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Background and aimsPain is a disabling symptom in knee osteoarthritis (KOA) and its underlying mechanism remains poorly understood. Dysfunction of descending pain modulatory pathways and reduced pain inhibition enhance pain facilitation in many chronic pain syndromes but do not fully explain pain levels in chronic musculoskeletal conditions. The objective of this study is to explore the association of clinical variables with pain intensity perception in KOA individuals with varying levels of Conditioned Pain Modulation (CPM) response.MethodsThis is a cross-sectional, exploratory analysis using baseline data of a randomized clinical trial investigating the effects of a non-invasive brain stimulation treatment on the perception of pain and functional limitations due to KOA. Sixty-three subjects with KOA were included in this study. Data on pain perception, mood perception, self-reported depression, physical function, quality of life, and quantitative sensory testing was collected. Multiple linear regression analysis was performed to explore the association between the clinical variables with pain perception for individuals with different levels of CPM response.ResultsFor KOA patients with limited CPM response, perception of limitations at work/other activities due to emotional problems and stress scores were statistically significantly associated with pain scores, F(2, 37) = 7.02,p p ConclusionsPain intensity perception is associated differently with clinical variables according to the individual CPM response. Mechanistic models to explain pain perception in these two subgroups of KOA subjects are discussed.

Endogenous pain inhibition is less efficient in chronic pain patients. Diffuse noxious inhibitory control (DNIC), a form of endogenous pain inhibition, is compromised in women and older people, making them more vulnerable to chronic pain. However, the underlying mechanisms remain unclear. Here, we used a capsaicin-induced DNIC test and resting-state functional MRI to investigate the impact of aging and sex on endogenous pain inhibition and associated brain circuitries in healthy rats. We found that DNIC was less efficient in young females compared with young males. Diffuse noxious inhibitory control response was lost in old rats of both sexes, but the brain networks engaged during DNIC differed in a sex-dependent manner. Young males had the most efficient analgesia with the strongest connectivity between anterior cingulate cortex (ACC) and periaqueductal gray (PAG). The reduced efficiency of DNIC in young females seemed to be driven by widespread brain connectivity. Old males showed increased connectivity between PAG, raphe nuclei, pontine reticular nucleus, and hippocampus, which may not be dependent on connections to ACC, whereas old females showed increased connectivity between ACC, PAG, and more limbic regions. These findings suggest that distinct brain circuitries including the limbic system may contribute to higher susceptibility to pain modulatory deficits in the elderly population, and sex may be a risk factor for developing age-related chronic pain.

BACKGROUND CONTEXT Although 40% of adolescent idiopathic scoliosis (AIS) patients present with chronic back pain, the pathophysiology and underlying pain mechanisms remain poorly understood. We hypothesized that development of chronic pain syndrome in AIS is associated with alterations in pain modulatory mechanisms. PURPOSE To identify the presence of sensitization in nociceptive pathways and to assess the efficacy of the diffuse noxious inhibitory control in patients with AIS presenting with chronic back pain. STUDY DESIGN Cross-sectional study. PATIENT SAMPLE Ninety-four patients diagnosed with AIS and chronic back pain. OUTCOME MEASURES Quantitative sensory testing (QST) assessed pain modulation and self-reported questionnaires were used to assess pain burden and health-related quality of life. METHODS Patients underwent a detailed pain assessment using a standard and validated quantitative sensory testing (QST) protocol. The measurements included mechanical detection thresholds (MDT), pain pressure threshold (PPT), heat pain threshold (HPT), heat tolerance threshold (HTT), and a conditioned pain modulation (CPM) paradigm. Altogether, these tests measured changes in regulation of the neurophysiology underlying the nociceptive processes based on the patient's pain perception. Funding was provided by The Louise and Alan Edwards Foundation and The Shriners Hospitals for Children. RESULTS Efficient pain inhibitory response was observed in 51.1% of patients, while 21.3% and 27.7% had sub-optimal and inefficient CPM, respectively. Temporal summation of pain was observed in 11.7% of patients. Significant correlations were observed between deformity severity and pain pressure thresholds (p=.023) and CPM (p=.017), neuropathic pain scores and pain pressure thresholds (p=.015) and temporal summation of pain (p=.047), and heat temperature threshold and pain intensity (p=.048). CONCLUSIONS Chronic back pain has an impact in the quality of life of adolescents with idiopathic scoliosis. We demonstrated a high prevalence of impaired pain modulation in this group. The association between deformity severity and somatosensory dysfunction may suggest that spinal deformity can be a trigger for abnormal neuroplastic changes in this population contributing to chronic pain syndrome.

Diffuse noxious inhibitory controls (DNICs) is a pain-inhibits-pain phenomenon demonstrated in humans and animals. Diffuse noxious inhibitory control is diminished in many chronic pain states, including neuropathic pain. The efficiency of DNIC has been suggested to prospectively predict both the likelihood of pain chronification and treatment response. Little is known as to why DNIC is dysfunctional in neuropathic pain. Here, we evaluated DNIC in the rat L5/L6 spinal nerve ligation (SNL) model of chronic pain using both behavioral and electrophysiological outcomes. For behavior, nociceptive thresholds were determined using response to noxious paw pressure on both hind paws as the test stimulus before, and after, injection of a conditioning stimulus of capsaicin into the left forepaw. Functionally, the spike firing of spinal wide-dynamic-range neuronal activity was evaluated before and during noxious ear pinch, while stimulating the ipsilateral paw with von Frey hairs of increased bending force. In both assays, the DNIC response was significantly diminished in the ipsilateral (ie, injured) paw of SNL animals. However, behavioral loss of DNIC was not observed on the contralateral (ie, uninjured) paw. Systemic application of nor-binaltorphimine, a kappa opioid antagonist, did not ameliorate SNL-induced hyperalgesia but reversed loss of the behavioral DNIC response. Microinjection of nor-binaltorphimine into the right central amygdala (RCeA) of SNL rats did not affect baseline thresholds but restored DNIC both behaviorally and electrophysiologically. Cumulatively, these data suggest that net enhanced descending facilitations may be mediated by kappa opioid receptor signaling from the right central amygdala to promote diminished DNIC after neuropathy.

Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.

The counterirritation phenomenon known as conditioned pain modulation, or diffuse noxious inhibitory control in animals, is of increasing interest due to its utility in predicting chronic pain and treatment response. It features considerable interindividual variability, with large subsets of pain patients and even normal volunteers exhibiting hyperalgesia rather than hypoalgesia during or immediately after receiving a conditioning stimulus. We observed that mice undergoing tonic inflammatory pain in the abdominal cavity (the conditioning stimulus) display hyperalgesia, not hypoalgesia, to noxious thermal stimulation (the test stimulus) applied to the hindpaw. In a series of parametric studies, we show that this hyperalgesia can be reliably observed using multiple conditioning stimuli (acetic acid and orofacial formalin), test stimuli (hindpaw and forepaw-withdrawal, tail-withdrawal, hot-plate, and von Frey tests) and genotypes (CD-1, DBA/2, and C57BL/6 mice and Sprague-Dawley rats). Although the magnitude of the hyperalgesia is dependent on the intensity of the conditioning stimulus, we find that the direction of effect is dependent on the effective test stimulus intensity, with lower-intensity stimuli leading to hyperalgesia and higher-intensity stimuli leading to hypoalgesia.

