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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

There is a lack of objective outcome measures for monitoring key neural mechanisms underlying chronic pain, such as central sensitization. Recently, we combined psychophysical Multiple Threshold Tracking (MTT) with evoked potentials (EPs) to study neurophysiological activity related to processing of single- and double-pulse electronociceptive stimuli. Results from pain-free subjects measured at the Technical Medical Center of the University of Twente suggest that the MTT-EP method might be a promising step toward a diagnostic tool for chronic pain patients. A next step is exploration of its replicability in a hospital environment and its behavior in chronic pain patients. We explored the replicability of the MTT-EP method in twenty pain-free subjects (Central Sensitization Inventory (CSI)-score 14.6 ± 8.8) at St. Antonius Hospital. Secondly, we measured nociceptive detection thresholds (NDTs) and EPs from seven failed back surgery syndrome (FBSS) patients (CSI-score 49.0 ± 15.5). Preliminary results show values of NDTs and EPs, habituation and paired-pulse facilitation, which are in line with results from the University of Twente. Again, EPs are modulated by stimulus detection and amplitudes. Strikingly, we found higher NDTs in FBSS patients and EPs appeared modulated by stimulus detection, but not by amplitudes. Since similar phenomena in NDTs and EPs were observed during nociceptive stimulation in pain-free subjects at St. Antonius hospital, it can be concluded that results of MTT-EP method can be replicated. Secondly, the observed altered behavior of NDTs and EPs in FBSS patients showing signs of central sensitization allows further hypotheses regarding responsiveness to mechanisms underlying chronic pain.

The paratrigeminal nucleus is an obscure region in the dorsal lateral medulla, which has been best characterized as a collection of interstitial cells located in the dorsal tip of the spinal trigeminal tract. The paratrigeminal nucleus receives afferent input from the vagus, trigeminal, spinal, and glossopharyngeal nerves, which contribute to its long-known roles in the baroreceptor reflex and nociceptive processing. More recently, studies have shown that this region is also involved in the processing of airway-derived sensory information. Notably, these studies highlight an underappreciated complexity in the neuronal content and circuit connectivity of the paratrigeminal nucleus. However, much remains to be understood about how paratrigeminal processing of vagal afferents is altered in disease. The aim of the present review is to provide an update of the current understanding of vagal afferent processing in the paratrigeminal nucleus and to explore how dysregulation at this site may contribute to vagal sensory neural dysfunction during disease.

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.

The activation of Kv7 channels and the resulting M-current is a powerful mechanism to control neuronal excitability with profound effects in pain pathways. Despite the lack of specific data on the expression and role of these channels in nociceptive processing, much attention has been paid at exploring their potential value as targets for analgesia. Here we have characterized the spinal actions of two novel subunit selective Kv7 activators, ICA-069673 and ML213, and compared their effects to those of retigabine that acts with similar affinity on all neuronal Kv7 channels. Spinal reflexes were recorded in a mouse spinal cord in vitro preparation to allow the testing of the compounds on native spinal pathways at known concentrations. As retigabine, novel compounds depressed spinal segmental transmission with particularly strong effects on wind up, showing an adequate pro-analgesic profile. ML213 presented the highest potency. In contrast to retigabine, the effects of ICA-069673 and ML213 were blocked by XE-991 even at the highest concentrations used, suggesting specific effect on Kv7 channels. In addition, the effects of ICA-069673 on repetitive stimulation are consistent with a mode of action involving state or activity dependent interaction with the channels. Compared to retigabine, novel Kv7 openers maintain strong depressant effects on spinal nociceptive transmission showing an improved specificity on Kv7 channels. The differential effects obtained with these Kv7 openers may indicate the existence of several Kv7 conformations in spinal circuits.

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.

Very preterm (VPT) infants are exposed to odors released by healthcare products, triggering the trigeminal and olfactory subsystems. Irritation of the nasal mucosa induces pain in adults. We examined whether preterm and full-term (FT) newborns perceived trigeminal odors at different cortical levels, whether these odors elicit pain, and if oral glucose modulates this pain. We performed 44 recording sessions in newborn (15 VPT infants, 12 VPT infants at term-equivalent age, and 17 FT infants) following exposure to trigeminal/olfactory stimuli from the hospital environment. We repeated the exposure after oral glucose administration. We recorded cortical activation in the olfactory, frontal, and somatosensory cortices by functional near-infrared spectroscopy, and analyzed pain behaviors from videotaped recordings. Newborns integrated trigeminal/olfactory stimuli in trigeminal/olfactory and nociceptive processing areas beginning at 31 weeks postmenstrual age, and also exhibited pain behaviors. Pain scores were positively associated with the level of cortical activation. Oral glucose inhibited pain behaviors and cortical activation. There were developmental differences in cortical integration related to brain maturation and duration of the extra-uterine experience. In conclusion, VPT and FT infants showed trigeminal sensitivity after exposure to alien odors that induce pain, potentially affecting the wiring of the neuronal circuits of the newborn brain.

