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EphrinB-EphB receptor signaling plays diverse roles during development, but recently has been implicated in synaptic plasticity in the matured nervous system and in pain processes. The present study investigated the correlation between expression of ephrinB and EphB receptor proteins and chronic constriction injury (CCI) of the sciatic nerve and dorsal rhizotomy (DR) in dorsal root ganglion (DRG) and spinal cord (SC); and interaction of CCI and DR on expression of these signals. Adult, male Sprague-Dawley rats were employed and thermal sensitivity was determined in the sham operated CCI and DR rats. Western blot and immunobiochemistry analysis and immunofluorescence staining techniques were used to detect the expression and location of the ephrinB-EphB receptor proteins in DRG and SC. The results showed that expression of ephrinB1 and EphB1 receptor proteins was significantly upregulated in DRG and SC in a time-dependent manner corresponding to the development of thermal hyperalgesia after CCI. The increased expression is predominately located in the medium- and small-sized DRG neurons, the superficial layers of spinal dorsal horn (DH) neurons, and the IB4 positive nociceptive terminals. DR increases ephrinB1 in DRG, not SC and EphB receptor in SC, not DRG. DR suppressed CCI-induced upregulation of ephrinB1 in SC and EphB1 receptor in DRG and SC. These findings indicate that ephrinB-EphB receptor activation and redistribution in DRG and DH neurons after nerve injury could contribute to neuropathic pain. This study may also provide a new mechanism underlying DR-induced analgesia in clinic.

Temporal summation of "second pain" (TSSP) is the result of C-fiber-evoked responses of dorsal-horn neurons, termed "windup". This phenomenon is dependent on stimulus frequency (0.33 Hz) and relevant for central sensitization as well as chronic pain. Whereas, our previous functional magnetic resonance imaging (fMRI) study characterized neural correlates of TSSP in 11 healthy volunteers, the present study was designed to compare brain responses associated with TSSP across these healthy participants and 13 fibromyalgia (FM) patients. Volume-of-interest analysis was used to assess TSSP-related brain activation. All participants underwent fMRI-scanning during repetitive heat pulses at 0.33 Hz and 0.17 Hz to the right foot. Stimulus intensities were adjusted to each individual's heat sensitivity to achieve comparable TSSP-ratings of moderate pain in all subjects. Experimental pain ratings showed robust TSSP during 0.33 Hz but not 0.17 Hz stimuli. When stimulus strength was adjusted to induce equivalent levels of TSSP, no differences in activation of pain-related brain regions occurred across NC and FM groups. Subsequently, the fMRI-data of both groups were combined to increase the power of our statistical comparisons. fMRI-statistical maps identified several brain regions with stimulus and frequency dependent activation consistent with TSSP, including ipsilateral and contralateral thalamus, medial thalamus, S1, bilateral S2, mid- and posterior insula, rostral and mid-anterior cingulate cortex. However, the stimulus temperatures necessary to evoke equivalent levels of TSSP and corresponding brain activity were less in FM patients. These results suggest that enhanced neural mechanisms of TSSP in FM are reflected at all pain related brain areas, including posterior thalamus, and are not the result of selective enhancement at cortical levels.

In adults, evidence is accumulating that migraine is associated with altered central processing of pain stimuli and, possibly, changes in the allocation of attentional resources to such stimuli. In pediatric migraine, however, little is known about altered pain processing. We examined 15 children with migraine and 15 controls (age 10-15) in an oddball standards task. Children had to respond to rare targets (tones) and ignore frequent painful (pain threshold) or non-painful mechanical standard stimuli while evoked potentials were obtained. Painful as compared to non-painful stimuli elicited significantly larger N150, P260 and P300 components of the somatosensory evoked potential in all children. The pain-evoked N150 and P260 components did not differ significantly between groups. However, in children with migraine, both painful and non-painful standard stimuli were associated with significantly larger P300 amplitudes at significantly shorter latencies. Perceived intensity of the painful and non-painful stimuli was comparable in both groups. The evoked potentials and reaction times to the target tones did not differ significantly between groups. Habituation across trials was similar in both groups. Hence, children with migraine may display an automatic attentional bias towards painful and potentially painful somatosensory stimuli. Consistent with the psychobiological perspective of chronic pain, such an attentional bias could constitute an important mechanism for migraine becoming a chronic problem.