Summary Introduction Heterotopic conditioned pain modulation (CPM) has provided potentially useful clinical information such as response to medication in neuropathic pain or the prediction of pain after surgical procedures. Despite these advances, several methodological aspects of CPM remain to be determined, such as the impact of the conditioning stimulus (CS) type upon CPM, if its evoked-pain intensity is controlled for [measured on a visual analogue scale (VAS: 0–100 mm)]. Objectives To explore potential differential effects of CPM using three distinct CS (having similar evoked-pain intensity) in the same individuals. Methods We conducted a cross-over randomized study in healthy volunteers (HV) and looked-for differences in the CPM effect evoked by three differing CS [cuff-pressure pain stimulation (CuPS), cold pressor test (CoPT), and thermode-based cold painful stimulation (TCPS)] on the same test stimulus [(TS)–supra-threshold heat pain stimulation with a contact-heat thermode). CPM was calculated as a ratio: [conditioned TS VAS – unconditioned TS VAS]/[unconditioned TS VAS]. Importantly, the range of pain evoked by the unconditioned-TS and by the CS was controlled for. Also, the unpleasantness evoked by the CS [visual analogue scale (VAS: 0–100 mm)] was measured before the initiation of the conditioned-TS. Results Pain intensity VAS of the three unconditioned-TSs were similar between the three sessions. CPM was significantly different between the three types of CS (CoPT = −0.43 ± 0.29; CuPS = −0.25 ± 0.24; and TCPS = −0.23 ± 0.35; P = .005): CoPT induced significantly more robust CPM compared to CuPS (P = .004) and TCPS (P = .005). Conclusions Significantly different intensities of CPM can be evoked on the same individual according to the nature of the CS, even when controlling for the intensity of the unconditioned-TS, and the pain evoked by the CS. This may have implications for the design of future recommendations and may impact the translation of CPM from the laboratory to clinical practice.

Aim Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. Methods Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. Results In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. Interpretation Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

ObjectiveTo assess the effect of different dosages of pain neuroscience education (PNE) programs on central nociceptive processing in patients with fibromyalgia. Second, to compare the effects of different dosages of PNE programs on numerical pain rating scale (NPRS), disability, and psychological variables.DesignSingle-blind randomized controlled trial.SettingThree fibromyalgia centers in Spain (Valencia, Alcorcón, Alcalá de Henares).SubjectsSeventy-seven patients with fibromyalgia.MethodsParticipants were randomized to four groups of PNE: 1) high-dose PNE (N = 20), 2) low–concentrated dose PNE (N = 20), 3) diluted low-dose PNE (N = 20), and (4) control treatment (N = 17), conducted in two 30–50-minute sessions in groups of four to six participants. Conditioned pain modulation (CPM), temporal summation (TS), and pressure pain thresholds (PPTs) were assessed at baseline and at three-month follow-up. Secondary outcome measures were the Fibromyalgia Impact Questionnaire, Pain Catastrophizing Scale, and Pain Anxiety Symptoms Scale.ResultsThere were significant between-group differences for NPRS in favor of the groups receiving high-dose PNE, with a large effect size at three-month follow-up (P 0.05). All groups improved for central nociceptive processing, psychological variables, disability, and pain intensity (NPRS).ConclusionsIn patients with fibromyalgia, higher dosages of PNE produced a larger improvement in pain severity at three-month follow-up than other dosages of PNE and biomedical education. However, PNE was not superior to biomedical education in the central nociceptive processing, disability, or psychological variables in patients with fibromyalgia.

Canine neuropathic pain (NeuP) has been poorly investigated. This study aimed to evaluate the pain burden, sensory profile and inflammatory cytokines in dogs with naturally-occurring NeuP. Twenty-nine client-owned dogs with NeuP were included in a prospective, partially masked, randomized crossover clinical trial, and treated with gabapentin/placebo/gabapentin-meloxicam or gabapentin-meloxicam/placebo/gabapentin (each treatment block of 7 days; total 21 days). Pain scores, mechanical (MNT) and electrical (ENT) nociceptive thresholds and descending noxious inhibitory controls (DNIC) were assessed at baseline, days 7, 14, and 21. DNIC was evaluated using ΔMNT (after-before conditioning stimulus). Positive or negative ΔMNT corresponded to inhibitory or facilitatory pain profiles, respectively. Pain scores were recorded using the Client Specific Outcome Measures (CSOM), Canine Brief Pain Inventory (CBPI), and short-form Glasgow Composite Measure Pain Scale (CMPS-SF). Data from baseline were compared to those of sixteen healthy controls. ΔMNT, but not MNT and ENT, was significantly larger in controls (2.3 ± 0.9 N) than in NeuP (-0.2 ± 0.7 N). The percentage of dogs with facilitatory sensory profile was similar at baseline and after placebo (61.5–63%), and between controls and after gabapentin (33.3–34.6%). The CBPI scores were significantly different between gabapentin (CBPI pain and CBPI overall impression) and/or gabapentin-meloxicam (CBPI pain and interference) when compared with baseline, but not placebo. The CBPI scores were not significantly different between placebo and baseline. The concentration of cytokines was not different between groups or treatments. Dogs with NeuP have deficient inhibitory pain mechanisms. Pain burden was reduced after gabapentin and/or gabapentin-meloxicam when compared with baseline using CBPI and CMPS-SF scores. However, these scores were not superior than placebo, nor placebo was superior to baseline evaluations. A caregiver placebo effect may have biased the results.

Diffuse noxious inhibitory control (DNIC), which involves endogenous pain modulation, has been investigated as a potential mechanism for the differences in pain modulation observed between men and women, though the literature shows contradictory findings. We used a capsaicin-induced DNIC behavioral assay and resting state functional magnetic resonance imaging (rsfMRI) to assess the effect of testosterone on pain modulation and related brain circuitry in rats. We hypothesized that testosterone is required for DNIC that leads to efficient pain inhibition by increasing descending pain modulation. Male, female, and orchidectomized (GDX) male rats had a capsaicin injection into the forepaw to induce DNIC and mechanical thresholds were observed on the hindpaw. rsfMRI scans were acquired before and after capsaicin injection to analyze the effects of DNIC on periaqueductal gray (PAG), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) connectivity to the whole brain. The strength of DNIC was higher in males compared to females and GDX males. PAG connectivity with prelimbic cortex (PrL), ACC and insula was stronger in males compared to females and GDX males, whereas females and GDX males had increased connectivity between the right ACC, hippocampus and thalamus. GDX males also showed a stronger connectivity between right ACC and NAc, and right NAc with PrL, ACC, insula and thalamus. Our findings suggest that testosterone plays a key role in reinforcing the endogenous pain inhibitory system, while circuitries related to reward and emotion are more strongly recruited in the absence of testosterone.

Background and aims Elite athletes reportedly have superior pain tolerances, but it is unclear if results extend to conditioned pain modulation (CPM). The aim of our study was to synthesize existing literature in order to determine whether CPM is increased in elite athletes compared to healthy controls. Methods A systematic review and random-effects meta-analysis was conducted. Cochrane Central Register of Controlled Trials, SPORTDiscus, PsycINFO, CINAHL, Web of Science, and PubMed were searched for English-language studies that examined CPM in adult elite athlete populations. Results Seven studies were identified; all were of poor to fair methodological quality. There was no overall difference in CPM between elite athletes and controls (Hedges g = 0.37, CI95 −0.03−0.76; p = 0.07). There was heterogeneity between studies, including one that reported significantly less CPM in elite athletes compared to controls. An exploratory meta-regression indicated that a greater number of hours trained per week was associated with higher CPM. Conclusions The overall number and quality of studies was low. Despite nominally favoring higher CPM in elite athletes, aggregate results indicate no significant difference compared to healthy controls. A possible factor explaining the high degree of variability between studies is the number of hours elite athletes spent training. Implications Based on available evidence, athletes do not have remarkable endogenous pain modulation compared to controls. High quality experimental studies are needed to address the effect of hours trained per week on CPM in athletes.

