative sequela of SA and non-SA trauma exposure.

Desmetramadol (INN) is an investigational analgesic consisting of the (+) and (-) enantiomers of the tramadol active M1 metabolite. Tramadol is schedule IV with better safety than schedule II opioids. Tramadol is racemic and exerts analgesia by a monoaminergic effect mediated by (-)-tramadol and (-)-M1, and an opioid effect mediated by (+)-M1. CYP2D6 metabolizes (+)-tramadol to (+)-M1. CYP2D6 ultra-metabolizers can produce dangerous (+)-M1 levels and respiratory depression, whereas poor metabolizers produce insufficient (+)-M1 for analgesia. The objectives of this study were to test the hypotheses that (i) desmetramadol and tramadol doses giving equal plasma (+)-M1 yield equal hypoalgesia in metabolically normal subjects, but that (ii) the same doses in metabolically deficient subjects result in desmetramadol having greater plasma (+)-M1 and greater hypoalgesia than tramadol. Consecutive double-blind, randomized, placebo-controlled, three segment cross-over trials ‘A’ and ‘B’ investigated steady-state pharmacokinetics and hypoalgesia of 20 mg desmetramadol and 50 mg tramadol in healthy subjects without (N=43) and with (N=60) cotreatment with the potent CYP2D6 inhibitor paroxetine (20 mg daily). In the absence of CYP2D6 inhibition (trial A), 20 mg desmetramadol and 50 mg tramadol dosed q6 hours gave bioequivalent plasma (+)-M1: Cssmin, 26 + 6 vs. 28 + 7 ng/mL (90% CI, 0.85-1.08); Cssmax, 36 + 10 vs. 37 + 10 ng/mL (90 CI, 0.88-1.13). Hypoalgesia (cold pressor) of desmetramadol and tramadol were significantly greater than placebo, but equal to each other. In trial B, CYP2D6 inhibition significantly depressed tramadol (+)-M1 Cssmin (-58%) and Cssmax (-60%), but increased desmetramadol (+)-M1 Cssmin (46%) and Cssmax (41%). In trial B desmetramadol produced significant hypoalgesia as it did in trial A, whereas in trial B tramadol hypoalgesia was insignificant and comparable to placebo. Desmetramadol offers tramadol analgesia without metabolic liabilities. Supported by grant R44 DA027304 from the National Institute on Drug Abuse (NIDA) of NIH.

The opioid epidemic has brought attention to the pain relieving effect of exercise, but exercise prescription for pain relief may be quite different from that typically recommended for cardiovascular and other health benefits. Exercise induced hypoalgesia (EIH) is complex and not entirely understood but possible mechanisms include the opioid and non-opioid systems. Hypoalgesia is also known to occur in response to pain itself. Conditioned pain modulation (CPM) is the inhibition of pain from a test stimulus by a painful conditioning stimulus. Studies of EIH often involve exercise paradigms in which long duration muscle contractions are used. Long duration muscle contractions are often painful so it raises the question, “Is it exercise or the pain associated with exercise that leads to EIH?” Nine individuals underwent pain testing on the right and left knees and middle finger before and after three conditions: 10 voluntary isometric contractions, 10 contractions elicited by neuromuscular electrical stimulation (NMES) and 10 bursts of noxious electrical stimulation without muscle contraction all on the right quadriceps muscles. The contractions or stimuli lasted 10 s separated by 50 s off. The average pain rating (0-100 VAS) during the noxious stimulation (84.4 +/- 12.1) was higher than during the NMES elicited contractions (61.4 +/- 18.9; p=0.001). Subjects reported no pain during the volitional contractions. The force of the contractions is reported in % maximum voluntary contraction (%MVIC) and the volitional contraction force averaged 59.6 (+/- 18.0) % MVIC while the NMES elicited contraction force averaged 52.0 (+/-14.5) % MVIC. Hypoalgesia was observed in the right and left knees response to the noxious stimulation and NMES elicited contractions but not the volitional contractions. The results suggest that the hypoalgesia associated with the NMES elicited contractions was due to the noxious nature of the contractions and that the mechanism involves spinal mechanisms.

