Search

A hallmark feature of chronic pain is its ability to impact other sensory and affective experiences. It is notably associated with hypersensitivity at the site of tissue injury. It is less clear, however, if chronic pain can also induce a generalized site-nonspecific enhancement in the aversive response to nociceptive inputs. Here, we showed that chronic pain in one limb in rats increased the aversive response to acute pain stimuli in the opposite limb, as assessed by conditioned place aversion. Interestingly, neural activities in the anterior cingulate cortex (ACC) correlated with noxious intensities, and optogenetic modulation of ACC neurons showed bidirectional control of the aversive response to acute pain. Chronic pain, however, altered acute pain intensity representation in the ACC to increase the aversive response to noxious stimuli at anatomically unrelated sites. Thus, chronic pain can disrupt cortical circuitry to enhance the aversive experience in a generalized anatomically nonspecific manner. DOI: http://dx.doi.org/10.7554/eLife.25302.001

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.

Noxious stimuli cause pain by activating cutaneous nociceptors. The Aδ- and C-fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I-II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter γ-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited. In this review, we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons, the BNP/NPR-A/PKG/BKCa channel pathway, the FSTL1/α1Na+-K+ ATPase pathway and the activin C/ERK pathway. These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain.

Primary processing of painful stimulation occurs in the dorsal horn of the spinal cord. In this article, we introduce mathematical models of the neural circuitry in the dorsal horn responsible for processing nerve fiber inputs from noxious stimulation of peripheral tissues and generating the resultant pain signal. The differential equation models describe the average firing rates of excitatory and inhibitory interneuron populations, as well as the wide dynamic range (WDR) neurons whose output correlates with the pain signal. The temporal profile of inputs on the different afferent nerve fibers that signal noxious and innocuous stimulation and the excitability properties of the included neuronal populations are constrained by experimental results. We consider models for the spinal cord circuit in isolation and when top-down inputs from higher brain areas that modulate pain processing are included. We validate the models by replicating experimentally observed phenomena of A fiber inhibition of pain and wind-up. We then use the models to investigate mechanisms for the observed phase shift in circadian rhythmicity of pain that occurs with neuropathic pain conditions. Our results suggest that changes in neuropathic pain rhythmicity can occur through dysregulation of inhibition within the dorsal horn circuit.

The different brain imaging techniques that have emerged in the last decades have raised major advancement in our understanding of the neurophysiological mechanisms implicated in pain in both healthy subjects and in patients suffering from different pain conditions. The new brain imaging protocols are developed based on the background of previous surgical, behavioral, psychophysical, and electrophysiological researches on nociception and pain in animal, healthy subject, and patients. Having a good background of normal and pathophysiological pain neurophysiology is essential for the design of research protocols that will take advantage of new brain imaging technologies to better investigate the complex phenomenon of pain. Pain is a dynamic phenomenon that is the end result of several factors. The association between nociceptive activity and pain perception depends on several intrinsic and extrinsic influences. For the same nociceptive stimulus, pain perception and related brain activity will greatly differ between subjects. Studies support that environment and genetic factors are both playing important roles and seem to be modality specific. The effect of environment on genetics, epigenetics (lasting changes in gene expression without alteration of DNA sequence), is essential to be taken into account in pain. Nerve injuries or even psychological factors could change the central nervous system by affecting DNA methylation and produce a “genomic” memory of pain in the adult cortex. Pain perception is then the result of inherited physiological and psychological factors that are influenced by and hopefully guide the development of new therapeutic approaches for the patients that are suffering.

Exogenous dinitrosyl iron complexes (DNIC) with thiolate ligands as NO and NO+ donors are capable of exerting both regulatory and cytotoxic effects on diverse biological processes similarly to those characteristic of endogenous nitric oxide. Regulatory activity of DNIC (vasodilatory, hypotensive, suppressing thrombosis, increasing erythrocyte elasticity, accelerating skin wound healing, inducing penile erection, etc.) is determined by their capacity of NO and NO+ transfer to biological targets of the latter (heme- and thiol-containing proteins, respectively) due to higher affinity of the proteins for NO and NO+ than that of DNIC. Cytotoxic activity of DNIC is provided by rapid DNIC decomposition under action of iron-chelating compounds, resulting in appearance of NO and NO+ in cells and tissues in high amounts. The latter mechanism is suggested to cause the blocking effect of DNIC as cytotoxic effectors on the development of benign endometrial tumors in rats with experimental endometriosis. It is also proposed that a similar mechanism can operate to cause at least a delay of malignant tumor proliferation under action of DNIC.

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.

