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Diabetic neuropathic pain (DNP) is a common complication of diabetes characterized by persistent pain. Emerging evidence links astrocytes to mechanical nociceptive processing, and the motor cortex (MCx) is a cerebral cortex region that is known to play a key role in pain regulation. However, the association between MCx astrocytes and DNP pathogenesis remains largely unexplored. Here, we studied this association using designer receptors exclusively activated by designer drugs to specifically manipulate MCx astrocytes. We proved that the selective inhibition of MCx astrocytes reduced DNP in streptozocin (STZ)-induced DNP models and discovered a potential mechanism by which astrocytes release cytokines, including TNF-α and IL-1β, to increase neuronal activation in the MCx, thereby regulating pain. Together, these results demonstrate a pivotal role for MCx astrocytes in DNP pathogenesis and provide new insight into DNP treatment strategies.

OBJECTIVE To compare spatial pain modulation capabilities between adolescents with and without migraine. BACKGROUND Conditioned pain modulation (CPM) responses at the leg are similar in adolescents with versus without migraine. However, the anatomical region of testing may affect spatial pain modulation capabilities as differences in nociceptive processing between patients with migraine and healthy controls are found in local areas that are near the site of clinical pain but not in nonlocal areas. This study aimed to examine spatial pain modulation capabilities tested by the CPM paradigm using test stimulus applied to a local body area. METHODS Nineteen adolescents with migraine (age 14.9 ± 2.3, mean ± SD; 16 female) and 20 healthy adolescents (age 13.8 ± 2.5, mean ± SD; 16 female) completed this case-control study at Cincinnati Children's Hospital Medical Center. Pressure pain thresholds (PPT) were assessed at the trapezius before and during immersion of the foot in a cold water bath (8°C). RESULTS In the migraine group (146.0 ± 79.1, mean ± SD), compared to healthy controls (248.0 ± 145.5, mean ± SD), significantly lower PPT (kilopascal) values were found (estimate = 124.28, 95% CI: 58.98, 189.59, p

Objective. Music has been shown to modulate pain, although the impact of music on specific aspects of nociceptive processing is less well understood. Using quantitative sensory testing (QST), we assessed the impact of a novel music app on specific aspects of nociceptive processing. Design. Within-subjects paired comparison of pain processing in control vs music condition. Setting. Human psychophysical laboratory. Subjects. Sixty healthy adult volunteers. Methods. Subjects were assessed for baseline anxiety, depression, and catastrophizing using validated questionnaires. QSTs measured included 1) pain threshold and tolerance to deep muscle pressure, 2) pain with mechanical pinprick, 3) temporal summation of pain (TSP) with a repeated pain stimulus, and 4) conditioned pain modulation (CPM) with a second painful stimulus. QSTs were performed in the absence and presence of music delivered through a music app. Results. We found an increase in pressure pain thresholds in both the forearm (P = 0.007) and trapezius (P = 0.002) with music, as well as a decrease in the amount of pinprick pain (P

Newborn mammals display robust responses to noxious or tissue-damaging stimulation. These nociceptive or “pain” responses arise from neural activity at different levels of the central nervous system. Protective reflex movements and physiological reactions mediated by spinal cord and brainstem circuits are essential for the preservation of life and well-being but should not be equated with pain awareness. The unique sensation of pain and its unpleasant, threatening quality requires activity in the cortical and subcortical regions of the brain. These brain regions also have the potential to actively increase or decrease pain experience by exerting top-down control of spinal cord and brainstem nociceptive circuits. This chapter summarizes our current knowledge of the development of central nociceptive pathways in the young mammalian brain and the postnatal maturation of top-down pain control. It aims to provide a scientific, mechanistic understanding of infant and childhood pain experience, and their ability to cope with painful events.

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemogenetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemo-genetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

Chronic pain is a common cause of disability worldwide and remains a global health and socio-economic challenge. Current analgesics are either ineffective in a significant proportion of patients with chronic pain or associated with significant adverse side effects. The PPARs, a family of nuclear hormone transcription factors, have emerged as important modulators of pain in preclinical studies and therefore a potential therapeutic target for the treatment of pain. Modulation of nociceptive processing by PPARs is likely to involve both transcription-dependent and transcription-independent mechanisms. This review presents a comprehensive overview of preclinical studies investigating the contribution of PPAR signalling to nociceptive processing in animal models of inflammatory and neuropathic pain. We examine current evidence from anatomical, molecular and pharmacological studies demonstrating a role for PPARs in pain control. We also discuss the limited evidence available from relevant clinical studies and identify areas that warrant further research. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