The aim of this study was to investigate the effect of baseline (pre-exercise) temporal summation (TS) on the change of TS following submaximal isometric exercise in young healthy men (M) and women (W). Fifty-seven participants (20.75 ± 1.81 years; 29 women) completed two randomized sessions (exercise or quiet rest session). Isometric exercise consisted of sustained contraction of the knee extensors at 30% of maximum voluntary contraction performed until task failure. TS was assessed by applying a mechanical noxious stimulus equivalent to either 1kg (Low group) or 1.5 kg (High group) on the index finger. The mechanical noxious stimulus was applied for one minute beyond pain threshold, and subjects were instructed to rate their pain every 15 seconds on a numerical pain rating scale (0-10). TS was evaluated before and after exercise and quiet rest. The magnitude of TS was calculated as: [last pain rating – first pain rating]. The change of TS was compared between the two groups within each sex (M-High, M-Low, W-High, and W-Low). Sex differences in exercise-induced hypoalgesia (EIH) occurred among the high TS stimulus intensity group (session X trial X sex X group; p= 0.01); only W-High group experienced EIH while M-High experienced no change (session X trial X sex; p=0.039). Among women, the W-High had greater EIH than W-Low (session X trial X group; p= 0.049). In addition, pre-exercise TS was positively correlated with the magnitude of EIH (r= 0.34, p= 0.01). These results suggest that baseline experimental pain may contribute to the magnitude of EIH and to the sex differences in EIH.

There is limited evidence regarding the variability in pain response following exercise, including the impact of pain catastrophizing. The purpose of this study was to investigate the relation of the pain response after exercise with pain catastrophizing levels in young healthy individuals. Fifty-seven participants (20.75±1.81 years, 29 women) completed two randomized sessions (exercise and quiet rest). Exercise consisted of sustained submaximal isometric contraction of the knee extensors, performed until task failure. Temporal summation (TS) was assessed before and after exercise and quiet rest, by applying a constant mechanical stimulus to the index finger for one minute after reported pain threshold. During the one minute, participants were asked to rate their pain every 15 seconds (0-10 Numerical Pain Rating Scale). TS was calculated as the last pain rating minus the first pain rating. Pain catastrophizing scale (PCS) was completed at the beginning of the first session. Situational catastrophizing (S-PCS) was completed after each TS protocol. Based on the change in pain following exercise, participants were divided into two groups, responders (hypoalgesia) and non-responders (no change or hyperalgesia). There was no difference in baseline PCS between groups (p=0.974). For S-PCS, there was a session x trial x group interaction (p

Pain management is still challenging in clinic as current analgesics either are not very effective or produce serious adverse effects. This study aimed to examine if old drugs could display the new use and to develop a novel therapy for inflammatory pain. Injection of carrageenan in hindpaw evoked hyperalgesia detected by noxious heat stimulation. Intraplantar (i.pl.) injection of the 5-HT1A receptor antagonist WAY-100635 increased paw withdrawal latency (PWL) above normal level (hypoalgesia) during the late phase of carrageenan-evoked inflammation. The hypoalgesia was completely abolished by systemic injection of naloxone chloride and naloxone methiodide. Moreover, i.pl. injection of a combination of WAY-100635 and ketanserin, a 5-HT2A receptor antagonist, at their minimal doses attenuated hyperalgesia in the late phase of carrageenan-evoked inflammation. Subcutaneous (s.c.) injection of both ketanserin and propranolol dose-dependently inhibited carrageenan-evoked hyperalgesia. The treatment with a combination of ketanserin and propranolol by s.c. injection abolished carrageenan-evoked hyperalgesia at the doses, at which the drugs failed to alter the hypersensitivity when they were given alone. Furthermore, the combination of ketanserin and propranolol was also effective in relieving arthritic hyperalgesia and muscle pain at a minimal dose. The present study suggests that the activation of 5-HT1A receptors suppressed naloxone-reversible antinociception contributing to the maintenance of inflammatory pain, and that the concomitant blockade of 5-HT1A and 5-HT2A receptors in the periphery produced synergistic effects on inflammatory hyperalgesia. It is proposed that the combination of ketanserin and propranolol injected s.c. could be a promising therapy for relieving inflammatory pain with minimal side effects.