Current analgesics predominately modulate pain transduction and transmission in neurons and have limited success in controlling disease progression. Accumulating evidence suggests that neuroinflammation, which is characterized by infiltration of immune cells, activation of glial cells and production of inflammatory mediators in the peripheral and central nervous system, has an important role in the induction and maintenance of chronic pain. This Review focuses on emerging targets - such as chemokines, proteases and the WNT pathway - that promote spinal cord neuroinflammation and chronic pain. It also highlights the anti-inflammatory and pro-resolution lipid mediators that act on immune cells, glial cells and neurons to resolve neuroinflammation, synaptic plasticity and pain. Targeting excessive neuroinflammation could offer new therapeutic opportunities for chronic pain and related neurological and psychiatric disorders.

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

Noxious stimuli usually cause pain and pain usually arises from noxious stimuli, but exceptions to these apparent truisms are the basis for clinically important problems and provide valuable insight into the neural code for pain. In this Review, we discuss how painful sensations arise. We argue that, although primary somatosensory afferents are tuned to specific stimulus features, natural stimuli often activate more than one type of afferent. Manipulating coactivation patterns can alter perception in ways that argue against each type of afferent acting independently (as expected for strictly labeled lines), suggesting instead that signals conveyed by different types of afferents interact. Deciphering the central circuits that mediate those interactions is critical for explaining the generation and modulation of neural signals that ultimately elicit pain. The advent of genetic and optical dissection techniques promise to dramatically accelerate progress toward this goal, which will facilitate the rational design of future pain therapeutics.

Medically unexplained chronic vulvar pain, or vulvodynia, is a common condition that affects many aspects of a woman’s life. The most common subtype of vulvodynia is provoked vestibulodynia (PVD), and recent research has demonstrated that its pathophysiology likely involves both peripheral and central dysregulation. In this review, the phenomenon of central sensitization is specifically described and linked to relevant findings in the PVD literature. Recommendations for further research in the area of vulvodynia are made, in particular, the examination of other vulvodynia subtypes and of subtypes within the PVD samples. In addition, support is given for the validation of an existing animal model of provoked vulvar pain in order to understand further spinal involvement and also mechanisms involved in the genesis and persistence of this condition.

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.

This paper reports on the neurophysiology of the esophagus, including on the uneven distribution of innervation in the esophagus, reflected by the increased sensitivity and perception of gastroesophageal reflux disease (GERD) events in the proximal rather than distal esophagus; the role of the enteric nervous system (ENS) in swallowing; the role of the physiological stress-responsive systems, including the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis in mediating esophageal pain; the advances in understanding pain mechanisms and brain structure provided by technological imaging advances; investigations into the efficacy of the descending-pain control system, including diffuse noxious inhibitory control (DNIC); the role of abnormal nervous signaling in afferent pathways in the pathogenesis of Barrett's esophagus (BE); and the contribution of the esophageal mucosa to reflux symptoms.

The expression and contribution of μ (MOPR) and δ opioid receptors (DOPR) in polymodal nociceptors have been recently challenged. Indeed, MOPR and DOPR were shown to be expressed in distinct subpopulation of nociceptors where they inhibit pain induced by noxious heat and mechanical stimuli, respectively. In the present study, we used electrophysiological measurements to assess the effect of spinal MOPR and DOPR activation on heat-induced and mechanically induced diffuse noxious inhibitory controls (DNICs). We recorded from wide dynamic range neurons in the spinal trigeminal nucleus of anesthetized rats. Trains of 105 electrical shocks were delivered to the excitatory cutaneous receptive field. DNICs were triggered either by immersion of the hindpaw in 49°C water or application of 300 g of mechanical pressure. To study the involvement of peptidergic primary afferents in the activation of DNIC by noxious heat and mechanical stimulations, substance P release was measured in the spinal cord by visualizing neurokinin type 1 receptor internalization. We found that the activation of spinal MOPR and DOPR similarly attenuates the DNIC and neurokinin type 1 receptor internalization induced either by heat or mechanical stimuli. Our results therefore reveal that the activation of spinal MOPR and DOPR relieves both heat-induced and mechanically induced pain with similar potency and suggest that these receptors are expressed on polymodal, substance P-expressing neurons.

Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is the phenomenon of central sensitization. Key processes for pain memory stabilizing could be considering processes of peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding non-injured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sym-pathetically maintained pain. Therefore, these persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long lasting synaptic plasticity as the long-term potentialtion at spinal and supra-spinal levels could undergo hyperalgesia and allodynia. The latter could be providing neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief.

One of the crucial cellular processes for major symptoms of pain, like hyperalgesia and allodynia, is considered as a phenomenon of sensitization. Key processes for pain memory stabilizing are peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding uninjured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sympathetically maintained pain. These persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long-lasting synaptic plasticity as long-term potentiation at spinal and supraspinal levels could be providing the neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in the spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief. This review presents findings from recent studies that examined the possibility of relations between pain and memory.