Chronic pain after spinal cord injury (SCI) is a form of central neuropathic pain that is debilitating and often refractory to current pharmacological treatments. Neurostimulation pain therapies, such as epidural spinal cord stimulation, have only moderate success in reducing SCI pain. The pathogenesis of SCI pain may involve a state of central neuronal hyperexcitability, especially in the spinal cord dorsal horn, that develops after injury. We hypothesize that the neuronal structures near the spinal cord injury site may be an important pain generator, and intraspinal microstimulation (ISMS) may normalize dorsal horn neuronal hyperexcitability and hence alleviate SCI pain. Specifically, ISMS may induce frequency-dependent conduction block on axons of afferent sensory neurons, in the spinothalamic tract and Lissauer’s tract. ISMS may also facilitate primary afferent depolarization that elicits presynaptic inhibition of incoming afferent inputs. Together, these actions will reduce abnormal afferent inputs and ascending pain signals before they can reach the brain. Furthermore, ISMS may directly induce inhibitory postsynaptic potentials in dorsal horn neurons, and trigger the release of endogenous inhibitory neurotransmitters, opioids and serotonin to inhibit postsynaptic neurons and restore the compromised segmental pain inhibition after SCI. Finally, ISMS may alter the frequency and pattern of discharge such that the rostrally conducted impulses no longer code pain or activate brain areas concerned with pain signaling. Based on recent progress in understanding spinal learning and plasticity, we also postulate that repetitive or long-term ISMS may help the dorsal horn “reset” neuronal excitability and regain normal pain processing for a prolonged period. By finely tuning the stimulation parameters (e.g., intensity, pulse width, frequency), position, and geometry of ISMS electrode, multiple spinal structures (e.g., dorsal horn, dorsal column, spinothalamic tract) may be modulated to induce synergistic pain inhibition. Our hypothesis can be readily tested in preclinical models of SCI pain by using a combination of in vivo electrophysiological (neuronal activity) and animal behavioral (pain response) approaches. Since ISMS electrodes stimulate the spinal structures directly, we expect that the effective stimulus intensity and energy consumption can be lower than that for epidural spinal cord stimulation. The proposed hypothesis may provide insights and rationales for developing a novel neurostimulation pain therapy by directly inhibiting the pain generators in the spinal cord, and ISMS may be an alternative strategy to treat SCI pain.

The aim of the present study was to compare the effects of explicit suggestions of analgesia and of the activation of the Diffuse Noxious Inhibitory Control (DNIC) by cold pressor test on pain perception and heart rate in healthy participants with high (highs, N=18), low (lows, N=18) and intermediate scores of hypnotizability (mediums, N=15) out of hypnosis. Pain reports and the stimulus-locked heart rate changes induced by electrical nociceptive stimulation of the left hand were studied in the absence of concomitant stimuli (Control), during suggestions of analgesia (SUGG, glove analgesia) and during cold pressor test used as a conditioning stimulus to the right hand (DNIC, water temperature=10-12°C) in the REAL session. Participants were submitted also to a SHAM session in which the DNIC water temperature was 30°C and the suggestions for analgesia were substituted with weather forecast information. Both suggestions and DNIC reduced pain significantly in all subjects; however, the percentage of reduction was significantly larger in highs (pain intensity=55% of the control condition) than in mediums (70%) and lows (80%) independently of the REAL/SHAM session and of the specific pain manipulation. Heart rate was not modulated consistently with pain experience. Findings indicate that both suggestions and DNIC influence pain experience as a function of hypnotizability and suggest that both sensory and cognitive mechanisms co-operate in DNIC induced analgesia.

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (heterotopic noxious conditioning stimulation, HNCS). While the effects of HNCS are thought to rely on a spino-bulbo-spinal mechanism in animals (termed diffuse noxious inhibitory controls, DNIC), the underlying neurophysiology in humans may involve other pathways. In this study, we investigated the role of concomitant supraspinal mechanisms during HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the cold pressor test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuli during HNCS can be ascribed entirely to supraspinal mechanisms. Electroencephalography (EEG) was recorded during HNCS, and auditory stimuli were administered in three blocks, before, during and after HNCS. Nociceptive withdrawal reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reduced during HNCS. Moreover, the amplitude of the NWR was significantly diminished during HNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions in humans is questionable. We conclude that the net effects of HCNS are not independent from attentional/cognitive influences. Fil: Torta, Diana M.. Université Catholique de Louvain; Bélgica. Katholikie Universiteit Leuven; Bélgica Fil: Jure, Fabricio A.. Aalborg Universitet; Fil: Andersen, Ole K.. Aalborg Universitet; Fil: Biurrun Manresa, José Alberto. Universidad Nacional de Entre Ríos. Instituto de Investigación y Desarrollo en Bioingeniería y Bioinformática - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Investigación y Desarrollo en Bioingeniería y Bioinformática; Argentina

Measures of sensory and cognitive inhibition were obtained from university students with and without a history of chronic pain. The form of sensory inhibition measured was diffuse noxious inhibitory controls (DNIC), the capacity of a painful stimulus to reduce the subjective intensity of a second stimulus delivered to a remote body site. To measure cognitive inhibition, the Stroop effect was used. Participants with a history of chronic pain showed less DNIC (i.e., less sensory inhibition) than the healthy controls, but had a smaller Stroop effect (indicating greater cognitive inhibition). The fact that chronic pain history is associated with opposite changes in these two measures casts doubt on the view that the two inhibitory processes are related. Scores on each experimental measure were equivalent in pain-history subjects with ongoing chronic pain and those whose chronic pain had resolved. This equivalence suggests that chronic pain in childhood or adolescence may have lingering effects on sensory and cognitive inhibition.

Functional abdominal pain disorders (FAPDs) are common among young individuals. To date, relatively little is known regarding the function of the endogenous analgesic mechanisms in this vulnerable group. Therefore, this case–control study aimed to compare conditioned pain modulation (CPM), pressure algometry, and psychosocial variables in 39 young children (aged 6-12 years) with FAPD and 36 age- and sex-matched pain-free controls. Pressure algometry was used to assess pressure pain thresholds (PPTs) at both symptomatic (umbilicus) as remote (trapezius and tibia) test sites. Conditioned pain modulation was recorded as an increase in the PPT at the trapezius test site in response to experimental conditioning pain imposed by the cold pressor task (12 ± 1°C). The assessors were blinded to the diagnoses. Parent-proxy and/or self-reported questionnaires were used to assess child's pain intensity, functional disability, pain-related fear, and parental pain catastrophizing. Compared with pain-free controls, young children with FAPD showed lower PPTs at all test sites (P < 0.05), a lower CPM response (P = 0.02), more functional disability (P < 0.001), and pain-related fear (P < 0.001). Parents of children with FAPD catastrophized more about their child's pain than parents of healthy children (P < 0.001). No sex differences were found for the experimental pain measurements (P > 0.05), nor was there a significant correlation between the child- and parent-reported questionnaires and the CPM effect (P > 0.05). In summary, young children with FAPD demonstrated secondary hyperalgesia and decreased functioning of endogenous analgesia., Functional abdominal pain disorders (FAPDs) are common among young individuals. To date, relatively little is known regarding the function of the endogenous analgesic mechanisms in this vulnerable group. Therefore, this case-control study aimed to compare conditioned pain modulation (CPM), pressure algometry, and psychosocial variables in 39 young children (aged 6-12 years) with FAPD and 36 age- and sex-matched pain-free controls. Pressure algometry was used to assess pressure pain thresholds (PPTs) at both symptomatic (umbilicus) as remote (trapezius and tibia) test sites. Conditioned pain modulation was recorded as an increase in the PPT at the trapezius test site in response to experimental conditioning pain imposed by the cold pressor task (12 ± 1°C). The assessors were blinded to the diagnoses. Parent-proxy and/or self-reported questionnaires were used to assess child's pain intensity, functional disability, pain-related fear, and parental pain catastrophizing. Compared with pain-free controls, young children with FAPD showed lower PPTs at all test sites (P < 0.05), a lower CPM response (P = 0.02), more functional disability (P < 0.001), and pain-related fear (P < 0.001). Parents of children with FAPD catastrophized more about their child's pain than parents of healthy children (P < 0.001). No sex differences were found for the experimental pain measurements (P > 0.05), nor was there a significant correlation between the child- and parent-reported questionnaires and the CPM effect (P > 0.05). In summary, young children with FAPD demonstrated secondary hyperalgesia and decreased functioning of endogenous analgesia.