Background Recently, event-related potentials (ERPs) evoked by skin puncture, commonly used for blood sampling, have received attention as a pain assessment tool in neonates. However, their latency appears to be far shorter than the latency of ERPs evoked by intraepidermal electrical stimulation (IES), which selectively activates nociceptive Aδ and C fibers. To clarify this important issue, we examined whether ERPs evoked by skin puncture appropriately reflect central nociceptive processing, as is the case with IES. Methods In Experiment 1, we recorded evoked potentials to the click sound produced by a lance device (click-only), lance stimulation with the click sound (click+lance), or lance stimulation with white noise (WN+lance) in eight healthy adults to investigate the effect of the click sound on the ERP evoked by skin puncture. In Experiment 2, we tested 18 heathy adults and recorded evoked potentials to shallow lance stimulation (SL) with a blade that did not reach the dermis (0.1 mm insertion depth); normal lance stimulation (CL) (1 mm depth); transcutaneous electrical stimulation (ES), which mainly activates Aβ fibers; and IES, which selectively activates Aδ fibers when low stimulation current intensities are applied. White noise was continuously presented during the experiments. The stimulations were applied to the hand dorsum. In the SL, the lance device did not touch the skin and the blade was inserted to a depth of 0.1 mm into the epidermis, where the free nerve endings of Aδ fibers are located, which minimized the tactile sensation caused by the device touching the skin and the activation of Aβ fibers by the blade reaching the dermis. In the CL, as in clinical use, the lance device touched the skin and the blade reached a depth of 1 mm from the skin surface, i.e., the depth of the dermis at which the Aβ fibers are located. Results The ERP N2 latencies for click-only (122 ± 2.9 ms) and click+lance (121 ± 6.5 ms) were significantly shorter than that for WN+lance (154 ± 7.1 ms). The ERP P2 latency for click-only (191 ± 11.3 ms) was significantly shorter than those for click+lance (249 ± 18.6 ms) and WN+lance (253 ± 11.2 ms). This suggests that the click sound shortens the N2 latency of the ERP evoked by skin puncture. The ERP N2 latencies for SL, CL, ES, and IES were 146 ± 8.3, 149 ± 9.9, 148 ± 13.1, and 197 ± 21.2 ms, respectively. The ERP P2 latencies were 250 ± 18.2, 251 ± 14.1, 237 ± 26.3, and 294 ± 30.0 ms, respectively. The ERP latency for SL was significantly shorter than that for IES and was similar to that for ES. This suggests that the penetration force generated by the blade of the lance device activates the Aβ fibers, consequently shortening the ERP latency. Conclusions Lance ERP may reflect the activation of Aβ fibers rather than Aδ fibers. A pain index that correctly and reliably reflects nociceptive processing must be developed to improve pain assessment and management in neonates.

Objectives: Pain catastrophizing has been associated with higher pain intensity, increased risk of developing chronic pain and poorer outcomes after treatment. Despite this, the mechanisms by which pain catastrophizing influences pain remain poorly understood. It has been hypothesized that pain catastrophizing may impair descending inhibition of spinal level nociception. The aims of this study were to compare spinal nociceptive processing in people with chronic widespread pain and pain-free controls and examine potential relationships between measures of pain catastrophizing and spinal nociception. Materials and Methods: Twenty-six patients with chronic widespread pain and 22 pain-free individuals participated in this study. Spinal nociception was measured using the nociceptive flexion reflex (NFR) threshold and NFR inhibition, measured as the change in NFR area during exposure to a second, painful conditioning stimulus (cold water immersion). Pain catastrophizing was assessed using the Pain Catastrophizing Scale and a situational pain catastrophizing scale. Results: Compared with pain-free controls, patients with chronic widespread pain had higher pain catastrophizing scores and lower NFR thresholds. Although NFR area was reduced by a painful conditioning stimulus in controls, this was not apparent in individuals with chronic widespread pain. No significant correlations were observed between measures of pain catastrophizing and spinal nociception. Discussion: Despite increased excitability and decreased inhibition of spinal nociception in patients with chronic widespread pain, we could find no evidence of a significant relationship between pain catastrophizing and measures of spinal nociceptive processing.

Chapter 2 describes the molecular events associated with pain signaling. The mechanisms associated with chemical, thermal, and mechanical pain signaling in the peripheral nerve endings are detailed. Molecular signaling mechanisms occurring in the spinal dorsal horn, including the primary afferent nociceptor, the inhibitory interneurons, and the descending on-cells and off-cells projecting from the nucleus raphe magnocellularis are described. Persistent increases in pain signaling resulting from inflammatory mediators are explained with reference to specific molecules. Signaling events at supraspinal levels, such as the thalamus, cortex, periaqueductal gray, and nucleus raphe magnus, including cannabinoids, opioids, and noradrenergic and serotonergic neurotransmitter events, are described as critical to pain pathways with relevance to potential pain therapies.