There is great interest in soy isoflavones as alternatives to endogenous estrogens not only in hormonal pathologies, but also in inflammatory, neurodegenerative diseases, and pain. We investigated the effect of the isoflavone genistein on neuropathic pain. Genistein binds estrogen receptors (ER) with higher affinity for the ERbeta particularly expressed in neuronal and immune cells. Neuropathy was induced in mice by means of chronic sciatic nerve constriction, and the subcutaneous administration of genistein from the third day after the lesion reversed pain hypersensitivity in a time- and dose-dependent manner. This effect may have been due to the activation of classical nuclear receptor and/or anti-oxidant, anti-inflammatory, and immunomodulating properties of genistein. The fact that a specific ERbeta antagonist prevented both its anti-allodynic and anti-hyperalgesic action, whereas a specific ERalpha antagonist was ineffective and a non-selective ER antagonist only reversed the anti-allodynic effect, suggests the involvement of ERbeta. Antioxidant effects are also involved as the anti-nociceptive dose reversed the increase in reactive oxygen species and malondialdehyde in injured paw tissues, and increased the activity of anti-oxidant enzymes. The phytoestrogen had immunomodulatory and anti-inflammatory activities as it reduced peripheral and central nuclear factor-kappaB, nitric oxide system and pro-inflammatory cytokine over-activation. Taken together, our results suggest that genistein could ameliorate painful neuropathy by multiple mechanisms.

During evolution, living organisms develop a specialized apparatus called nociceptors to sense their environment and avoid hazardous situations. Intense stimulation of high threshold C- and Adelta-fibers of nociceptive primary sensory neurons will elicit pain, which is acute and protective under normal conditions. A further evolution of the early pain system results in the development of nociceptor sensitization under injury or disease conditions, leading to enhanced pain states. This sensitization in the peripheral nervous system is also called peripheral sensitization, as compared to its counterpart, central sensitization. Inflammatory mediators such as proinflammatory cytokines (TNF-alpha, IL-1beta), PGE(2), bradykinin, and NGF increase the sensitivity and excitability of nociceptors by enhancing the activity of pronociceptive receptors and ion channels (e.g., TRPV1 and Na(v)1.8). We will review the evidence demonstrating that activation of multiple intracellular signal pathways such as MAPK pathways in primary sensory neurons results in the induction and maintenance of peripheral sensitization and produces persistent pain. Targeting the critical signaling pathways in the periphery will tackle pain at the source.

The involvement of reactive oxygen species (ROS) in an augmented sensitivity to painful stimuli (hyperalgesia) during inflammation has been suggested, yet how and where ROS affect the pain signaling remain unknown. Here we report a novel role for the superoxide-generating NADPH oxidase in the development of hyperalgesia. In mice lacking Nox1 (Nox1(-/Y)), a catalytic subunit of NADPH oxidase, thermal and mechanical hyperalgesia was significantly attenuated, whereas no change in nociceptive responses to heat or mechanical stimuli was observed. In dorsal root ganglia (DRG) neurons of Nox1(+/Y), pretreatment with chemical mediators bradykinin, serotonin, or phorbol 12-myristate 13-acetate (PMA) augmented the capsaicin-induced calcium increase, whereas this increase was significantly attenuated in DRG neurons of Nox1(-/Y). Concomitantly, PMA-induced translocation of PKCepsilon was markedly perturbed in Nox1(-/Y) or Nox1(+/Y) DRG neurons treated with ROS-scavenging agents. In cells transfected with tagged PKCepsilon, hydrogen peroxide induced translocation and a reduction in free sulfhydryls of full-length PKCepsilon but not of the deletion mutant lacking the C1A domain. These findings indicate that NOX1/NADPH oxidase accelerates the translocation of PKCepsilon in DRG neurons, thereby enhancing the TRPV1 activity and the sensitivity to painful stimuli.