Background Conditioned pain modulation (CPM) is impaired in people with chronic pain such as knee osteoarthritis (KOA). The purpose of this randomized, controlled clinical trial was to investigate whether strong electroacupuncture (EA) was more effective on chronic pain by strengthening the CPM function than weak EA or sham EA in patients with KOA. Methods In this multicenter, three-arm parallel, single-blind randomized controlled trial, 301 patients with KOA were randomly assigned. Patients were randomized into three groups based on EA current intensity: strong EA (> 2 mA), weak EA (

Introduction Several observations would suggest that dystonic pain is not simply muscular in origin. While ascending nociceptive pathways are normal in cervical dystonia, it is unknown whether descending inhibitory pain pathways are also normal. Methods We applied a conditioned pain modulation protocol and concomitantly recorded laser evoked potentials in patients with cervical dystonia (n = 15), blepharospasm (n = 15) and healthy volunteers (n = 15). Results During the application of a heterotopic noxious conditioning stimulation, patients with cervical dystonia, but not with blepharospasm, lacked the physiological reduction of the perceived intensity of a painful test stimulus as well as of the related evoked potential. This was observed in cervical dystonia patients regardless of the presence of clinical pain. Conclusions Our results suggest that pain in CD is not simply muscular in origin but it also possibly reflects a dysfunction of the descending pain inhibitory control, thus providing a novel venue to explore the pathophysiology of pain in CD.

The 10 Hz repetitive transcranial magnetic stimulation (10 Hz-rTMS) to the left dorsolateral prefrontal cortex produces analgesia, probably by activating the pain modulation system. A newer rTMS paradigm, called theta burst stimulation (TBS), has been developed. Unlike 10 Hz-rTMS, prolonged continuous TBS (pcTBS) mimics endogenous theta rhythms, which can improve induction of synaptic long-term potentiation. Therefore, this study investigated whether pcTBS to the left dorsolateral prefrontal cortex reduced pain sensitivity more efficiently compared with 10 Hz-rTMS, the analgesic effects lasted beyond the stimulation period, and the reduced pain sensitivity was associated with increased efficacy of conditioned pain modulation (CPM) and/or intracortical excitability. Sixteen subjects participated in a randomized cross-over study with pcTBS and 10 Hz-rTMS. Pain thresholds to heat (HPT), cold, pressure (PPT), intracortical excitability assessment, and CPM with mechanical and heat supra-pain threshold test stimuli and the cold pressor test as conditioning were collected before (Baseline), 3 (Day3) and 4 days (Day4) after 3-day session of rTMS. HPTs and PPTs increased with 10 Hz-rTMS and pcTBS at Day3 and Day4 compared with Baseline (P = .007). Based on pooled data from pcTBS and 10 Hz-rTMS, the increased PPTs correlated with increased efficacy of CPM at Day3 (P = .008), while no correlations were found at Day4 or with the intracortical excitability. Perspective Preliminary results of this comparative study did not show stronger pain sensitivity reduction by pcTBS compared with 10 Hz-rTMS to the L-DPFC. Both protocols maintained increased pain thresholds up to 24-hours after the last session, which were partially associated with modulation of CPM efficacy but not with the intracortical excitability changes.

Objective To determine if the perceived pain intensity during the application of shock waves (SWs) is a determinant mechanism in producing hypoalgesic changes in pressure pain thresholds (PPTs) in asymptomatic individuals. Design A randomised, single-blind controlled trial [NCT03455933]. Setting University. Participants Sixty-three asymptomatic individuals. Interventions Participants were randomised into three groups: 1-SWs causing mild pain (SW-DP); 2-SWs generating moderate pain (SW-MP); and 3-cold pressor test (CPT). Main outcome measurements Before and after the intervention, the PPT was evaluated bilaterally at the following points: lateral epicondyle, median nerve in the flexure of the elbow, and tibia. Results The results showed differences between various groups over time for all PPTs assessments, due to the existence of statistically significant differences in the interaction group x times (dominant arm lateral epicondyle [P 0.80). The CPT group only showed significantly higher results, and of high magnitude (d > 0.80), regarding the SW-DP group for the PPT evaluation in the dominant member. The SW-MP group showed differences compared with the CPT only for the PPT obtained in the nondominant arm. Conclusions The findings show that SW treatment generates a hypoalgesic effect on the application point, with moderate pain. Further studies are necessary in order to link these hypoalgesic changes to the activation of the descending inhibitory systems.

Fibromyalgia is characterized by chronic widespread musculoskeletal pain. A hypofunction in descending pain inhibitory systems is considered to be involved in the chronic pain of fibromyalgia. We examined functional changes in descending pain inhibitory systems in rats with specific alternation of rhythm in temperature (SART) stress, by measuring the strength of diffuse noxious inhibitory controls (DNIC). Hindpaw withdrawal thresholds to mechanical von Frey filament or fiber-specific electrical stimuli by the Neurometer system were used to measure the pain response. To induce DNIC, capsaicin was injected into the intraplantar of the forepaw. SART-stressed rats were established by exposure to repeated cold stress for 4 days. In the control rats, heterotopic intraplantar capsaicin injection increased withdrawal threshold, indicative of analgesia by DNIC. The strength of DNIC was reduced by naloxone (μ-opioid receptor antagonist, intraperitoneally and intracerebroventricularly), yohimbine (α2-adrenoceptor antagonist, intrathecally), and WAY-100635 (5-HT1A receptor antagonist, intrathecally) in the von Frey test. In SART-stressed rats, capsaicin injection did not increase withdrawal threshold in the von Frey test, indicating deficits in DNIC. In the Neurometer test, deficient DNIC in SART-stressed rats were observed only for Aδ- and C-fibers, but not Aβ-fibers stimulation. Analgesic effect of intracerebroventricular morphine was markedly reduced in SART-stressed rats compared with the control rats. Taken together, in SART-stressed rats, capsaicin-induced DNIC were deficient, and a hypofunction of opioid-mediated central pain modulation system may cause the DNIC deficit.