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.

Activation of both cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors reduces nociceptive processing in acute and chronic animal models of pain. In addition, nociceptive processing is tonically modulated by endogenous cannabinoids (endocannabinoids, ECs). This review examines the role of cannabinoids and ECs in the brain stem–spinal pathway of pain inhibition. Preclinical studies evaluating cannabinoids in neuropathic pain management are also reviewed. Pharmacological tools modulating the interaction of cannabinoids with its receptors and the treatment of pain by the augmentation of EC levels, specifically anandamide, are discussed. Particular attention is attributed to neuropathic pain in which pharmacological manipulation resulting in EC accumulation can be protective and produce antinociception, thereby making the system an attractive therapeutic target. Finally, the therapeutic value of cannabinoids in clinical research is summarized. WIREs Membr Transp Signal 2013, 2:121–132. doi: 10.1002/wmts.83 For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article.

This article is part of a Special Issue entitled: Pain.; International audience; The dorsal horn (DH) of the spinal cord receives a variety of sensory information arising from the inner and outer environment, as well as modulatory inputs from supraspinal centers. This information is integrated by the DH before being forwarded to brain areas where it may lead to pain perception. Spinal integration of this information relies on the interplay between different DH neurons forming complex and plastic neuronal networks. Elements of these networks are therefore potential targets for new analgesics and pain-relieving strategies. The present review aims at providing an overview of the current knowledge on these networks, with a special emphasis on those involving interlaminar communication in both physiological and pathological conditions.

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 malfunctioning of the nociceptive system may contribute to post-surgical chronic pain development. Psychophysical methods are used to observe nociceptive stimulus processing and sensory function by the estimation of a pain threshold. With these methods, it is possible to identify nociceptive disease. It remains, however, difficult to obtain information about individual contributions of underlying mechanisms to stimulus processing. Furthermore, a single thresholds estimate cannot be used to observe changes in the threshold as a result of changes in the nociceptive system. By presenting stimuli with various temporal stimulus properties (e.g., pulse-width, number of pulses, or inter-pulse interval) and estimating corresponding thresholds, the individual contributions of peripheral and central nociceptive processes to stimulus processing might be distinguished. Moreover, tracking these thresholds over time might help observing changes in the nociceptive system. Combined, this could contribute to an improved observation of nociceptive processing. The primary objective of the work presented in this thesis is to develop a tool allowing the simultaneous observation of individual contributions of nociceptive mechanisms to sensory processing. Two goals are identified in order to achieve the primary objective: 1) develop experimental techniques allowing the simultaneous observation of multiple non-stationary psychophysical thresholds, and 2) characterize the contributions of nociceptive mechanisms to sensory processing. The research presented in this thesis provides psychophysical methods for improved observation of nociceptive processing. With the developed methods, it is possible to simultaneously observe the contributions of various nociceptive processes. Based on the results described in this thesis, several recommendations are provided for setting up and performing relatively short psychophysical experiments. An experiment lasting for about 30 minutes can contribute to observation of peripheral and central processes, as well as the effect of a conditioning stimulus on these processes. The duration can be shortened to about 10 minutes when the effect of a conditioning stimulus is irrelevant.

This paper summarizes a behavioral paradigm that was developed as a novel method to dissociate the multidimensional pain experience in rodents. The place escape/avoidance paradigm (PEAP) is based on the assumption that if animals escape and/or avoid a noxious stimulus, then the stimulus is aversive to the animal. Data is presented showing that when animals are placed in a specific environmental condition, they will perform purposeful behavior to escape and/or avoid the noxious stimulus. Additional data is presented to demonstrate the validity of the behavioral paradigm and how the paradigm has been used to test the hypothesis that the affective/motivational dimension of pain can be dissociated and studied independent of sensory pain processing. The behavioral paradigm highlights the emerging trend in the area of pain research and management towards developing more realistic behavioral paradigms to assess nociceptive processing in rodent models of chronic pain.

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.