Background and objectives The association between prediabetes and distal polyneuropathy (DPN) remains controversial. Here we test whether the prevalence of small fiber sensory distal polyneuropathy is increased in prediabetes. Methods Prospectively recruited cohorts of healthy subjects and those with prediabetes from Olmsted County, Minnesota, were assessed for positive neuropathic sensory symptoms, or pain symptoms characteristic of small fiber sensory DPN. Hyperalgesia and hypoalgesia were assessed by “smart” quantitative sensation testing (QST). The prevalence of symptoms and QST abnormalities were compared among the groups. Results There was no significant increase in the prevalence of positive neuropathic sensory or pain symptoms, nor of hyper- or hypoalgesia in the prediabetes group. There was an increased prevalence of hypoalgesia of the foot only in newly diagnosed diabetes. Conclusions Based on positive sensory and pain symptoms and QSTs, we did not find an increase in small fiber sensory DPN in prediabetes. Recognizing that obesity and diabetes mellitus are implicated in macro- and microvessel complications, physicians should encourage healthy living and weight loss in patients with prediabetes. In medical practice, alternate causes should be excluded before concluding that small fiber sensory distal neuropathy is secondary to prediabetes.

Opioid system has been reported to be involved in the consequences of post-weaning social isolation stress (SIS) such as hypoalgesia and social behaviors. Also, previous studies have shown that SIS increases mu opioid receptor expression in the regions of the brain associated with epileptogenesis such as basolateral amygdala and cortex. Interestingly, experiencing SIS increases seizure risk in the adulthood. Regarding the SIS-induced alterations in the opioid system, we hypothesize that increase in opioidergic system activity (mostly by mu receptor) may be associated with increase in vulnerability to seizures. In non-stressed mice, morphine at low doses (1 mg/kg) has an anticonvulsant effect on seizure threshold while higher doses (60 mg/kg) are proconvulsant. To support the hypothesis, we showed that administration of anticonvulsant dose of morphine (1 mg/kg) to socially isolated male mice not only was not able to reverse the negative effect of SIS on seizure susceptibility to pentylenetetrazole but also enhanced it. These results support our hypothesis that proconvulsant effect of post-weaning social isolation stress may be associated with dysregulation of opioid system in the adult male mice.

The utility and inter-session repeatability of sensory threshold measurements using an electronic von Frey anesthesiometer (VFA) were assessed in a group of six neurologically normal dogs. Sensory threshold values obtained in neurologically normal dogs were compared to those of dogs with acute spinal cord injury (SCI) caused by intervertebral disc extrusion (n=6) and to a group of neurologically normal dogs with cranial cruciate ligament rupture (CCLR; n=6). Sensory threshold values in neurologically normal dogs were 155.8 ± 37.7 g and 154.7 ± 67.2 g for the left and right pelvic limbs, respectively. The difference in mean sensory threshold values obtained for the group when two distinct testing sessions were compared was not statistically significant (P>0.05). Mean sensory threshold values for the group with SCI were significantly higher than those for neurologically normal dogs at 351.1 ± 116.5 g and 420.3 ± 157.7 g for the left and right pelvic limbs, respectively (P=0.01). A comparison of sensory threshold values for the group with CCLR and neurologically normal dogs was not statistically significant (P>0.05). The modified dorsal technique for VFA described here represents a reliable method to assess sensory threshold in neurologically normal dogs and in those with SCI.