Heterotopic noxious counter-stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non-nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter-balanced sessions, including non-nociceptive (selective Aβ-fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20-min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0-100 scale, where 0 is no pain and 100 the worst pain imaginable). Non-nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII-reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non-nociceptive (P

The role of spinal α 2‐adrenoceptors in mediating long‐lasting modulation of hind limb withdrawal reflexes following acute noxious chemical stimulation of distant heterotopic and local homotopic locations has been investigated in pentobarbitone‐anaesthetized rabbits. Reflexes evoked in the ankle extensor muscle medial gastrocnemius (MG) by electrical stimulation of the ipsilateral heel, and reflexes elicited in the ankle flexor tibialis anterior and the knee flexor semitendinosus by stimulation at the base of the ipsilateral toes, could be inhibited for over 1 h after mustard oil (20%) was applied to either the snout or into the contralateral MG. The heel–MG response was also inhibited after applying mustard oil across the plantar metatarsophalangeal joints of the ipsilateral foot, whereas this homotopic stimulus facilitated both flexor responses. Mustard oil also caused a significant pressor effect when applied to any of the three test sites. The selective α2‐adrenoceptor antagonist, RX 821002 (100–300 μg, intrathecally), had no effect on reflexes per se, but did cause a decrease in mean arterial blood pressure. In the presence of the α2‐blocker, inhibitory and facilitatory effects of mustard oil on reflexes were completely abolished. These data imply that long‐lasting inhibition of spinal reflexes following acute noxious stimulation of distant locations involves activation of supraspinal noradrenergic pathways, the effects of which are dependent on an intact α2‐adrenoceptor system at the spinal level. These pathways and receptors also appear to be involved in facilitation (sensitization) as well as inhibition of reflexes following a noxious stimulus applied to the same limb.

Diffuse noxious inhibitory control (DNIC) is a phenomenon to reflect descending pain modulation in animals. Conditioned pain modulation (CPM) is the human counterpart of DNIC and is reduced in patients with several chronic pain conditions. Duloxetine is a serotonin and noradrenaline reuptake inhibitor that ameliorates CPM impairment in patients with diabetic neuropathy. Although some studies have reported the effects of different pharmacological agents on CPM, few studies have compared the effects of some analgesics in both humans and rodents. Therefore, we established a stable evaluation method for DNIC in rats and determined whether duloxetine and other specific analgesics affect DNIC impairment in rat models of peripheral neuropathic pain and osteoarthritis pain, two types of chronic pain. As a conditioning stimulus, capsaicin was injected into the forepaw of rats. The paw withdrawal threshold (PWT) in response to mechanical pressure was measured for the hindpaw. Peripheral neuropathic pain and osteoarthritis pain models were developed by partial sciatic nerve ligation (PSNL) and the intra-articular injection of 2 mg monoiodoacetate (MIA), respectively. Capsaicin (30–100 μg/site) increased the PWT, in a dose-dependent manner, in naive rats. The threshold significantly increased at 30 μg and reached its maximal level at 100 μg. The change in PWT following capsaicin injection was significantly reduced in PSNL-treated rats, but the threshold was increased by the subcutaneous administration of duloxetine (10 mg/kg). The oral administrations of pregabalin (10 mg/kg) and celecoxib (3 mg/kg) did not affect the PWT in PSNL-treated rats. Similarly, MIA-injected rats also showed a reduced change in PWT following capsaicin injection. Duloxetine, but not pregabalin and celecoxib, significantly increased the PWT in MIA-injected rats. These results suggested that duloxetine can directly ameliorate DNIC impairment in rat models of chronic pain. Duloxetine may be useful for modulating chronic pain by restoring function to the endogenous, descending, inhibitory pathway.

Introduction Acupuncture has become a relevant complementary and alternative treatment for acute migraine; however, the neurophysiological mechanism (C-fibers) underlying this effect remains unclear. C-fibers play a crucial role for diffuse noxious inhibitory controls (DNIC) at wide dynamic range (WDR) neurons in the trigeminocervical complex (TCC) in migraine attacks, and we supposed that this may be the mechanism of acupuncture analgesia. This study aimed to examine the neurophysiology of acupuncture intervention in an acute migraine rat model. Methods Inflammatory soup (IS) or saline was injected into the dura mater to establish a migraine and control model in rats. To explore the neurobiological mechanism of acupuncture for migraine, we implemented electro-acupuncture (EA), non-electric-stimulation acupuncture, and no-acupuncture in IS and saline injected rats, and recorded the single-cell extraneural neurophysiology of the atlas (C1) spinal dorsal horn neurons in the TCC. Results Our research shows that electro-acupuncture at GB8 (Shuaigu), located in the periorbital region receptive field of the trigeminal nerve, may rapidly reduce the C-fiber evoked WDR neuronal discharges of the TCC within 60 s. Discussion This study provides pioneering evidence of a potential neurobiological mechanism for the analgesic effect on migraine attacks achieved by electro-acupuncture intervention via DNIC. The data indicates that EA may become a crucial supplementary and alternative therapy for migraineurs that failed to respond to acute medications, e.g., fremanezumab, which achieves its analgesic effect via modulating Aσ-fibers, not C-fibers.

Background Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose‐limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia. Methods Using electrophysiological single‐unit recordings taken from spinal wide dynamic range neurons, Diffuse Noxious Inhibitory Controls (DNIC) were assessed as a marker of potential changes in descending controls in a monoiodoacetate (MIA) model of OA. We investigated if a subcutaneous injection of tapentadol or pregabalin, both alone and in combination, inhibited neuronal responses and restored the expression of DNIC, quantified as a reduction in neuronal firing in the presence of a conditioning noxious stimulus. Results Tapentadol restored DNIC‐induced neuronal inhibition in MIA animals, while pregabalin inhibited pre‐conditioned mechanically evoked neuronal responses but did not restore DNIC. Given in combination, tapentadol and pregabalin restored DNIC expression and also inhibited spinal neuronal responses. Conclusions We propose that there is both central sensitization and an imbalance in inhibitory and facilitatory descending controls in MIA animals. The combination therapy of tapentadol and pregabalin restored descending noradrenergic inhibitory tone and also inhibited nociceptive transmission at the level of the spinal cord. Significance This study shows that pregabalin and tapentadol target different mechanisms of centrally driven chronic pain associated with osteoarthritis, and that when administered together can restore descending inhibitory tone whilst also tackling spinal neuronal hyperexcitability and may therefore provide superior analgesia.

Maximal anaerobic exercise, is a short high intensity effort, involves activation of the hypothalamus-pituitary-adrenal axis, and may suggest hypoalgesic effects. In addition, this exercise-induced muscle pain may contribute to hypoalgesia via the pain inhibits pain phenomenon, which is related to the diffuse noxious inhibitory control (DNIC) mechanism. We aimed to investigate whether: 1) a single bout of 30 s maximal anaerobic exercise has an analgesic effect on experimental pain sensitivity; 2) DNIC is the underlying mechanism of anaerobic exercise-induced hypoalgesia (EIH). Fifty healthy subjects participated. The experimental group performed the ‘Wingate Anaerobic Test’ (WAT) and controls set on the bikes without exercising. Psychophysical tests, performed before and after the intervention, in local and remote areas, included: heat (HPT) and pressure pain thresholds (PPT); suprathreshold heat and cold pain stimulation; the conditioned pain modulation (CPM) paradigm testing the DNIC mechanism. Following WAT, PPT and HPT increased (p

Chronic pain is a common consequence of traumatic brain injury (TBI) that can increase the suffering of a patient and pose a significant challenge to rehabilitative efforts. Unfortunately, the mechanisms linking TBI to pain are poorly understood, and specific treatments for TBI-related pain are still lacking. Our laboratory has shown that TBI causes pain sensitization in areas distant to the site of primary injury, and that changes in spinal gene expression may underlie this sensitization. The aim of this study was to examine the roles that pain modulatory pathways descending from the brainstem play in pain after TBI. Deficiencies in one type of descending inhibition, diffuse noxious inhibitory control (DNIC), have been suggested to be responsible for the development of chronic pain by allowing excess and uncontrolled afferent nociceptive inputs. Here we expand our knowledge of pain after TBI in two ways: (1) by outlining the neuropathology in pain-related centers of the brain and spinal cord involved in DNIC using the rat lateral fluid percussion (LFP) model of TBI, and (2) by evaluating the effects of a potent histone acetyl transferase inhibitor, anacardic acid (AA), on LFP-induced pain behaviors and neuropathology when administered for several days after TBI. The results revealed that TBI induces transient mechanical allodynia and a chronic persistent loss of DNIC. Further, while short-term AA treatment can block acute nociceptive sensitization and some early neuropathological changes, this treatment neither prevented the loss of DNIC nor did it alter long-term neuropathological changes in the brain or spinal cord.