Although previous studies have suggested that depression may be associated with inhibition of evoked pain but facilitation of spontaneous pain, the mechanisms underlying these relationships are unclear. The present study investigated whether the difference between evoked and spontaneous pain on sensory (descending inhibition) and affective (avoidance motivation) components contributes to the divergent effects of depression on them. Depressive-like behavior was produced in male Wistar rats by unpredictable chronic mild stress (UCMS). Tone-laser conditioning and formalin-induced conditioned place avoidance (F-CPA) were used to explore avoidance motivation in evoked and spontaneous pain, respectively. Behavioral pharmacology experiments were conducted to examine descending inhibition of both evoked (thermal stimulation) and spontaneous pain behavior (formalin pain). The results revealed that the inhibitory effect of depression on evoked pain was eliminated following repeated thermal stimuli. Avoidance behavior in the tone-laser conditioning task was reduced in UCMS rats, relative to controls. However, avoidance motivation for formalin pain in the UCMS group was similar to controls. 5-HT1A receptor antagonism interfered with inhibition of pain responses over time. The present study demonstrated that the inhibitory effect of depression on evoked pain dissipates with increased nociception and that the sensory-discriminative and affective-motivational components of pain are jointly involved in the divergent effects of depression on pain.

Les personnes vieillissantes doivent composer au quotidien avec des douleurs chroniques. Le but de ce travail est de mieux comprendre les mécanismes sous-jacents qui contribueraient aux douleurs chroniques liées au vieillissement et par là, ouvrir un chemin vers de nouvelles perspectives thérapeutiques. Les contrôles inhibiteurs diffus nociceptifs (CIDN) ont un rôle qui n’est pas des moindres dans le contrôle de la douleur. Des études expérimentales examinant l’effet analgésique de la contre stimulation hétérotopique nociceptive (HNCS), un protocole permettant de tester l’efficacité de ces CIDN, suggèrent que le recrutement des CIDN au sein de cette population était plus faible (i.e. moins d’inhibition) comparé à une population plus jeune. En revanche, les études examinant la sensibilisation centrale induite par sommation temporelle (TS) de la douleur rapportent des résultats mitigés. De plus, une composante importante influençant l’expérience de douleur, les ressources cognitives, dont l’inhibition cognitive, se voient aussi décliner avec l’âge. Premièrement, le recrutement des CIDN a été comparé entre des participants sains, jeunes et des plus âgés avec la HNCS, et le recrutement des mécanismes de sensibilisation centrale avec la TS. La stimulation électrique du nerf sural a été choisie pour permettre de quantifier la douleur, tout en prenant une mesure indicative de la nociception spinale qu’est le réflexe nociceptif spinal (RIII). Nos sujets ont aussi participé à une tâche cognitive (le Stroop), testant l’inhibition cognitive. Deuxièmement, l’efficacité des CIDN ainsi que de l’inhibition cognitive a été testée chez les jeunes et les aînés en imagerie par résonance magnétique (IRM), afin de vérifier la relation entre ces deux mesures psychophysiques et l’épaisseur corticale des régions qui y sont impliquées ainsi que l’effet de l’âge sur celles-ci. Les résultats suggèrent un moindre recrutement des CIDN chez les plus âgés lors de l’expérimentation de la HNCS. Également, les sujets âgés présentaient des capacités d’inhibitions cognitives plus faibles que les jeunes. En plus, une corrélation entre l’inhibition cognitive et la modulation du réflexe RIII par la HNCS a été mise en évidence. Pour l’expérience de TS, les résultats étaient comparables pour les deux groupes, suggérant que les mécanismes impliqués dans la régulation de la douleur ne subiraient pas l’effet de l’âge de la même manière. Pour l’étude de l’épaisseur corticale, on y trouve une diminution globale de l’épaisseur corticale liée à l’âge, mais aussi une corrélation de l’analgésie par la HNCS avec l’inhibition cognitive et également, une relation des deux avec l’épaisseur corticale du cortex orbitofrontal (OFC) latéral gauche, suggérant la possibilité d’une existence d’un réseau neuronal au moins partiellement commun du contrôle inhibiteur descendant sensoriel et cognitif. Ce travail montre que l’effet de l’âge sur les mécanismes centraux de la régulation de la douleur est loin d’être uniforme. Également, il montre une corrélation entre la modulation endogène de la douleur et l’inhibition cognitive, ces deux processus seraient associés à une même région cérébrale. Ces résultats pourraient contribuer à identifier d’autres méthodes thérapeutiques, ouvrant ainsi une nouvelle avenue vers d’autres options dans la prise en charge des douleurs chroniques chez les personnes vieillissantes., Elderly have to deal daily with chronic pain. The diffuse inhibitory descending controls (DNIC) are much involved in the pain control. It was shown that the DNIC recruitment was lower in elderly than in young population, using the analgesic effect of the heterotopic noxious counter stimulation (HNCS), a protocol allowing testing the efficiency of the DNIC. However, the studies assessing the central sensitization by the temporal summation of pain after repetitive stimuli have reported mixed results, the effect of age is still unclear. In addition, there is an age-related decline of an important component, which has an influence on pain perception, the cognitive resources and especially the cognitive inhibition. The goal of this work is to understand the underling mechanisms of the chronic pain related to the normal aging, which can leads to a new therapeutic perspectives. First, the recruitment of the CIDN was compared between healthy young and elderly participants using the HNCS, and the central sensitization was tested using TS. The sural nerve electric shock stimulation was chosen, because it allows us to have two measures, the pain rating and the nociceptive spinal reflex (RIII), an indicative measure of the nociception. Our participants were also invited to participate in a cognitive task (the Stroop), to assess the cognitive inhibition. Second, the efficacy of the CIDN and the cognitive inhibition in elderly and young participants was tested, but this time in a magnetic resonance imaging session. We have wanted to test the association between these two-psychophysics measures, with the cortical thickness of the regions involved into these two processes, and the effect of the normal aging on them. The results have showed a less recruitment of the DNIC in elderly in the HNCS experiment. Also, the elderly have performed less than young in the cognitive inhibition. In addition, a correlation between the cognitive inhibition and the modulation of the RIII-reflex was found. For the TS experiment, no difference was shown between the two groups, suggesting that aging may affect differently the mechanisms involved in endogenous pain modulation. The morphometric study has showed a global diminution of the cortical thickness with aging. Furthermore, there was an association, between the HNCS analgesia and the performance in cognitive inhibition, and between theses two processes and the cortical thickness of the left lateral OFC. These results suggest an eventual existence of at least a partial neuronal common network for the sensorial and cognitive descending inhibitory control. This thesis has showed that the effect of normal aging on the central mechanisms of the pain regulation might be not uniform. Also, on one hand a correlation between the endogenous modulation of pain and cognitive inhibition was reported, and on the other hand that these two processes would be related to the same cortical area. Together, these findings would help to develop new therapeutic methods and offer more options to the management of pain in the elderly.