An inverse association between resting blood pressure (BP) and acute pain sensitivity is well documented. Whether BP-related hypoalgesia differs by gender is unclear from prior work. Whether it increases proportionally with BP throughout the full BP range is also unknown. We examined BP-related hypoalgesia in a general population sample (n = 10,371, aged 30-87) of equal gender distribution reflecting the extremely low through hypertensive BP range. Resting BP was assessed and individuals participated in a standardized cold pressor test, providing pain ratings every 9 seconds. For systolic BP (SBP), a significant SBP × Gender interaction was observed on mean pain ratings (P.001). Females displayed significant BP-related hypoalgesia (P.001), with males showing a 38% smaller effect (P .001). A similar DBP × Gender interaction was also observed (P.05). Spline regression indicated a significant (P.001) change in slope of the SBP-pain association at 140 mmHg. Among individuals with lower resting SBP (140/90), increasing hypoalgesia with increasing SBP levels was observed (P .001), with no further increases in those with higher BP (≥140/90; P.10). This is the first large-scale study to confirm past results suggesting that BP-related hypoalgesia differs by gender; that is, females exhibited greater hypoalgesia. BP-related hypoalgesia appears subject to ceiling effects in the hypertensive BP range.Females show greater BP-related hypoalgesia than males, highlighting gender differences in endogenous antinociceptive systems. Extent of BP-related hypoalgesia does not increase further once resting pressures reach the hypertensive range, suggesting persistent maximal demands on these antinociceptive systems among hypertensive individuals.

Streptozotocin (STZ)-induced type 1 diabetes in rats leads to the development of peripheral diabetic neuropathy (PDN) manifested as thermal hyperalgesia at early stages (4th week) followed by hypoalgesia after 8weeks of diabetes development. Here we found that 6–7week STZ-diabetic rats developed either thermal hyper- (18%), hypo- (25%) or normalgesic (57%) types of PDN. These developmentally similar diabetic rats were studied in order to analyze mechanisms potentially underlying different thermal nociception. The proportion of IB4-positive capsaicin-sensitive small DRG neurons, strongly involved in thermal nociception, was not altered under different types of PDN implying differential changes at cellular and molecular level. We further focused on properties of T-type calcium and TRPV1 channels, which are known to be involved in Ca2+ signaling and pathological nociception. Indeed, TRPV1-mediated signaling in these neurons was downregulated under hypo- and normalgesia and upregulated under hyperalgesia. A complex interplay between diabetes-induced changes in functional expression of Cav3.2 T-type calcium channels and depolarizing shift of their steady-state inactivation resulted in upregulation of these channels under hyper- and normalgesia and their downregulation under hypoalgesia. As a result, T-type window current was increased by several times under hyperalgesia partially underlying the increased resting [Ca2+]i observed in the hyperalgesic rats. At the same time Cav3.2-dependent Ca2+ signaling was upregulated in all types of PDN. These findings indicate that alterations in functioning of Cav3.2 T-type and TRPV1 channels, specific for each type of PDN, may underlie the variety of pain syndromes induced by type 1 diabetes.

An increased vulnerability to pain complaints, along with a simultaneous increase in experimental pain thresholds, shows the paradoxical phenomenon of pain perception in depressive patients. Clomipramine, a tricyclic antidepressant, could also ameliorate syndromes in chronic pain patients. However, few studies have focused on the effect of antidepressants on experimental pain thresholds. By using a rat model, the learned helplessness paradigm, the present study explored the effect of clomipramine on behavioral deficits and experimental pain thresholds to different stimuli in "helpless" rats. Helpless rats were administered clomipramine (10mg/kg, i.p, b.i.d.) for 5 consecutive days. The depressive-like and anxiety-like behaviors were detected by shuttle box, open field and elevated plus maze test before and after inescapable shock and after medication. The sensitivity to the thermal and mechanical stimuli was also measured by the von Frey hair and Hargreaves test at the indicated time points. Helpless rats displayed shorter total travel distance and fewer rearing times in the open field test and decreased percentage of time spent in the open arms in the elevated plus maze test. In addition, they exhibited significant hypoalgesia/hypoesthesia to mechanical and thermal stimuli. Clomipramine alleviate depressive-like and anxiety-like behaviors and increased the sensitivity to von Frey filament stimuli with no effect on the sensitivity to radiant heat stimuli in helpless rats. These suggested that clomipramine could reverse mechanical but not thermal hypoalgesia/hypoesthesia and simultaneously improved behavioral deficits.