The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.

Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (μ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.

Race and ethnicity shape the experience of pain in adults. African Americans typically exhibit greater pain intensity and evoked pain responsiveness than non-Hispanic whites. However, it remains unclear whether there are racial differences in conditioned pain modulation (CPM) and if these are present in youth. CPM refers to a reduction in perceived pain intensity for a test stimulus during application of a conditioning stimulus and may be especially relevant in determining risk for chronic pain. The present study assessed CPM to evoked thermal pain in 78 healthy youth (ages 10–17 years), 51% of whom were African American and 49% of whom were non-Hispanic white. African American youth reported lower mean conditioning pain ratings than non-Hispanic white youth, controlling for mean preconditioning pain ratings, which is consistent with stronger CPM. Multilevel models demonstrated stronger CPM effects in African American than non-Hispanic white youth, as evident in more rapid within-person decreases in pain ratings during the conditioning phase. These findings suggest that diminished CPM likely does not account for the enhanced responsiveness to evoked thermal pain observed in African American youth. These results may have implications for understanding racial differences in chronic pain experienced in adulthood. Perspective This study evaluated conditioned pain modulation to evoked thermal pain in African American and non-Hispanic white youth. Findings could have implications for the development of personalized chronic pain treatment strategies that are informed by race and ethnicity.

It is known that specific alteration of rhythm in temperature (SART) stress produces somatic pain. However, it remains to be investigated whether SART stress induces visceral pain. In this study, we investigated the visceral hypersensitivity in the SART stress model by pharmacological tools and heterotopical nociception. Four-week-old Sprague–Dawley rats were exposed to repeated cold stress. Visceral pain was measured by visceromotor response to colorectal distension, and the effects of alosetron and duloxetine on visceral pain were investigated in SART rats. Heterotopical nociception was given by capsaicin injection into the left forepaw to induce diffuse noxious inhibitory controls (DNIC). SART stress induced visceral hypersensitivity that was sustained at minimum for one week. In pharmacological analysis, alosetron and duloxetine improved SART stress-induced visceral hypersensitivity. Heterotopical nociception induced DNIC in normal conditions, but was disrupted in SART rats. On the other hand, RMCP-II mRNA in distal colon was not affected by SART stress. In conclusion, SART rats exhibit several features of visceral pain in IBS, and may be a useful model for investigating the central modification of pain control in IBS.

There are no standardized bedside assessments for subtyping patients with osteoarthritis (OA) based on pain mechanisms. Thus, we developed a bedside sensory testing kit (BSTK) to classify OA patients based on sensory profiles potentially indicative of pain mechanism. After usability and informal reliability testing (n = 22), the kit was tested in a formal reliability study (n = 20). Patients completed questionnaires and sensory testing: pressure algometry to detect hyperalgesia; repeat algometry after heterotopic noxious conditioning stimulation to measure diffuse noxious inhibitory control (DNIC); light touch using Von Frey filaments; and cold allodynia using a brass rod. The procedure was brief and well tolerated. Algometry and filament testing were highly reliable [intra-class correlation coefficients (ICCs) 0.71-0.91]; DNIC was acceptably reliable (ICCs 0.53-0.91); brass rod reliability was inconclusive. Patients were classified empirically into four groups: "All abnormal findings" (primary and secondary hyperalgesia and dysfunctional DNIC); "all normal findings"; and two intermediate groups. The "all abnormal findings" group had more neuropathic pain symptoms, and lower WOMAC total, stiffness, and activity scores than the "all normal findings" group. Simple BSTK procedures, consolidated in a kit, reliably classified OA patients into subgroups based on sensory profile, suggesting that OA patients differ in underlying pain mechanisms. Further research is needed to confirm these subgroups and determine their validity in predicting response to treatment.

Background Various conditioned pain modulation (CPM) methodologies have been used to investigate diffuse noxious inhibitory control pain mechanisms in healthy and clinical populations. Occlusion cuff parameters have been poorly studied. We aimed to investigate whether occlusion cuff intensity and/or duration influenced CPM magnitudes. We also investigated the role of physical activity levels on CPM magnitude. Methods Two studies were performed to investigate the role of intensity and duration of occlusion cuff conditioning stimulus on test stimulus (tibialis anterior pressure pain thresholds). In Study 1, conditioning stimulus intensity of 2/10 or 5/10 (duration 0.22). Conclusions This study demonstrated that an occlusion cuff of 5/10 conditioning stimulus intensity, when compared to 2/10, significantly increased CPM magnitude. Maintaining 2/10 conditioning stimulus for 3 min did not increase CPM magnitude. Significance Dysfunctional conditioned pain modulation (CPM) has been associated with poor health outcomes. Various factors can influence CPM outcomes. The role of occlusion cuff conditioning stimulus intensity and duration has not been previously investigated. Intensity (5/10), but not duration of lower intensity (2/10) conditioning stimulus, affects CPM magnitude.

The aim of the present study was to assess inhibition of pain and somatosensory-evoked potentials (SEPs) by heterotopic noxious counter-stimulation (HNCS) and by selective attention in patients with chronic non-specific LBP. Seventeen patients and age/sex-matched controls were recruited (10 men, 7 women; mean age ± SD: 43.3 ± 10.4 and 42.7 ± 11.1, respectively). On average, patients with LBP reported pain duration of 7.6 ± 6.5 years, light to moderate disability (19.3 ± 5.7/100) and low clinical pain intensity (21.8 ± 1.5/100), while pain catastrophizing, state and trait anxiety and depressive symptoms were not significantly different between groups (all p's0.05). HNCS and selective attention had differential inhibitory effects on pain and SEP, but no difference was observed between groups. Across both groups, HNCS decreased pain (p = 0.06) as well as the N100 and the N150 components of SEP (p's0.001), while selective attention only decreased pain (p 0.01) and the N100 (p0.001). In contrast, the P260 was decreased by HNCS only when attention was directed toward the HNCS stimulus (p0.01). This indicates that patients with the characteristics described above do not show altered pain inhibitory mechanisms involved in HNCS and selective attention. Importantly, this experiment was carefully designed to control for non-specific effects associated with the repetition of the test stimulus and the effect of an innocuous counter-stimulation. It remains to be determined if these results hold for patients with severe LBP and psychological symptoms or whether symptom severity may be associated with pain inhibition deficits.