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.

Conditioned pain modulation (CPM) is a phenomenon whereby an initial painful stimulus is reduced by the application of a second painful stimulus, i.e. pain inhibits pain. The variability of an individuals CPM capacity is important clinically, as reduced CPM ability is associated with increased postoperative pain, the presence of persistent pain conditions and the efficacy of analgesic medications. Experimental animal investigations and human lesion studies suggest that the brainstem is critical for CPM expression, in particular the subnucleus reticularis dorsalis (SRD). The aims of this thesis were to employ high resolution functional magnetic resonance imaging to define the central circuits responsible for CPM in humans, and whether these changes reflect differences at rest, i.e. in the absence of a CPM paradigm. The results presented in this thesis show, for the first time, that CPM analgesia in healthy individuals is associated with reduced activity within the primary synapse that is significantly influenced by the SRD. Furthermore, our data suggest that the engagement of higher brain sites prevents the generation of this analgesic mechanism, raising the raising the possibility that altered responsiveness in these cortical regions may underlie the reduced CPM observed in individuals with chronic pain. Finally, we have shown that these group differences exhibit similar alterations in the pain-free state, and that on-going activity and connections of certain brain regions can predict the effectiveness of an individuals’ endogenous analgesic brain circuitry. Overall, these data reveal that CPM responsiveness is underpinned by differences in the pain-free state, which in turn could influence an individuals’ propensity for developing chronic pain following injury. This body of work sets the precedence for future investigations to determine whether individuals with chronic pain syndromes displayed similar differences in resting state brain activity and provides a framework for future development of analgesic medications to target this circuitry.