STUDY DESIGN: Systematic review and meta-analysis. BACKGROUND: Quantitative mechanical sensory testing (QST) assesses sensory functioning and detects functional changes in (central) nociceptive processing. In the current low back pain literature it has been hypothesized that these functional changes might be apparent in people with non-specific low back pain (NSLBP), although the results are mixed. OBJECTIVE: The aim of this systematic review/meta-analysis was to appraise and summarize the literature about QST outcomes in people with subacute and chronic NSLBP and healthy controls (HC). METHODS: This systematic review and meta-analysis was reported using PRISMA guidelines. Five databases were searched for relevant literature. Studies comparing mechanical QST-measures involving people with subacute and chronic low back pain and HC were included if 1) pressure pain thresholds (PPTs), 2) temporal summation (TS) and/or 3) conditioned pain modulation (CPM) were reported. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale (NOS). If possible, the results from different studies were pooled. RESULTS: Twenty-four studies were included. NOS scores varied between one and six points. Meta-analysis showed that people with NSLBP, compared to HC have significantly lower PPTs at remote sites and increased TS at the lower back. For example, PPTs measured at the scapula, were significantly lower in patients with NSLBP than in HC (pooled mean difference (MD): 119.2, 95% confidence interval (CI): (91.8, 146.6), P

Debilitating abdominal and pelvic pain conditions are highly prevalent in adults and adolescents. Assessing sensory functioning among people with painful conditions is important in understanding the disease. Reference values for Quantitative Sensory Testing (QST), used to assess sensory perception, are well established for other regions but not the abdomen. The aim of this study was to establish QST reference values for the abdomen in a diverse group of males and female adults and adolescents. In this cross-sectional study, 181 healthy, pain-free males and females from age 12-50 years completed a comprehensive QST battery in upper and lower abdomen and a control site. The QST battery consisted of: Dynamic Mechanical Touch (DMT), Light Touch Detection (LTD), Sharp Prick Detection (SPD), Pressure Pain Threshold (PPT), Temporal Summation of Pain (TSP), Cool and Warmth Detection Thresholds (CDT, WDT), and Cold and Heat Pain Thresholds (CPT, HPT). Participants also answered pain-related questionnaires including the Pain Catastrophizing Scale, 36-Item Short Form Survey, Pain Sensitivity Questionnaire (PSQ). Mean and standard deviation values were calculated for each QST sub-test and separated by age, sex, and body site (upper and lower abdomen, and control site). Results of RMANOVAs indicated that pain sensitivity differed by site and modality, with no consistent pattern indicating one area was generally more sensitive than others. There were also effects of sex with males experienced less sensitivity to pressure and cold pain than females. Self-reported pain sensitivity (PSQ) was associated with greater abdominal sensitivity to punctate, cold, and heat pain. This paper successfully established reference QST values for the upper and lower abdominal sites for healthy, pain-free male and female adolescents and adults which will be critical in understanding somatosensory nervous system function among patients with abdominal and pelvic pain. These data will be critical in understanding nociceptive processing in the abdominal region. Boston Center for Endometriosis/Marriott Family Foundation Investigator Grant Office of Faculty Developtment at Boston Children's Hospital.

Pain disorders can be initiated and maintained by malfunctioning of one or several mechanisms underlying the nociceptive function. Psychophysical procedures allow the estimation of nociceptive detection thresholds using intra-epidermal electrical stimuli. By varying the temporal properties of electrical stimuli, various contributions of nociceptive processes to stimulus processing can be observed. To observe the responsiveness of nociceptive thresholds to changes in nociceptive function, a model of capsaicin-induced nerve defunctionalization was used. Its effect on nociceptive detections thresholds was investigated over a period of 84 days. A cutaneous capsaicin (8 %) patch was applied for 60 min to the upper leg of eight healthy human participants. Single- and double-pulse electrical stimuli were presented in a pseudo-random order using an intra-epidermal electrode. Stimuli and corresponding responses were recorded on both treated and untreated skin areas prior to capsaicin application and on days 2, 7, 28, and 84. Increases in electrical detection thresholds at the capsaicin area were observed on days 2 and 7 for single-pulse stimuli. Detection thresholds corresponding to double-pulse stimuli were increased on days 7 and 28, suggesting a delayed and longer lasting effect on double-pulse stimuli. In the present study, it was demonstrated that the responsiveness of detection thresholds to capsaicin application depends on the temporal properties of electrical stimuli. The observation of capsaicin-induced changes by estimation of detection thresholds revealed different time patterns of contributions of peripheral and central mechanisms to stimulus processing.