We investigated role of capsaicin-sensitive afferents within and without the areas of Zusanli (ST36)/Shangjuxu (ST37) acupoints along the stomach (ST) meridian in the perception and modulation of pain assessed by visual analog scale of pain and its distribution rated by subjects, pressure pain threshold (PPT), and heat pain threshold (HPT) in humans. Compared with the treatment of non-acupoint area, capsaicin (100 mu g/50 mu l) administered into either ST36 or ST37 acupoint caused the strongest pain intensity and the most extensive pain distribution, followed by rapid onset, bilateral, long-lasting secondary mechanical hyperalgesia and slower onset secondary heat hypoalgesia (1 day after the capsaicin treatment). Between treatments of different acupoints, capsaicin administrated into the ST36 acupoint exhibited the stronger pain intensity and more widespread pain distribution compared with the treatment of ST37 acupoint. A period of 30- to 45-min, but not 15-min, 43 degrees C heating-needle stimulation applied to the ST36 acupoint significantly enhanced the HPT, and had no effect on PPT. Upon trapezius muscle pain elicited by the i.m. injection of 5.8% saline, pre-emptive treatment of the contralateral ST36 acupoint with 43 degrees C heating-needle stimulation alleviated the ongoing muscle pain, reduced painful area, and reversed the decrease in HPT. It is suggested that (1) pain elicited from the acupoint and non-acupoint areas differs significantly, which are supposed to be dependent on the different distributions and contributions of capsaicin-sensitive afferents. (2) Non-painful heat stimulation is a valid approach in prevention of ongoing muscle pain with associated post-effects of peripheral and central sensitization. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Background: Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. Methods: Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. Results: DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. Conclusions: We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. Significance: Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.

Recent human neuroimaging studies have investigated the neural correlates of either noxious stimulus intensity or reported pain. Although useful, analyzing brain relationships with stimulus intensity and behavior separately does not address how sensation and pain are linked in the central nervous system. In this study, we used multi-level mediation analysis to identify brain mediators of pain—regions in which trial-by-trial responses to heat explained variability in the relationship between noxious stimulus intensity (across 4 levels) and pain. This approach has the potential to identify multiple circuits with complementary roles in pain genesis. Brain mediators of noxious heat effects on pain included targets of ascending nociceptive pathways (anterior cingulate, insula, SII, and medial thalamus) and also prefrontal and subcortical regions not associated with nociceptive pathways per se. Cluster analysis revealed that mediators were grouped into several distinct functional networks, including the following: somatosensory, paralimbic, and striatal-cerebellar networks that increased with stimulus intensity; and 2 networks co-localized with ‘‘default mode’’ regions in which stimulus intensity-related decreases mediated increased pain. We also identified ‘‘thermosensory’’ regions that responded to increasing noxious heat but did not predict pain reports. Finally, several regions did not respond to noxious input, but their activity predicted pain; these included ventromedial prefrontal cortex, dorsolateral prefrontal cortex, cerebellar regions, and supplementary motor cortices. These regions likely underlie both nociceptive and non-nociceptive processes that contribute to pain, such as attention and decision-making processes. Overall, these results elucidate how multiple distinct brain systems jointly contribute to the central generation of pain.

The analgesic effect of heterotopic noxious counter-stimulation (HNCS; "pain inhibits pain") has been shown to decrease in older persons, while some neuropsychological studies have suggested a reduction in cognitive inhibition with normal aging. Taken together, these findings may reflect a generalized reduction in inhibitory processes. The present study assessed whether the decline in the efficacy of pain inhibition processes is associated with decreased cognitive inhibition in older persons. Healthy young (18-46 years old; n=21) and older (56-75 years old; n=23) adult volunteers participated in one experimental session to assess the effect of HNCS (cold pain applied on the left forearm) on shock pain and RIII reflex induced by transcutaneous electrical stimulation of the right sural nerve. In the same session, participants also performed a modified Stroop task, including a target condition requiring the frequent switching between inhibition and no inhibition of the meaning of color words. The analgesic effect induced by HCNS was significantly smaller in older participants for both shock-pain ratings (P

Objectives To examine the temporal stability of conditioned pain modulation (CPM), formerly termed diffuse noxious inhibitory controls, among a sample of patients with chronic pain. The study also examined the factors that might be responsible for the stability of CPM. Design, Subjects, and Methods In this test-retest study, patients underwent a series of standardized psychophysical pain-testing procedures designed to assess CPM on two separate occasions (i.e., baseline and follow up). Patients also completed self-report measures of catastrophizing (Pain Catastrophizing Scale [PCS] and negative affect [NA]). Results Overall, results provided evidence for the stability of CPM among patients with chronic pain. Results, however, revealed considerable sex differences in the stability of CPM. For women, results revealed a significant test-retest correlation between baseline and follow-up CPM scores. For men, however, the test-retest correlation between baseline and follow-up CPM scores was not significant. Results of a Fisher's Z-test revealed that the stability of CPM was significantly greater for women than for men. Follow-up analyses revealed that the difference between men and women in the stability of CPM could not be accounted for by any demographic (e.g., age) and/or psychological factors (PCS and NA). Conclusions Our findings suggest that CPM paradigms possess sufficient reliability to be incorporated into bedside clinical evaluation of patients with chronic pain, but only among women. The lack of CPM reproducibility/stability observed among men places limits on the potential use of CPM paradigms in clinical settings for the assessment of men's endogenous pain-inhibitory function.

Study Design An experimental laboratory study with a repeated-measures crossover design. Background Treatment effects of joint mobilization may occur in part by decreasing excitability of central nociceptive pathways. Impaired conditioned pain modulation (CPM) has been found experimentally in persons with knee and hip osteoarthritis, indicating impaired inhibition of central nociceptive pathways. We hypothesized increased effectiveness of CPM following application of joint mobilization, determined via measures of deep tissue hyperalgesia. Objective To examine the effect of joint mobilization on impaired CPM. Methods An examination of 40 individuals with moderate/severe knee osteoarthritis identified 29 (73%) with impaired CPM. The subjects were randomized to receive 6 minutes of knee joint mobilization (intervention) or manual cutaneous input only, 1 week apart. Deep tissue hyperalgesia was examined via pressure pain thresholds bilaterally at the knee medial joint line and the hand at baseline, postintervention, and post-CPM testing. Further, vibration perception threshold was measured at the medial knee epicondyle at baseline and post-CPM testing. Results Joint mobilization, but not cutaneous input intervention, resulted in a global increase in pressure pain threshold, indicated by diminished hyperalgesic responses to pressure stimulus. Further, CPM was significantly enhanced following joint mobilization. Diminished baseline vibration perception threshold acuity was enhanced following joint mobilization at the knee that received intervention, but not at the contralateral knee. Resting pain was also significantly lower following the joint intervention. Conclusion Conditioned pain modulation was enhanced following joint mobilization, demonstrated by a global decrease in deep tissue pressure sensitivity. Joint mobilization may act via enhancement of descending pain mechanisms in patients with painful knee osteoarthritis. J Orthop Sports Phys Ther 2016;46(3):168-176. Epub 1 Jan 2016. doi:10.2519/jospt.2016.6259.

Heterotopic noxious counterstimulation (HNCS) by the application of a sustained noxious stimulus has been shown to inhibit nociceptive processes and decrease pain induced by a competing noxious stimulus. However, it is still not clear how attentional processes contribute to these effects. The main objective of this study was to compare the analgesic effects of HNCS in 2 sessions during which top-down attention was manipulated. Acute shock pain and the nociceptive flexion reflex were evoked by transcutaneous electrical stimulations of the right sural nerve in 4 blocks (15 stimuli/block): baseline, heterotopic innocuous counterstimulation (HICS), HNCS, and recovery. Counterstimulation was applied on the left upper limb with a thermode (HICS) or a cold pack (HNCS). Attention was manipulated between sessions by instructing participants to focus their attention on shock pain or counterstimulation. Shock pain ratings decreased significantly during counterstimulation (P < .001) with stronger effects of HNCS vs HICS in both sessions (P < .01). Furthermore, shock pain inhibition during HNCS relative to baseline was stronger with attention focusing on counterstimulation compared to attention focusing on shocks (P = .015). However, the relative decrease in pain ratings during HNCS vs HICS was not significantly affected by the direction of attention (P = .7). As for spinal nociceptive processes, nociceptive flexion reflex amplitude was significantly decreased during counterstimulation (P < .001) with larger reductions during HNCS compared to HICS (P = .03). However, these effects were not altered by attention (P = .35). Together, these results demonstrate that top-down attention and HNCS produce additive analgesic effects. However, attentional modulation of HNCS analgesia seems to depend on supraspinal processes.