The neuropathic pain is caused by the injury or damage on the sensory nervous system; its pathological manifestations include allodynia, hyperalgesia, and spontaneous pain. About 4–8% of people in our society are suffering from this disease. The maladaptive plasticity refers to the plasticity in the nervous system that leads to a disruption of the function and may be considered as a disease state [1]. Emerging evidences from both human patients and animal models showed that maladaptive plastic changes happened along the sensory pathways, from the peripheral to central nervous system, which may contribute to the generation, development, and maintenance of neuropathic pain. The current special issue focused on the molecular mechanism underlying maladaptive plasticity along sensory pathways; different laboratories around the world investigated the maladaptive change in different signaling pathways at different levels; the contributions in this area will highlight the pain managements in the future. The transient receptor potential cation channel subfamily V member 1 (TRPV1) is the first identified member of TRPV proteins. TRPV1 can be activated by high temperature or specific chemical stimuli. The activation of TRPV1 in the terminal of nociceptive primary afferents conveys noxious information to the spinal cord and superspinal regions. Recent studies also identified critical roles of TRPV1 in the central regions of pain pathway in pain regulation. In the current issue, T. Jian et al. report that TRPV1 in dorsal root ganglia (DRG) modulates histamine H4 receptor-mediated itch. This finding will extend our understanding of the mechanisms of histamine-induced itch and the interaction of the itch and pain. S.-I. Choi et al. review recent studies on TRPV1-regulated pain, especially pathological pain, and suggest that TRPV1 contributes to pain maintenance. The new data may have revealed novel insights into the roles of spinal cord TRPV1 in regulating spinal plasticity, which may identify a new target for modulating pathological pain. Low back pain affects a large number of patients. Deformation of DRGs and their nerve roots is implicated in the pathogenesis. W.-J. Han et al. evaluate the analgesic effects of a novel synthesized nitronyl (NIT) nitroxide radicals on radicular low back pain in a rat model generated by chronic DRG compression. The authors report a significant analgesic effect of this agent, probably due to its antioxidation and anti-inflammation effects. Y-.B. Xie et al. describe a new rat animal model of human low back pain, by chronic compression of multiple DRGs on one side of lumber. This rat model develops spontaneous pain, cold allodynia, and hyperalgesia. Activating transcription factor 3 (ATF3) and CGRP are upregulated in bilateral DRG neurons and may contribute to the expression of DRG compression-induced pain. Matrix metalloproteinases (MMPs) play important roles in nociception and allodynia. Q. Wang et al. report a critical role of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN)/OX47, a key regulator of MMP activities, in neuropathic pain development. Their studies show that SNL leads to OX47 upregulation in ipsilateral DRG and that downregulation of OX47 attenuates SNL-induced mechanical allodynia. Gate-control theory of pain proposed by Melzack and Wall (1965) explains the regulation of noxious information transmission in the spinal substantia gelatinosa. F. J. R. Pelaez and S. Taniguchi have revisited this theory from the perspective of NMDA receptor-mediated synaptic plasticity and intrinsic plasticity, and the Melzack and Wall circuit was slightly modified by using strictly excitatory nociceptive afferences and was further tested at different pain conditions. Spinal microglia play critical roles in the developments of chronic pain. A. Jurga et al. report the contribution of TLR2 and TLR4 to neuropathic pain in a chronic constriction injury (CCI) model. They describe a time-dependent upregulation of TLR2, TLR4, MyD88, and TRIF mRNA and protein. In addition, blockade of TLR2 and TLR4 impairs the expression of pain behaviors and opioid analgesia. These findings support TLR2 and TLR4 as putative targets for developing therapeutic approaches. J. Wang et al. report the involvements of mammalian target of rapamycin (mTOR) in the RVM, a key relay region for the descending pathway, in regulation of neuropathic pain. They show that phosphorylated mTOR protein increases mainly in RVM serotonergic spinally projecting neurons in the spared nerve injury (SNI) model. Infusion of rapamycin decreases both excitatory synaptic transmission and intrinsic excitability of serotonergic neurons, which may underlie the analgesic effects. These findings suggest a novel mechanism by which mTOR inhibitor causes analgesia. The anterior cingulate cortex (ACC) is a heterogeneous brain region and is involved in regulation of pain, emotion, and sex attraction. Z.-X. Zuo et al. report that nerve ligation leads to AChE upregulation in the ACC. They have tested the analgesic effects of huperzine A, an alkaloid isolated from a Chinese club-moss, on evoked pain and spontaneous pain, and reported a significant analgesic effect on evoked pain but not spontaneous pain, indicating a specific role of AChE in regulation of evoked pain. We are pleased to introduce this special issue that focuses on the maladaptive plasticity in the pain pathway, in both PNS and CNS. It is becoming clear that pain-related maladaptive changes can occur at a cellular level such as alteration of synaptic transmission and at a molecular level such as the dysregulation of various signaling pathways. The studies collected in this issue will help elucidate the pathogenic mechanism of neuropathic pain and facilitate the development of novel strategies for the pain treatments.

Background: Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. Methods: This systematic review follows the PRISMA guidelines. Pubmed and Web of Science were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. Results: Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. Conclusion: It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required.

OBJECTIVES: The objective of the study was to assess diffuse noxious inhibitory control (DNIC) function in women with provoked vestibulodynia (PVD) compared with healthy controls through the use of 2 different methodologies. Furthermore, the study aimed to assess whether pain characteristics correlate with DNIC in women with PVD. METHODS: Twenty-three healthy control women and 23 women diagnosed with PVD by the study gynecologist participated in the study. To assess DNIC, heat pain tolerance, determined through an ascending method of limits and temporal summation of thermal pain were used as test stimuli and a cold water bath was used as the conditioning stimulus. Participants reported on pain characteristics as potential correlates with DNIC function. RESULTS: No significant group differences were found in the number of DNIC responders per group when using heat pain tolerance or temporal summation procedures to examine DNIC. The magnitude of the DNIC response was examined for the overall groups and for positive DNIC responders only. When all participants were included in the analyses with the heat pain tolerance procedure, women with PVD displayed a higher magnitude of DNIC responding. Correlations between pain variables and DNIC responding and magnitude were nonsignificant. DISCUSSION: Results support previous findings of intact DNIC function in women with PVD, using both an ascending method of limits and a temporal summation paradigm. Pain-related variables were not correlated with DNIC function in women with PVD, perhaps this unexpected finding is due to the possibility that central processes other than DNIC, such as descending facilitation, provoke or maintain this chronic pain condition.