The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.

The etiology of irritable bowel syndrome (IBS) is complex and multifaceted. Psychosocial factors play a role in such a process. Several reports suggest that IBS patients have increased psychopathology scores as compared with population controls. The influence of depressive symptoms on rectal sensitivity thresholds vary across different studies. The influence of predominant bowel habits on rectal sensitivity thresholds as determined by barostat-based investigations is not well established. The present report aimed to investigate the influence of depressive symptoms on rectal sensitivity in different subtypes of IBS patients (diarrhea/constipation-predominant vs. alternating subtypes). Depressive symptoms correlated well with first pain sensitivity threshold in alternating patients (n = 8; [rho] = -0.77; p = 0.02) but not in diarrhea/constipation predominant symptoms (n = 11; [rho] = -0.44; p = 0.27). These data suggest that depressive symptoms might impact pain thresholds differently according to the subtype of IBS.

A large body of evidence indicates that the release of nitric oxide (NO) is crucial for the central sensitization of pain pathways during both inflammatory and neuropathic pain. Here, we investigated the distribution of NO-sensitive guanylyl cyclase (NO-GC) in the spinal cord and in dorsal root ganglia, and we characterized the nociceptive behavior of mice deficient in NO-GC (GC-KO mice). We show that NO-GC is distinctly expressed in neurons of the mouse dorsal horn, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. GC-KO mice exhibited a considerably reduced nociceptive behavior in models of inflammatory or neuropathic pain, but their responses to acute pain were not impaired. Moreover, GC-KO mice failed to develop pain sensitization induced by intrathecal administration of drugs releasing NO or carbon monoxide. Surprisingly, during spinal nociceptive processing, cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I (cGKI), whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production. Together, our results provide evidence that NO-GC is crucially involved in the central sensitization of pain pathways during inflammatory and neuropathic pain.

All biological bodies live in a thermal environment with the human body as no exception, where skin is the interface with protecting function. When the temperature moves out of normal physiological range, skin fails to protect and pain sensation is evocated. Skin thermal pain is one of the most common problems for humans in everyday life as well as in thermal therapeutic treatments. Nocicetors (special receptor for pain) in skin play an important role in this process, converting the energy from external noxious thermal stimulus into electrical energy via nerve impulses. However, the underlying mechanisms of nociceptors are poorly understood and there have been limited efforts to model the transduction process. In this paper, a model of nociceptor transduction in skin thermal pain is developed in order to build direct relationship between stimuli and neural response, which incorporates a skin thermomechanical model for the calculation of temperature, damage and thermal stress at the location of nociceptor and a revised Hodgkin-Huxley form model for frequency modulation. The model qualitatively reproduces measured relationship between spike rate and temperature. With the addition of chemical and mechanical components, the model can reproduce the continuing perception of pain after temperature has returned to normal. The model can also predict differences in nociceptor activity as a function of nociceptor depth in skin tissue.

Unlabelled: Human females are more sensitive than males to brief nociceptive stimuli such as heat and cold. However, a more pronounced peripheral vasoconstriction by females than by males during prolonged nociceptive stimulation predicts that females would be more sensitive to prolonged cold but not heat stimulation. We tested this possibility with reflex (lick/guard) and operant escape and preference tests of sensitivity to prolonged stimulation of Long-Evans and Sprague-Dawley rats. Escape responses to cold stimulation revealed a greater sensitivity of females. In contrast, males were more sensitive to nociceptive heat stimulation. An operant preference test of relative sensitivity to cold or heat stimulation confirmed these results. Cold was more aversive than heat for females, but heat was more aversive than cold for males. Recordings of skin temperature during nociceptive heat stimulation were consistent with the results of operant testing. A reduction in skin temperature (peripheral vasoconstriction) during nociceptive stimulation should increase cold sensitivity as observed for females relative to males. Lick/guard testing did not confirm the results of operant testing. Lick/guard (L/G) responding to nociceptive heat stimulation was greater for females than for males. Female escape responses to heat were more variable than males, but L/G responding of males to the same stimulus was more variable than for females., Perspective: A variety of chronic pain conditions are more prevalent for females, and psychological stress (with attendant sympathetic activation) is implicated in development and maintenance of these conditions. Therefore, understanding relationships between gender differences in pain sensitivity and sympathetic activation could shed light on mechanisms for some varieties of chronic pain.