Fibromyalgia (FM) is difficult to diagnose and manage chronic pain condition whose symptoms have no clear pathophysiological cause, although it is thought that patient hypersensitivity to a range of stimuli may give rise to mechanical hyperalgesia as a result of altered central nociceptive processing. The 1990 American College of Rheumatology (ACR) classification criteria, which have been widely used in clinical practice, require the existence of chronic widespread pain (CWP) for >3months, and the presence of at least 11 out of 18 specified tender points upon digital palpation, although this latter criterion has long been criticised. The newer 2010 ACR diagnostic criteria state that FM can be defined as CWP associated with somatic symptoms, and recommend the use of a widespread pain index and a scale to rate symptom severity. A modified version of the 2010 criteria removed the physician assessment of the extent of somatic symptoms and replaced it by a summary score of three self-reported symptoms, thus making it easier to use while maintaining its sensitivity. This review discusses the advantages and limitations of all of these criteria.

Purpose of review:In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies. Recent findings:In Parkinson's disease, specific neurodegenerative changes may cause alterations in nociceptive processing at multiple levels. Optimization of dopaminergic therapies should always be the first step in the management of Parkinson's disease pain. Reportedly, rotigotine transdermal patch, a monoamine oxidase type B inhibitor safinamide (as an add-on therapy to levodopa), subcutaneous apomorphine and intrajejunal levodopa infusion therapy may have a beneficial effect on pain sensations in Parkinson's disease patients. Among the nondopaminergic pharmacological therapies, prolonged-release oxycodone/naloxone and duloxetine may be effective in the treatment of chronic pain in Parkinson's disease. Botulinum toxin (BTX) injections should be considered for the treatment of dystonic Parkinson's disease pain. Deep brain stimulation (DBS) may lead to pain relief with a long-lasting effect in Parkinson's disease patients. Physiotherapy and physical activity in general are essential for Parkinson's disease patients suffering from pain. Summary:Pain in Parkinson's disease is not simply a consequence of motor complainants. The management of Parkinson's disease-related pain implicates maintenance of stable levels of dopaminergic drugs. Nondopaminergic pharmacological therapies (prolonged-release oxycodone/naloxone, duloxetine, BTX) and nonpharmacological interventions (DBS, physiotherapie) may also be beneficial in treatment of Parkinson's disease pain.

Pain research is based broadly on physiological disciplines and its development follows the methodological progress of the era, from classical psychophysiology to electrophysiological investigations at peripheral and central nociceptive systems, single cells and ion channels to modern imaging of nociceptive processing. Physiological pain research in Germany has long been part of an interdisciplinary research network extending beyond all political boundaries, and this situation has continued since molecular techniques started to dominate all biomedical research. Current scientific questions, such as intracellular nociceptive signal mechanisms, interactions with other physiological systems including the immune system, or the genetic basis of epidemic and chronic pain diseases can only be solved interdisciplinary and with international collaboration.

Transcranial static magnetic field stimulation (tSMS) is a novel and inexpensive, non-invasive brain stimulation (NIBS) technique. Here, we performed non-invasive modulation of intra-epidermal electrical stimulation-evoked potentials (IES-EPs) by applying tSMS or sham stimulation over the primary motor (M1) and somatosensory (S1) cortices in 18 healthy volunteers for 15 min. We recorded EPs after IES before, right after, and 10 min after tSMS. The IES-EP amplitude was significantly reduced immediately after tSMS over M1, whereas tSMS over S1 and sham stimulation did not affect the IES-EP amplitude. Thus, tSMS may affect cortical nociceptive processing. Although the results of intervention for experimental acute pain in healthy subjects cannot be directly translated into the clinical situation, tSMS may be a potentially useful NIBS method for managing chronic pain, in addition to standard of care treatments.

OBJECTIVE: Mastication may be able to activate endogenous pain inhibitory mechanisms and therefore lead to modulation of nociceptive processing. The purpose of this study was to examine the possible effect of food consistency on noxious input from the spinal system.METHODS: Three groups of adult male Sprague-Dawley rats were given an injection of complete Freund adjuvant in a hind paw 10 days after eating soft or hard food (one group received a saline injection-the control group [C]; the other group (D) received no injection). Nocifensive behavior was assessed with the use of the hot plate and tail flick assays at 1, 3, 6, and 12 hours and at 6.5 days after injection for groups A/B, and c-Fos activity was assessed in the brain after testing. Groups C/D had hot plate testing at 1 hour and 6.5 days. The data were analyzed by general linear modeling and 1-way analysis of variance.RESULTS: There was a small increase in the hot plate percent maximum possible effect (MPE) from -45.7 to -61.1 in group A over the length of the experiment, but a very small decrease for group B over the same period (-33.5 to -28.8). For the saline control group, there was a small increase toward 0 %MPE over the same time frame (-15.0 to 1.7). The %MPE differences were significant between groups A and C (P < .0005), but not significant between the other groups (F = 13.34, df = 2, P = .001, observed power = 99%). Using the pooled results (all time points), the differences between all groups were significant (P < .0005). There were no significant differences in the tail flick test. c-Fos was mainly observed in the raphe pallidus area with significant differences between groups A and B at 3 and 6 hours after injection of CFA (P = .027 and .022, respectively).CONCLUSIONS: The results of this study indicate that food consistency (hardness) influences nocifensive behavior in this animal model via a descending pathway operating at the supraspinal level.