The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain.

Sleep of good quantity and quality is considered a biologically important resource necessary to maintain homeostasis of pain-regulatory processes. To assess the role of chronic sleep disturbances in pain processing, we conducted laboratory pain testing in subjects with primary insomnia. Seventeen participants with primary insomnia (mean ± SEM 22.6 ± 0.9 yrs, 11 women) were individually matched with 17 healthy participants. All participants wore an actigraph device over a 2-week period and completed daily sleep and pain diaries. Laboratory pain testing was conducted in a controlled environment and included (1) warmth detection threshold testing, (2) pain sensitivity testing (threshold detection for heat and pressure pain), and (3) tests to access pain modulatory mechanisms (pain facilitation and inhibition). Primary insomnia subjects reported experiencing spontaneous pain on twice as many days as healthy controls during the at-home recording phase (p 0.05). During laboratory testing, primary insomnia subjects had lower pain thresholds than healthy controls (p 0.05 for heat pain detection threshold, p 0.08 for pressure pain detection threshold). Unexpectedly, pain facilitation, as assessed with temporal summation of pain responses, was reduced in primary insomnia compared to healthy controls (p 0.05). Pain inhibition, as assessed with the diffuse noxious inhibitory control paradigm (DNIC), was attenuated in insomnia subjects when compared to controls (p 0.05). Based on these findings, we propose that pain-inhibitory circuits in patients with insomnia are in a state of constant activation to compensate for ongoing subclinical pain. This constant activation ultimately may result in a ceiling effect of pain-inhibitory efforts, as indicated by the inability of the system to adequately function during challenge.

BACKGROUND: Conditioned pain modulation paradigms are often used to assess the diffuse noxious inhibitory control (DNIC) system. DNICs provide one of the main supraspinal pain inhibitory pathways and are impaired in several chronic pain populations. Only one previous study has examined the psychometric properties of the conditioned pain modulation technique and this study did not evaluate intersession reliability.OBJECTIVES: To evaluate and compare the intra- and intersession reliability of two conditioned pain modulation paradigms using different conditioning stimuli, and to determine the time course of conditioned pain inhibition following stimulus removal.METHODS: An electronic pressure transducer was used to determine the pressure-pain threshold at the knee during painful conditioning of the opposite hand using the ischemic arm test and the cold pressor test. Assessments were completed twice on one day and repeated once approximately three days later.RESULTS: The two conditioning stimuli resulted in a similar increase in the pressure-pain threshold at the knee, reflecting presumed activation of the DNIC system. Intrasession intraclass correlation coefficients for the cold pressor (0.85) and ischemic arm tests (0.75) were excellent. The intersession intraclass correlation coefficient for the cold pressor test was good (0.66) but was poor for the ischemic arm test (−0.4). Inhibition of the pressure-pain threshold remained significant at 10 min following conditioning, but returned to baseline by 15 min.CONCLUSIONS: Within-session reliability of DNIC assessment using conditioned pain modulation paradigms was excellent, but the applicability of assessing pain modulation over multiple sessions was influenced by the conditioning stimulus. The cold pressor test was the superior technique.

Although many studies have investigated the effectiveness of distraction as a method of pain control, the cognitive processes by which attentional re-direction is achieved, remain unclear. In this study the role of executive functioning abilities (inhibition, task switching and working memory) in the effectiveness of distraction is investigated. We hypothesized that the effectiveness of distraction in terms of pain reduction would be larger in participants with better executive functioning abilities. Ninety-one undergraduate students first performed executive functioning tasks, and subsequently participated in a cold pressor task (CPT). Participants were randomly assigned to (1) a distraction group, in which an attention-demanding tone-detection task was performed during the CPT, or (2) a control group, in which no distraction task was performed. Participants in the distraction group reported significantly less pain during the CPT, but the pain experience was not influenced by executive functioning abilities. However, the performance on the distraction task improved with better inhibition abilities, indicating that inhibition abilities might be important in focussing on a task despite the pain. (C) 2011 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing.In situhybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3−/−mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover,CNGA3−/−mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.

To elucidate the neural mechanisms underlying the remote effects produced by dry needling rabbit skeletal muscle myofascial trigger spots (MTrSs) via analyses of their endplate noise (EPN) recordings.Experimental animal controlled trial.An animal laboratory of a university.Male New Zealand rabbits (N=96) (body weight, 2.5-3.0kg; age, 16-20wk).Animals received no intervention for neural interruption in group I, transection of the tibial nerve in group II, transection of L5 and L6 spinal cord in group III, and transection of the T1 and T2 spinal cord in group IV. Each group was further divided into 4 subgroups: animals received ipsilateral dry needling, contralateral dry needling, ipsilateral sham needling, or contralateral sham needling of gastrocnemius MTrSs.EPN amplitudes of biceps femoris (BF) MTrSs.BF MTrS mean EPN amplitudes significantly increased (P.05) initially after gastrocnemius verum needling but reduced to a level significantly lower (P.05) than the preneedling level in groups I and IV with ipsilateral dry needling or contralateral dry needling, and in group II with contralateral dry needling (but not ipsilateral dry needling). No significant EPN amplitude changes were observed in BF MTrS in group III or in the control animals receiving superficial needling (sham).This remote effect of dry needling depends on an intact afferent pathway from the stimulating site to the spinal cord and a normal spinal cord function at the levels corresponding to the innervation of the proximally affected muscle.

Episodic migraine (EM) may evolve into the more disabling chronic migraine (CM, monthly migraine days ⩾ 8 and headache days ⩾ 15) with unknown mechanism. Aiming to elucidate the pathophysiology of CM and its relationship with EM, this study characterized the visual cortical responses in CM and EM. Neuromagnetic visual-evoked responses to left-hemifield checkerboard reversals were obtained in patients with EM (interictal or ictal states), CM (interictal) and age-matched controls. For each subject, the 1500 evoked responses were sequentially divided into 30 blocks and percentage changes of P100m amplitude in blocks 2, 9, 16, 23, and 30 compared to the first block were computed to assess habituation. At the end of visual stimulation (block 30), P100m amplitude was decreased (habituated) in the controls (n = 32) (35.2 ± 2.6 nAm vs. 41.9 ± 2.7, p = 0.005) but increased (potentiated) in the interictal state of EM (n = 29) (39.7 ± 3.8 vs. 33.5 ± 3.0, p = 0.007). In CM (n = 25), P100m was habituated (46.5 ± 2.9 vs. 51.6 ± 3.7, p = 0.013) but higher at the initial block than in those of the interictal state of EM (p = 0.001). These CM features also characterized the P100m in the ictal state of EM (n = 9). There was no difference of P100m between CM and ictal state of EM. In conclusion, patients with CM demonstrate a persistent ictal-like excitability pattern of the visual cortex between migraine attacks which may implicate central inhibitory dysfunction.