Recently, we hypothesized that supraspinal structures may have important functions in discriminating between noxious mechanically and heat mediated nociception through distinct functions: facilitation and inhibition. In this study, conducted in conscious rats, we explored the role of different thalamic nuclei: the mediodorsal (MD) nucleus, the central medial (CM) nucleus, the submedius (SM) nucleus, the ventralmedial (VM) nucleus and the ventral posterolateral (VPL) nucleus, in the descending control of secondary and contralateral mechanical hyperalgesia and heat hypoalgesia occurring in intramuscularly hypertonic (HT, 5.8%) saline-induced muscle nociception. We found that the MD nuclei participated in the descending facilitation of mechanical hyperalgesia, and that the VM nuclei were specifically involved in the descending inhibition of heat hypoalgesia. Neither descending facilitation nor descending inhibition was affected after electrolytic lesion of the thalamic CM, SM, and VPL nuclei. This descending facilitatory and inhibitory modulation of nociception was strengthened by glutamate, and weakened by GABA, microinjected into the thalamic MD and VM nuclei. It is suggested that (1) thalamic MD nucleus and VM nucleus form two distinct endogenous systems in the control of noxious mechanically and heat evoked responses, and (2) the strengthening of descending inhibition and the weakening of descending facilitation by means of up regulation and down regulation of appropriate receptor expression in the VM and MD nuclei may provide a new strategic policy in treating pathological pain.

The purpose of this article was to examine the effects of acute exercise on pain perception in healthy adults and adults with chronic pain using meta-analytic techniques. Specifically, studies using a repeated measures design to examine the effect of acute isometric, aerobic, or dynamic resistance exercise on pain threshold and pain intensity measures were included in this meta-analysis. The results suggest that all 3 types of exercise reduce perception of experimentally induced pain in healthy participants, with effects ranging from small to large depending on pain induction method and exercise protocol. In healthy participants, the mean effect size for aerobic exercise was moderate (dthr = .41, dint = .59), while the mean effect sizes for isometric exercise (dthr = 1.02, dint = .72) and dynamic resistance exercise (dthr = .83, dint = .75) were large. In chronic pain populations, the magnitude and direction of the effect sizes were highly variable for aerobic and isometric exercise and appeared to depend on the chronic pain condition being studied as well as the intensity of the exercise. While trends could be identified, the optimal dose of exercise that is needed to produce hypoalgesia could not be systematically determined with the amount of data available. Perspective This article presents a quantitative review of the exercise-induced hypoalgesia literature. This review raises several important questions that need to be addressed while also demonstrating that acute exercise has a hypoalgesic effect on experimentally induced pain in healthy adults, and both a hypoalgesic and hyperalgesic effect in adults with chronic pain.

Background context Neuropathic pain after nerve injuries is characterized by positive and negative sensory symptoms and signs. The extent of sensory fiber loss after nerve injuries has been demonstrated to correlate with symptoms of neuropathic pain by quantitative sensory testing and confirmed by biopsies of small nerve fibers. However, the relationship between the pathologic changes of large nerves on injuries and resulting pain symptoms remains unclear. Purpose To investigate the relationship between the extent of dorsal root injury and resulting symptoms of neuropathic pain. Study design Nerve injury and assessment of the following pain-related behaviors and neuropathologic changes. Methods A total of 24 adult male Sprague-Dawley rats weighing 250 to 300 g were randomly divided into three groups (n=8 each): sham group operated on but without nerve compression, 70 gf group, and 180 gf group; a compression force of 70 or 180 g was applied to the right C7 dorsal root, separately. Threshold thermal and mechanical pains were measured before surgery (baseline) and on the first, third, fifth, and seventh day after surgery. On the seventh day after surgery, all rats were killed, and the structural alterations of nerve fibers within the compressed areas were examined. Results A compression force of 70 g resulted in hyperalgesia, whereas a compression force of 180 g induced hypoalgesia in the ipsilateral forepaw in response to both mechanical and thermal stimulations within 7 days after injury. Light microscopy and electron microscopy revealed a mild to moderate sensory fiber loss after 70-gf compression and a more severe sensory fiber loss after 180-gf compression. Conclusions Transient injuries on sensory fibers can produce either positive or negative symptoms of neuropathic pain, and the different extent of sensory fiber loss after different degrees of injuries might account for the varied resulting symptoms of neuropathic pain.