Healthy or pathological states of nociceptive subsystems determine different stimulus-response relations measured from quantitative sensory testing. In turn, stimulus-response measurements may be used to assess these states. In a recently developed computational model, six model parameters characterize activation of nerve endings and spinal neurons. However, both model nonlinearity and limited information in yes-no detection responses to electrocutaneous stimuli challenge to estimate model parameters. Here, we address the question whether and how one can overcome these difficulties for reliable parameter estimation. First, we fit the computational model to experimental stimulus-response pairs by maximizing the likelihood. To evaluate the balance between model fit and complexity, i.e., the number of model parameters, we evaluate the Bayesian Information Criterion. We find that the computational model is better than a conventional logistic model regarding the balance. Second, our theoretical analysis suggests to vary the pulse width among applied stimuli as a necessary condition to prevent structural non-identifiability. In addition, the numerically implemented profile likelihood approach reveals structural and practical non-identifiability. Our model-based approach with integration of psychophysical measurements can be useful for a reliable assessment of states of the nociceptive system.

The aim of this paper was to review the physical and psychological processes associated with whiplash-associated disorders. There is now much scientific data available to indicate the presence of disturbed nociceptive processing, stress system responses, muscle and motor changes as well as psychological factors in both acute and chronic whiplash-associated disorders. Some of these factors seem to be associated with the transition from acute to chronic pain and have demonstrated prognostic capacity. Further investigation is required to determine if these processes can be modified and if modification will lead to improved outcomes for this condition. The burden of whiplash injuries, the high rate of transition to chronicity, and evidence of limited effects of current management on transition rates demand new directions in evaluation and management. The understanding of processes underlying this condition is improving and this lays the foundation for the development of more effective management approaches.

Dysfunction of the descending circuitry that modulates nociceptive processing is thought to facilitate primary headache disorders such as migraine and cluster headache, either by reducing inhibitio...

Objectives. This study attempts to confirm the hypothesis that transcutaneous electrical stimulation (TENS) of peripheral Aβ fibers inhibits nociceptive processing, by quantifying the change of laser-evoked potential (LEP) components, using a 980-nm diode laser. Materials and Methods. Cutaneous heat stimuli were delivered to the dorsum of the right hand in 13 volunteers. LEPs and pain intensity ratings were recorded before, during, and after the use of TENS (110 Hz) at the dorsolateral forearm. Area under the curve (AUC), LEP amplitudes (N2P2), and peak latencies (N2, P2) were calculated. The paired samples t-test was used for statistical analysis. Results. A significant reduction of LEP amplitudes and AUC was found during and after the use of TENS (p

There is now increasing evidence that pathological pain states are at least in part driven by changes in the brain itself. Descending modulatory pathways are known to mediate top-down regulation of nociceptive processing, transmitting cortical and limbic influences to the dorsal horn. However, these modulatory pathways are also intimately intertwined with ascending transmission pathways through positive and negative feedback loops. Models of persistent pain that fail to include descending modulatory pathways are thus incomplete. Although teasing out individual links in a recurrent network is never straightforward, it is imperative that understanding of pain modulation be fully integrated into how we think about pain.

The use of amphibian and mammalian in vitro spinal cord preparations, e.g., hemisected cord and transverse slices, has gained in popularity over the years due to the flexibility and ease of use of such preparations compared to classical in vivo approaches. When combined with modern experimental methodologies, such as patch clamping of visualized single cells or post-experimental neuroanatomy, this approach provides a powerful addition to the armamentarium available to study nociceptive processing in the dorsal horn. Some of these novel experimental approaches and the insight into nociception that they have provided are described below.