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.

Background and purpose In animal studies, enhanced sensitivity to painful stimuli succeeding chronic stress has been reported, while acute stress is reported to induce analgesia. Human studies on the effect of mental stress on pain are more equivocal. A disturbed stress-response resulting in an increased sensitivity to painful stimuli has also been discussed as a potential mechanism for e.g., the fibromyalgia syndrome. Endogenous analgesia may be studied in humans by measuring the analgesic effect of heterotopic noxious conditioning stimulation. In neurophysiological animal studies this phenomenon was originally denoted “diffuse noxious inhibitory controls” (DNIC), but for human studies it has been suggested to use the term conditioned pain modulation (CPM). The clinical relevance of aberrances in CPM is not clear. Inhibitory CPM is reported as being reduced in several medically unexplained syndromes with musculoskeletal pain aggravated by mental stress. However, whether the reported reduced CPM effects are causally related to clinical pain is unknown. In the present study the effect of a mental stressor on CPM is studied. Methods With tourniquet-induced pain as the conditioning stimulus we estimated the CPM effect in twenty healthy subjects. Heat pain threshold (HPT), supra-threshold heat pain level (SHPL) and pressure pain threshold (PPT) were used as test stimuli. Measurements were performed at baseline, after a stressful task and after a non-stressful task presented in a blinded cross-over design. We used repeated-measures ANOVAs in the analysis with simple contrasts for post hoc analysis. Results With a ANOVA repeated measures model we found a significant task effect (F = 18.5, p ≤ 0.001), indicating that CPM was successfully induced. In our ANOVA model, we found a significant effect of stress in the contrast analysis (F = 5.2, p = 0.037), indicating that CPM was affected by the stressful task. The effects on PPT could not be analyzed due to a significant carry-over effect (for PPT only). Conclusions In the present blinded crossover study, we found a significant small to medium inhibitory effect of mental stress upon the CPM of thermal pain. Implications Our results suggest that previously reported reduced inhibitory CPM in several medically unexplained syndromes with musculoskeletal pain aggravated by mental stress possibly can be related to confounding or clinically relevant stress level differences. However, the result might be modality-specific. Further studies in patients are obviously needed, and the impact of mental stress on CPM should be investigated also with other stressors.

In this review we provide the updates on last years' advancements in basic science, imaging methods, efficacy, and safety of dry needling of myofascial trigger points (MTrPs). The latest studies confirmed that dry needling is an effective and safe method for the treatment of MTrPs when provided by adequately trained physicians or physical therapists. Recent basic studies have confirmed that at the site of an active MTrP there are elevated levels of inflammatory mediators, known to be associated with persistent pain states and myofascial tenderness and that this local milieu changes with the occurrence of local twitch response. Two new modalities, sonoelastography and magnetic resonance elastography, were recently introduced allowing noninvasive imaging of MTrPs. MTrP dry needling, at least partially, involves supraspinal pain control via midbrain periaqueductal gray matter activation. A recent study demonstrated that distal muscle needling reduces proximal pain by means of the diffuse noxious inhibitory control. Therefore, in a patient too sensitive to be needled in the area of the primary pain source, the treatment can be initiated with distal needling.

The intensity of acute and chronic pain depends on interactions between peripheral impulse input and CNS pain mechanisms, including facilitation and inhibition. Whereas tonic pain inhibition is a characteristic of most pain-free individuals, pain facilitation can be detected in many chronic pain patients. The capability to inhibit pain is normally distributed along a wide continuum in the general population and can be used to predict chronic pain. Accumulating evidence suggests that endogenous pain inhibition depends on activation of the prefrontal cortex, periaqueductal gray and rostral ventral medulla. Quantitative sensory test paradigms have been designed to acquire detailed information regarding each individual’s endogenous pain inhibition and facilitation. Such tests include: temporal summation of pain, which is mostly used to assess facilitatory pain modulation by measuring the change in pain perception during a series of identical nociceptive stimuli; and conditioned pain modulation, which tests pain inhibition by utilizing two simultaneously applied painful stimuli (the ‘pain inhibits pain’ paradigm). Considerable indirect evidence seems to indicate that not only increased pain facilitation but also ineffective pain inhibition represents a predisposition for chronic pain. This view is supported by the fact that many chronic pain syndromes (e.g., fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, headache and chronic fatigue syndrome) are associated with hypersensitivity to painful stimuli and reduced endogenous pain inhibition. However, future prospective studies will be necessary to provide definitive evidence for this relationship. Such research would not only provide important information about mechanisms relevant to chronic pain but would also permit identification of individuals at high risk for future chronic pain.

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.