Although the cingulate cortex is frequently activated in acute human pain studies, postsynaptic responses are not known nor are links between nociceptive afferents, neuronal responses, and outputs to other structures. Intracellular potentials were recorded from neurobiotin-injected, pyramidal neurons in anterior cingulate area 24b following noxious stimulation of the sciatic nerve in anesthetized rabbits. Layer IIIc pyramids had extensive and horizontally oriented basal dendrites in layer IIIc where nociceptive afferents terminate. They had the longest excitatory postsynaptic potentials (EPSPs; 545 ms) that were modulated with hyperpolarizing currents. Pyramids in layer V had an intermediate tuft of oblique apical dendrites in layer IIIc that were 150–350 μm from somata in layer Va and 351–550 μm in layer Vb. Although average EPSP durations were short in layers II–IIIab (222 ± 31), Va (267 ± 65), and Vb (159 ± 31), there were five neurons in layers IIIab–Va that had EPSP durations lasting >300 ms (548 ± 63 ms). Neurons in layers IIIc, Va, and Vb had the highest amplitude EPSPs (6.25, 6.84 ± 0.58, and 6.4 ± 0.47 mV, respectively), whereas those in layers II–IIIab were 5 ± 0.56 mV. Nociceptive responses in layer Vb were complex and some had initial inhibitory postsynaptic potentials with shorter-duration EPSPs. Layers II–IIIab had dye-coupled pyramids and EPSPs in these layers had short durations (167 ± 33 ms) compared with those in layers IIIc–Va (487 ± 28 ms). In conclusion there are two populations of anterior cingulate cortex pyramids with EPSPs of significantly different durations, although their dendritic morphologies do not predict EPSP duration. Short-duration EPSPs are thalamic-mediated, nociceptive responses lasting ≤200 ms. Longer, “integrative” EPSPs are >350 ms and are likely modulated by intracortical axon collateral discharges. These findings suggest that links between nociception and projections to cortical and motor systems are instantaneous because nociceptive responses are generated directly by pyramidal projection neurons in all layers.

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.

Der Kopfschmerz vom Spannungstyp (KST) ist die haufigste Form primarer Kopfschmerzen. Mit einer Jahrespravalenz von etwa 40 % hat der KST eine herausragende klinische und soziookonomische Bedeutung. Gleichzeitig ist der KST der am wenigsten untersuchte Kopfschmerz mit infolgedessen weitgehend unklarer Pathophysiologie. Die wesentliche Ursache fur diese Diskrepanz zwischen medizinischer Relevanz und wissenschaftlichem Neglekt ist das Fehlen eines geeigneten Tiermodells. Ausgehend von dem Leitsymptom der gesteigerten Druckschmerzempfindlichkeit bei Patienten mit KST zielt das translationale Forschungsprojekt A3 des Deutschen Kopfschmerzkonsortiums auf ein Tiermodell zur Untersuchung der myofaszialen Nozizeption aus der Nackenmuskulatur. Bei Labormausen in Allgemeinanasthesie werden Nozizeptoren der Nackenmuskeln durch intramuskulare Injektionen von hypertoner Kochsalzlosung, Nervenwachstumsfaktor und Adenosintriphosphat (ATP) erregt. Der nozizeptive Impakt auf sensorische Neurone des Hirnstammes und des oberen Zervikalmarkes wird durch elektromyographische Ableitung des Kieferoffnungsreflexes bestimmt. Bilaterale Injektionen insbesondere von ATP fuhren beim Menschen zu tiefem Muskelschmerz und lokalem Spannungsgefuhl und beim Versuchstier zu einer klaren Bahnung des Reflexes im Sinne einer zentralen Sensibilisierung. Eine Episode des KST dauert beim Patienten zwischen 30 Minuten und sieben Tagen. Die Reflexbahnung im Tierexperiment halt mindestens vier Stunden an. Das entwickelte Tiermodell ermoglicht die Untersuchung der Physiologie und Pharmakologie der myofaszialen Nozizeption im Nackenbereich und eroffnet neue Perspektiven zum Verstandnis der Pathophysiologie und Therapie des KST. Tension-type headache (TTH) is the most frequent form of primary headache. A 1-year prevalence of approximately 40 % indicates the extreme clinical and socioeconomic importance of TTH. In contrast, the pathophysiology of TTH is still unknown due to the lack of major scientific interest. The main reason for the discrepancy between medical relevance and scientific neglect is the lack of an appropriate animal experimental model. The most significant abnormal finding in TTH patients is increased pericranial tenderness. Based on this finding the translational research project A3 of the German Headache Consortium addresses an animal model in order to investigate myofascial nociception from neck muscles. In mice under general anaesthesia muscle nociceptors are excited by intramuscular administration of hypertonic saline, nerve growth factor, and adenosine triphosphate (ATP). The nociceptive impact on sensory processing in the brainstem and upper cervical spinal cord is electromyographically monitored by the jaw-opening reflex. Bilateral intramuscular injections, especially of ATP, evoke deep muscle pain and local tenderness in man and strong reflex facilitation corresponding to central sensitisation in mice. TTH episodes in patients take between 30 minutes and seven days. Reflex facilitation in mice takes at least four hours. The developed animal model allows for an investigation of the physiology and pharmacology of myofascial nociceptive processing in the neck and may open up new vistas into the pathophysiology and treatment of TTH.