Pain has long been thought to wax and wane in relative proportion to fluctuations in the intensity of noxious stimuli. Dynamic aspects of nociceptive processing, however, remain poorly characterized. Here we show that small decreases (+/-1-3 degrees C) in noxious stimulus temperatures (47-50 degrees C) evoked changes in perceived pain intensity that were as much as 271% greater than those of equal magnitude increases. These decreases in perceived pain intensity were sufficiently large to be indistinguishable from those evoked by 15 degrees C decreases to clearly innocuous levels. Furthermore, decreases in pain ratings following noxious stimulus offset were significantly greater than those occurring during adaptation to constant temperature stimuli. Together, these findings indicate that an analgesic mechanism is activated during noxious stimulus offset. This analgesic phenomenon may serve as a temporal contrast enhancement mechanism to amplify awareness of stimulus offset and to reinforce escape behaviors. Disruption of this mechanism may contribute importantly to chronic pain.

SENSORY assessment of regional analgesia is performed routinely for clinical purposes and also plays an important role in anesthesia and pain research. In the past years, new methods were developed and old methods were improved. Technological progress has allowed a more reliable delivery of different stimulation patterns and more advanced recordings of physiologic parameters related to nociceptive processing and modulation. Important developments include methods that explore the activation of different nerve fibers, models that activate specific spinal cord mechanisms (such as temporal summation), and methods that evaluate muscle and visceral pain. As a result of this new knowledge, the application of sensory testing of regional analgesia in humans must be redetermined. New indications of the use of these methods then can be provided. In the current article, we update the knowledge available in the field of sensory assessment of regional analgesia in humans. The aims are as follows: (1) to describe and analyze the methods, (2) to define the applications, (3) to provide evidence-based indications for the use of these methods in anesthesia and pain research, and (4) to define areas in which further research is needed.

The substantial increase in our collective knowledge of pain physiology and pharmacology over the past decade has had a significant effect on the practice of clinical veterinary medicine. An overview of the basic anatomical and physiologic components of nociceptive processing is presented, as well as a discussion of the sensitizing events that occur within the nervous system in acute and chronic pathologic pain states. The unique features of visceral and neuropathic pain are also outlined. With the goal of improving the success of our therapeutic interventions, the final section is devoted to the various classes of analgesic drugs and techniques, and how they are best incorporated into pain management strategies.

Headaches are among the most frequent symptoms for which Americans seek physician advice and treatment. Although headache may herald a serious underlying organic or psychological illness, it more commonly represents a primary disorder of brain stem nociceptive processing and modulation. Chronic daily headache characteristically develops gradually from episodic tension or migraine-type headaches into a refractory syndrome often associated with medication overuse and disability. Better understanding of the pathophysiology and evolutionary mechanisms involved in the development of chronic headache has led to recommended changes in nosology originally proposed by the International Headache Society (IHS). Recent scientific and clinical observations prompting revised classification have also led to the integration of pathoanatomic models, which explain persistent headache. Strategies for the management of chronic craniofacial pain should emphasize key behavioral and attitudinal changes and avoidance of medication overusage.

Cannabinoids suppress nociceptive processing of acute stimuli, but little is known about their effects on processes that lead to hyperexcitability of nociceptive neurons following prolonged noxious stimulation. Wind-up, the increasingly strong response of spinal nociceptive neurons to repetitive noxious electrical stimuli, results from a fast-rising cumulative depolarization and increase in intracellular calcium concentration. These processes produce central sensitization, the increased excitability of spinal nociceptive neurons that contributes to the hyperalgesia and allodynia associated with chronic pain. Intravenous injection of the potent, synthetic cannabinoid agonist WIN 55, 212-2, but not the inactive enantiomer, WIN 55,212-3, dose-dependently decreased the wind-up of spinal wide dynamic range and nociceptive-specific neurons independent of acute responses to activation of low- and high-threshold primary afferents. This is the first direct evidence that cannabinoids inhibit the activity-dependent facilitation of spinal nociceptive responses.

This article summarizes current knowledge regarding the involvement of cholinergic mechanisms of the central nervous system in transmission and modulation of nociceptive information, with emphasis on the spinal nociceptive processing. Major topics reviewed include the antinociceptive activity of cholinergic drugs, experimental evidence of the presence of the central cholinergic systems, subclasses of muscarinic receptors involved in antinociceptive effects, and a possible physiologic role of the central cholinergic mechanisms.

Objective To determine whether manipulation of the expectation of pain inhibition can enhance the efficacy of conditioned pain modulation in healthy participants Methods A conditioned pain modulation paradigm was used to investigate the effect of psychological manipulation of expectation on pain inhibition. In 19 healthy men, the lower limb nociceptive flexion reflex was elicited in isolation (test stimulus) and during application of 2 forms of conditioning stimuli. Following application of the first conditioning stimulus (CS1), the participants were informed that the subsequent conditioning stimulus (CS2) would elicit a greater amount of inhibition of test pain compared with the first. Lower limb flexion reflex size, perceived pain ratings of the test stimulus, and ratings of expected pain modulation were obtained for both test and conditioning protocols. Results The inhibition of perceived pain was significantly greater with CS2 compared with CS1; however, there was no significant difference in inhibition of nociceptive flexion reflex size or the participant's reported expectation of pain modulation between the 2 conditioning stimuli. Discussion As perceived pain inhibition was enhanced but flexion reflex size unchanged following the intervention, we suggest that the intervention gave rise to an inhibition of ascending nociceptive information at a supraspinal level resulting in reduced pain perception without influencing spinal level processing of nociceptive input. The finding that conditioned pain modulation can be enhanced is of relevance to clinical pain populations who commonly show impaired inhibition.