Background Systemic administration of dexmedetomidine (DEX; selective α2-adrenoceptor agonist) is found to inhibit diffuse noxious inhibitory control in rats, now referred to as conditioned pain modulation (CPM) in humans. The present study was designed to investigate the effect of intravenous administration of DEX on CPM in humans. Methods There were two sequential sessions in this double blind, randomized study. The first session was the control with normal saline infusion (N1st, L1st, H1st). During the second session, three types of agents were infused: normal saline (N2nd); a low plasma concentration of DEX (0.04 ng/mL; L2nd); and a high plasma concentration of DEX (0.08 ng/mL; H2nd). The amplitude of somatosensory evoked potentials (ampSEP)s and the visual analogue scale of tooth pain (VASt) induced by electrical tooth stimulation were evaluated with and without conditioning CO2 laser stimulation of the hand. The inhibition rate (% inhibition) was calculated [= (1-[ampSEP or VASt with conditioning stimuli]/[ampSEP or VASt without conditioning stimuli]) × 100] to compare the magnitude of the DEX effects on CPM. Results The inhibition rates of ampSEPs and VASt in Types N, L and H varied significantly, demonstrating a dose-dependent reduction of CPM effects of ampSEP and VASt during randomized DEX administration, consistent with results from animal studies. Conclusions The present study shows that systemic administration of an α2-adrenoceptor agonist (DEX), less than the clinical dose, inhibited CPM in humans. These results may provide some mechanistic insight into why many chronic pain patients show impaired CPM.

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.

It was shown that retinal ischemia entailed apoptosis in the inner layers of the retina. Administration of an NO-synthase inhibitor suppressed the development of ischemic apoptosis. To ascertain whether nitric oxide could induce the retinal apoptosis by itself, a nontoxic NO donor—dinitrosyl iron complex (DNIC) with glutathione—was injected into the vitreous body. DNIC at low concentrations induced apoptosis in the same retinal layers as in ischemia. However, with increasing DNIC doses, the number of apoptotic nuclei decreased markedly. Simultaneous administration of excess glutathione prevented apoptosis at any DNIC dose. The obtained data demonstrate the neurotoxic properties of the excess of nitric oxide in the retina.

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.

Study Design. Nonsystematic review. Objective. To review the current knowledge on detecting altered central pain processing in individual patients with chronic pain. Summary of Background Data. Alterations in central pain processing are mainly characterized by hyperexcitability of the central nervous system and disturbances in endogenous pain modulation. Although these mechanisms are widely recognized as important determinants of pain and disability, there is need for translation of this knowledge into benefi ts for patients. To this purpose, the fi rst step is the detection of abnormalities in pain processing in individual patients. Quantitative sensory tests (QST) explore aspects of nociception and pain perception, and are therefore potentially useful for diagnostic purposes. Methods. Nonsystematic review of the reliability, validity and reference values of QST for the assessment of altered central pain processing in chronic pain patients. Results. The reliability of QST is generally high. However, most studies have been performed on healthy volunteers, and few reliability data in patients are available. Furthermore, little is known on the reliability of measures of endogenous pain modulation. The face validity of QST is acceptable. The construct validity cannot be tested, because there is no gold standard for the detection of altered central pain processing in humans. Reference values of different types of QST for applications in neuropathic and musculoskeletal pain have been determined in large samples of pain-free subjects. Conclusion. QST can be used in clinical practice to assess the presence of sensory abnormalities in individual patients. Because information on the reliability and validity of the tests is incomplete, the fi ndings should be interpreted with caution. It is still unclear to what extent disturbances in central pain processing are relevant for the determination of symptoms in individual patients. Furthermore, the therapeutic consequences of these assessments remain undetermined. These are challenges of future translational research.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder involving abdominal pain and bowel dysfunction. IBS pain symptoms have been hypothesized to depend on peripheral and central mechanisms, but the pathophysiology is still unclear. The aim of the present study was to assess the contribution of cerebral and cerebrospinal processes to pain inhibition deficits in IBS. Fourteen female patients with diarrhea-predominant IBS (IBS-D) and 14 healthy female volunteers were recruited. Acute pain and the nociceptive withdrawal reflex (RIII reflex) were evoked by transcutaneous electrical stimulation of the right sural nerve with modulation by hetero-segmental counter-irritation produced by sustained cold pain applied on the left forearm. Psychological symptoms were assessed by questionnaires. Shock pain decreased significantly during counter-irritation in the controls (P