Visceral manual therapy is increasingly used by UK osteopaths and manual therapists, but there is a paucity of research investigating its underlying mechanisms, and in particular in relation to hypoalgesia. The aim of this study was to investigate the immediate effects of osteopathic visceral mobilisation on pressure pain thresholds. A single-blinded, randomised, within subjects, repeated measures design was conducted on 15 asymptomatic subjects. Pressure pain thresholds were measured at the L1 paraspinal musculature and 1st dorsal interossei before and after osteopathic visceral mobilisation of the sigmoid colon. The results demonstrated a statistically significant improvement in pressure pain thresholds immediately after the intervention (P

Slow breathing is used as a means to reduce pain, yet the mechanisms responsible for respiration-induced hypoalgesia are poorly understood. The present study asked 30 healthy partici- pants (Mage = 21 years, Meducation = 15 years, 80% white non-Hispanic) to breathe at normal, slow (50% normal), and fast (125% normal) rates while constant-intensity, suprathreshold electric stimu- lations were delivered to the sural nerve to elicit pain and the nociceptive flexion reflex (NFR, a mea- sure of spinal nociception). Stimulations were equally balanced across inhalations and exhalations to determine whether parasympathetic activation during exhalations contributes to hypoalgesia. Respi- ration rate, heart rate variability (HRV, a measure of parasympathetic activity), heart rate, and subjec- tive arousal were assessed as manipulation checks. Slow breathing reduced pain relative to normal breathing and fast breathing, but NFR was not influenced by breathing. Further, pain and NFR did not differ between exhalations and inhalations, and changes in HRV did not correlate with changes in pain or NFR. Together, these findings suggest that respiration-induced hypoalgesia does not re- quire gating of spinal nociception or changes in parasympathetic activity. Perspective: Slow breathing reduced pain relative to normal and fast breathing. This respiration- induced hypoalgesia does not appear to be due to gating of spinal nociception or changes in para- sympathetic activity.

The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT₇ receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT₇ receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT₇ receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT₇ receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT₇ receptor agonists may have clinical utility in treating diabetic neuropathic pain.

Objectives: Non-invasive interactive neurostimulation (InterX®) delivers high amplitude electrical pulsed currents at points of low impedance on the skin. This study compared the hypoalgesic effect of non-invasive interactive neurostimulation with transcutaneous electrical nerve stimulation (TENS). Materials and Methods: A repeated measures parallel group study on healthy human volunteers randomized to receive strong non-painful TENS or non-invasive interactive neurostimulation for 21 min on the forearm (N= 10/group). Pressure algometry was used to determine blunt pressure pain threshold at baseline, 10, and 20 min during stimulation, and 5 min post stimulation. Results: Low impedance sites were found in half of the participants receiving non-invasive interactive neurostimulation. ANOVA found no effects for intervention (p= 0.923), time × intervention interaction (p= 0.21), or time (p= 0.094). Conclusions: Given the limited power of this study, we show that there were no significant differences in hypoalgesia between non-invasive interactive neurostimulation and TENS. Unlike our previous studies we also failed to detect a change pain threshold during TENS. Nevertheless, our findings can be used to inform the design of an appropriately powered study on pain patients.