Pain is a multidimensional phenomenon and processed in a neural network. The supraspinal, brain mechanisms are increasingly recognized in playing a major role in the representation and modulation of pain. The aim of the current study is to investigate the functional interactions between cortex and thalamus during nociceptive processing, by observing the pain-related information flow and neuronal correlations within thalamo-cortical pathways. Pain-evoked, single-neuron activity was recorded in awake Sprague-Dawley rats with a Magnet system. Eight-wire microarrays were implanted into four different brain regions, i.e., the primary somatosensory (SI) and anterior cingulate cortex (ACC), as well as ventral posterior (VP) and medial dorsal thalamus (MD). Noxious radiant heat was delivered to the rat hind paws on the side contralateral to the recording regions. A large number of responsive neurons were recorded in the four brain areas. Directed coherence analysis revealed that the amount of information flow was significantly increased from SI cortex to VP thalamus following noxious stimuli, suggesting that SI cortex has descending influence on thalamic neurons during pain processing. Moreover, more correlated neuronal activities indicated by crosscorrelation histograms were found between cortical and thalamic neurons, with cortical neurons firing ahead of thalamic units. On basis of the above findings, we propose that nociceptive responses are modulated by corticothalamic feedback during nociceptive transmission, which may be tight in the lateral pathway, while loose in the medial pathway.

Objects approaching us may pose a threat, and signal the need to initiate defensive behavior. Detecting these objects early is crucial to either avoid the object or prepare for contact most efficiently. This requires the construction of a coherent representation of our body, and the space closely surrounding our body, i.e. the peripersonal space. This study, with 27 healthy volunteers, investigated how the processing of nociceptive stimuli applied to the hand is influenced by dynamical visual stimuli either approaching or receding from the hand. On each trial a visual stimulus was either approaching or receding the participant's left or right hand. At different temporal delays from the onset of the visual stimulus, a nociceptive stimulus was applied either at the same or the opposite hand, so that it was presented when the visual stimulus was perceived at varying distances from the hand. Participants were asked to respond as fast as possible at which side they perceived a nociceptive stimulus. We found that reaction times were fastest when the visual stimulus appeared near the stimulated hand. Moreover, investigating the influence of the visual stimuli along the continuous spatial range (from near to far) showed that approaching lights had a stronger spatially dependent effect on nociceptive processing, compared to receding lights. These results suggest that the coding of nociceptive information in a peripersonal frame of reference may constitute a safety margin around the body that is designed to protect it from potential physical threat.

Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics.

Long-term potentiation (LTP) in rat spinal dorsal horn neurons was induced by electrical high-frequency stimulation (HFS) of afferent C fibers. LTP is generally assumed to be a key mechanism of spinal sensitization. To determine the contribution of skin and muscle afferents to LTP induction, the sural nerve (SU, pure skin nerve) or the gastrocnemius-soleus nerve (GS, pure muscle nerve) were stimulated individually. As a measure of spinal LTP, C-fiber-induced synaptic field potentials (SFPs) evoked by the GS and by the SU were recorded in the dorsal horn. HFS induced a sustained increase of SFPs of the same nerve for at least 3 h, indicating the elicitation of homosynaptic nociceptive spinal LTP. LTP after muscle nerve stimulation (HFS to GS) was more pronounced (increase to 248%, P < 0.05) compared with LTP after skin nerve stimulation (HFS applied to SU; increase to 151% of baseline, P < 0.05). HFS applied to GS also increased the SFPs of the unconditioned SU (heterosynaptic LTP) significantly, whereas HFS applied to SU had no significant impact on the SFP evoked by the GS. Collectively, the data indicate that HFS of a muscle or skin nerve evoked nociceptive spinal LTP with large effect sizes for homosynaptic LTP (Cohen's d of 0.8–1.9) and small to medium effect sizes for heterosynaptic LTP (Cohen's d of 0.4–0.65). The finding that homosynaptic and heterosynaptic LTP after HFS of the muscle nerve were more pronounced than those after HFS of a skin nerve suggests that muscle pain may be associated with more extensive LTP than cutaneous pain.