Despite the prevalence of self-injurious behavior (SIB) in many genetic developmental disorders associated with severe intellectual impairment, very little is known about the neurobiological underpinnings of this comorbidity. SIB occurs in different sectors of the normal population, but its frequency is much higher among individuals with developmental disorders that negatively influence brain function. Several recent advances in preclinical models of such disorders have led to a greater understanding of how mutations in genes that cause these diseases lead to changes in the structure and function of the central nervous system (CNS). At the same time, a greater appreciation of plasticity in the CNS as it pertains to chronic pain conditions has led to the recognition that molecular mechanisms of pain amplification are remarkably similar to those of learning and memory ( Ji et al. 2003). Here we will summarise recent evidence for aberrant pain processing in humans affected by developmental disorders that cause intellectual disability (ID) and in preclinical models of these diseases. We will place these findings into the context of what is currently known about the initiation and persistence of SIB and discuss possible molecular mechanisms and anatomic pathways that may be disrupted in these diseases. We will outline an experimental framework for further work in this area to test the role of defective pain amplification in SIB that can potentially point to new therapeutic avenues. We will also discuss chronic pain as a potential contributing factor in SIB, which is a complex behaviour. Understanding the role of the nociceptive system in SIB may improve therapeutic outcomes.

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.

PURPOSE OF REVIEW The causes of inflammatory pain and neuropathic pain are fundamentally different. There are, however, common mechanisms underlying the generation of each pain state. We will discuss some specific elements observed in both tissue and nerve injury pain states and consider the hypothesis that these two states actually demonstrate a convergence over time. RECENT FINDINGS The increased pain sensation following tissue and nerve injury results from several mechanisms, including altered ion channel expression in dorsal root ganglion neurons, enhanced dorsal horn glutamate release from primary afferents, enhanced glutamate receptor function in second-order neurons, disinhibition in the dorsal horn and glia cell activation. The role of specific subtypes of receptors, ion channels and glutamate transporters is revealed at peripheral and central sites. Importantly over time, a number of changes, in the dorsal root ganglion and in dorsal horn observed after tissue injury resemble changes observed after nerve injury. SUMMARY Recognition of mechanisms common to both inflammatory pain and neuropathic pain might shed light on the understanding of the transition from acute pain to persistent pain.

Fibromyalgia (FM) is a complex chronic pain syndrome with a well-defined clinical phenotype that results from disordered central pain-related mechanisms. The etiology is multifaceted with links to genetic factors, personality, psychological distress, environmental triggers and peripheral musculoskeletal function. Central brain and spinal cord ‘top-down’ mechanisms dominate the pathophysiology of FM. We review the disordered pain-related neurological processes that are present in FM and discuss treatments that target these relevant mechanisms.

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.

Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na(V)1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na(V)1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects. The conditional knockout of delta-opioid receptor in primary afferent Na(V)1.8 neurons augmented mechanical allodynia in persistent pain models and abolished delta opioid analgesia in these models.

To investigate the pain-modulatory effects of a local inflammatory stimulus on pain elsewhere in the body, capsaicin was applied topically to the forearm of 14 healthy female volunteers. Pressure-pain thresholds and sensitivity to sharpness were assessed on each side of the forehead twice per day during 48 hours of capsaicin treatment, and in the treated and contralateral forearm before and at the end of treatment. Heat was applied to the treated area to rekindle pain at times of forehead assessment. Hyperalgesia to sharpness, but not pressure pain, developed in the treated area whereas sensations remained stable in the contralateral forearm. Sharpness ratings decreased bilaterally in the forehead after 6 hours of treatment, and ipsilateral analgesia to pressure pain developed in the forehead when the capsaicin site was heated after 48 hours of treatment. These findings suggest that pain modulation involves unilateral regulatory mechanisms in addition to local and generalized pain control. The dissociated changes to sharpness and pressure pain indicate distinct cutaneous and deep central pain pathways. Perspective The findings lend support to an increasing body of research which demonstrates that pain modulation involves hemilateral mechanisms in addition to local and generalized controls. Elucidation of mechanisms that modulate ipsilateral pain processing may help to clarify the pathophysiology of complex regional pain syndrome, which is characterized by hemilateral hyperalgesia.

Ablating or functionally compromising sets of sensory neurons has provided important insights into peripheral modality-specific wiring in the somatosensory system. Inflammatory hyperalgesia, cold pain, and noxious mechanosensation have all been shown to depend upon Na v 1.8-positive sensory neurons. The release of fast-acting neurotransmitters, such as glutamate, and more slowly released neuropeptides, such as substance P (SP), contribute to the diversified responses to external stimuli. Here we show that deleting Vglut2 in Na v 1.8 Cre -positive neurons compromised mechanical pain and NGF-induced thermal hyperalgesia, whereas tactile-evoked sensation, thermal, formalin-evoked, and chronic neuropathic pain were normal. However, when Vglut2 f/f ;Na v 1.8 Cre mice were injected with a SP antagonist before the formalin test, the second phase pain response was nearly completely abolished, whereas in control mice, the pain response was unaffected. Our results suggest that VGLUT2-dependent signaling originating from Na v 1.8-positive neurons is a principal sensing mechanism for mechanical pain and, together with SP, inflammatory pain. These data define sets of primary afferents associated with specific modalities and provide useful genetic tools with which to analyze the pathways that are activated by functionally distinct neuronal populations and transmitters.