Aims: The sensitization of central pain pathways is described both as a consequence and as a risk factor for the development and maintenance of chronic headache. Recent studies have shown that already children with migraine have an increased sensitization to painful mechanical stimuli. However, studies in children with tension type headache had inconsistent findings. This study examines (1) whether sensitization presents only in children with migraine or also in children with pure forms of tension-type headache (TTH), and (2) if the processing of painful mechanical stimuli is specific, or if the processing of painful thermal stimuli and nonpainful stimuli is affected also. Methods: A total of 192 children and adolescents (aged between 8 and 17 years; 62% female) with chronic headaches, including 111 with TTH and 81 with tension-type headache plus migraine headaches (TTH + M) were tested with the quantitative sensory testing following the protocol of the German research network of neuropathic pain. Results were compared with existing reference data of healthy children. Results: No differences were found between TTH + M and TTH patients. Compared with healthy controls, subjects with TTH + M as well as children with TTH showed lower pain thresholds for pressure pain, mechanical pain threshold, mechanical pain sensitivity, and wind-up ratio. There were no differences in the processing of thermal pain perception and nonpainful thermal and mechanical perception between patients and controls. Conclusion: Overall, the results confirm the relevance of central sensitization processes in chronic headaches. However, it remains unclear why these are limited to mechanical stimuli and whether they are more of a risk factor or a consequence of chronic headaches. Further studies, if possible with longitudinal designs, are necessary to specify the relationship between chronic pain and central sensitization processes.

To study nociceptive processing in patients with chronic tension-type headache.Forty patients with chronic tension-type headache and 40 healthy controls were examined. Pericranial tenderness was recorded by manual palpation, pressure pain detection and tolerance thresholds were recorded with an electronic pressure algometer, and the relative (pain detection minus sensory detection) electrical pain threshold was recorded with a constant current stimulator.Patients were considerably more tender than controls at all the locations examined by manual palpation (P.001). Pressure pain detection and tolerance thresholds recorded in the finger were significantly lower in patients than in controls (P.001). A nonsignificant similar trend was observed in the temple (Por =.12). Detection and tolerance thresholds were decreased to a similar degree in patients compared with controls, and pain thresholds recorded in the finger and in the temple were highly correlated (r=.84, P.001). The relative electrical pain threshold recorded at the labial commissure was significantly decreased in patients compared with controls (P=.03). All of the examined pain thresholds were significantly correlated to the pericranial tenderness recorded by palpation (r=-.35 to -.53, Por = .03).The present finding of a general hypersensitivity to pain stimuli in chronic tension-type headache indicates that central factors play an important role in the pathogenesis of this disorder.

High-intensity afferent input, tissue injury and inflammation, and injury to the peripheral nerve will initiate pain states with characteristic psychophysical properties. As will be considered below, this information processing can be modified to change the content of the message generated by a given stimulus to enhance the pain state (e.g., produce hyperalgesia), normalize a hyperalgesic state, or produce a decrease in pain sensitivity (e.g., produce analgesia). Management of that pain state is addressed by the use of agents or interventions which though specific targets at the level of the sensory afferent, the spinal dorsal horn or at higher-order levels (supraspinal) modify the contents of the sensory message generated by that physical stimulus. The important advances in the development of pain therapeutics have reflected upon the role played by specific underlying mechanisms which regulate these events.

You-Hong Jin1, Motohide Takemura2, Akira Furuyama3 and Norifumi Yonehara4 1Department of Anatomy the Affiliated Stomatological, Hospital of Nanchang University, Nanchang, Jiangxi Province, 2Department of Oral Anatomy and Neurobiology, Osaka University Graduate School of Dentistry, 3Departments of Oral Physiology 4Oral Medical Science (Division of Dental Pharmacology), Ohu University School of Dentistry, Koriyama, Fukushima, 1China 2,3,4Japan

published his observations on the analgesic effects of electrical stimulation in the midbrain of the rat. For many years attention focused on the roles played by the periaqueductal gray–rostral ventromedial medulla–spinal cord axis (PAG-RVM-SC) in modulating the pain signal. 3,21 However, it is now apparent from behavioral, physiologic, pharmacologic, and anatomic studies that many brainstem structures have roles in the regulation of nociceptive processing. Furthermore, not only do these supraspinal structures interact with each other, their interactions provide the framework for the coordination of pain control with the regulation of other physiologic functions, such as motor control and autonomic outflow. Perhaps most striking is the high degree of anatomic and functional overlap between central structures involved in the control of nociceptive processing

The p value in the legends of Figures 3, 4, 5, 6, and 7 are incorrect. The correct p values are: "< 0.05."

Objective: The study was conducted to investigate the after-effect of transcranial direct current stimulation (tDCS) applied over the human primary motor cortex (M1) on trigeminal and extracranial nociceptive processing. Basic procedures: Nineteen healthy volunteers were stimulated using cathodal, anodal (both 1 mA) or sham tDCS for 20 minutes. Pain processing was assessed by recording trigeminal and extracranial pain-related evoked potentials (PREPs) following electrical stimulation of the contralateral forehead and hand at baseline, 0, 20 and 50 minutes post-tDCS. Main findings: Cathodal tDCS resulted in decreased peak-to-peak amplitudes (PPAs) by 18% while anodal tDCS lead to increased PPAs of PREPs by 35% ( p Principal conclusions: The decreased PPAs suggest an inhibition and the increased PPAs of PREPs suggest an excitation of trigeminal and extracranial pain processing induced by tDCS of the M1. These results may provide evidence for the effectiveness of tDCS as a therapeutic instrument in treating headache disorders.

Introduction: The aim was to investigate bilateral, wide-spread pressure pain hyperalgesia in symptomatic (trigeminocervical) and non-symptomatic (pain-free distant) regions in children with frequent episodic tension-type headache (FETTH). Methods: Twenty-five children, 6 boys and 19 girls (mean age, 8.9 ± 1.8 years) with FETTH and 50 age- and sex-matched healthy children (12 boys, 38 girls; mean age: 8.8 ± 1.7 years) were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over temporalis muscle, upper trapezius muscle, second metacarpal and tibialis anterior muscles in a blinded design. Results: The results showed that PPT levels were significantly decreased bilaterally over the temporalis, upper trapezius and tibialis muscles, and the second metacarpal in children with FETTH as compared to controls (all sites, P s = −0.415; P = 0.045). Conclusions: The findings revealed bilateral, wide-spread pressure pain hypersensitivity in children with FETTH suggesting that wide-spread central sensitisation is involved in children with this headache pain condition.

In this review, we present data from functional, structural, and molecular imaging studies in patients and animals supporting the notion that it might be time to reconsider chronic pain as a disease. Across a range of chronic pain conditions, similar observations have been made regarding changes in structure and function within the brains of patients. We discuss these observations within the framework of the current definition of a disease. Perspective Neuroimaging studies have made a significant scientific impact in the study of pain. Knowledge of nociceptive processing in the noninjured and injured central nervous system has grown considerably over the past 2 decades. This review examines the information from these functional, structural, and molecular studies within the framework of a disease state.

Purpose of review Neuroimaging methods are widely used by researchers and clinicians interested in better understanding the functioning of the human brain in health and disease. Advances have been made in understanding how nociceptive processing within the healthy human central nervous system generates a conscious perception of pain. The focus has now shifted towards patient-related research, harnessing earlier developments to test specific hypotheses in a broad range of chronic pain disorders. The timing is ideal to assess the utility of data generated from these studies. Recent findings This review discusses how clinical pain is represented in the human brain as compared with the processing of acute pain in healthy controls. The imaging literature is reviewed for hypotheses that have been tested in patients regarding mechanisms that might contribute towards the development of chronic pain. Issues related to plasticity, central sensitization, psychological confounds, genetics, and necrosis are examined. Summary Results to date strongly support the notion that neuroimaging will aid our understanding of basic mechanisms contributing to the generation of chronic pain states. These techniques might help diagnose a patient's pain condition in a more objective and robust way, enabling better targeting of therapies and rapid development of compounds to alleviate pain.

Pain after chronic transection of the spinal cord is hypothesized to develop because of a hyperactivity in nociceptive neurones rostral to the lesion. One of the key substances in central nervous nociceptive processing is nitric oxide (NO). It has been demonstrated to tonically inhibit the background activity of dorsal horn neurones. Here, we show that in rats with chronic transection of the spinal cord there is a reduction of NO-synthesizing neurones on both sides of the lesion. This reduction is likely to be associated with a local lack of NO which could lead to an increased background activity of nociceptive dorsal horn neurones. The increased background activity of nociceptive neurones just rostral to the lesion might cause spontaneous pain that is perceived in segments close to the level of the lesion.