Unlabelled: Substantial evidence indicates that the experience of both clinical and experimental pain differs among ethnic groups. Specifically, African Americans generally report higher levels of clinical pain and greater sensitivity to experimentally induced pain; however, little research has examined the origins of these differences. Differences in central pain-inhibitory mechanisms may contribute to this disparity. Diffuse noxious inhibitory controls (DNIC), or counterirritation, is a phenomenon thought to reflect descending inhibition of pain signals. The current study assessed DNIC in 57 healthy young adults from 2 different ethnic groups: African Americans and non-Hispanic whites. Repeated assessments of the nociceptive flexion reflex (NFR) as well as ratings of electrical pain were obtained before, during, and after an ischemic arm pain procedure (as well as a sham procedure). The DNIC condition (ie, ischemic arm pain) produced substantial reductions in pain ratings as well as electrophysiologic measures of the NFR for all participants when compared with the sham condition (P < .001). The DNIC condition produced significantly greater reductions in verbal pain ratings among non-Hispanic whites when compared with African Americans (P = .02), whereas ethnic groups showed comparable reductions in NFR. The findings of this study suggest differences in endogenous pain inhibition between African Americans and non-Hispanic whites and that additional research to determine the mechanisms underlying these effects is warranted., Perspective: This study adds to the growing literature examining ethnic differences in experimental pain perception. Our data suggest that these variations may be influenced by differences in descending inhibition.

Elektrophysiological methods provide objective data about the function of the somatosensory system. Broadly established methods like neurography, myography, sensory evoked potentials and electrically evoked reflexes are in contrast to less well known techniques as laser-evoked potentials and microneurography. It is important to keep in mind that neurography and sensory evoked potentials comprise the function of myelinated nerve fibers with big axonal diameters. Unlike, laser-evoked potentials and microneurography describe the functionality of nonmyelinated, small diameter nerve fibers, which transmit pain and temperatures as sensory signals. Investigation of the sympathetic sudomotoric system can provide evidence for lesions within sympathetic nerves.

Unlabelled: To investigate the mechanisms underlying cancer pain, we developed a rat model of cancer pain by inoculating SCC-158 into the rat hind paw, resulting in squamous cell carcinoma, and determined the time course of thermal, mechanical sensitivity, and spontaneous nocifensive behavior in this model. In addition, pharmacological and immunohistochemical studies were performed to examine the role played by transient receptor potential vanilloid (TRPV)1 and TRPV2 expressed in the dorsal root ganglia. Inoculation of SCC-158 induced marked mechanical allodynia, thermal hyperalgesia, and signs of spontaneous nocifensive behavior, which were diminished by systemic morphine administration. Intraplantar administration of the TRPV1 antagonist capsazepine or TRP channels antagonist ruthenium red did not inhibit spontaneous nocifensive behavior at all. However, intraplantar administration of capsazepine or ruthenium red completely inhibited mechanical allodynia and thermal hyperalgesia produced by SCC-158 inoculation. Immunohistochemically, the number of TRPV1-positive, large-sized neurons increased, whereas there was no change in small-sized neurons in the dorsal root ganglia. Our results suggest that TRPV1 play an important role in the mechanical allodynia and thermal hyperalgesia caused by SCC-158 inoculation., Perspective: We describe a cancer pain model that induced marked mechanical allodynia, thermal hyperalgesia, signs of spontaneous nocifensive behavior, and upregulation of TRPV1. Mechanical allodynia and thermal hyperalgesia were inhibited by TRP channel antagonists. The results suggest that TRPV1 plays an important role in the model of cancer pain.

Objective: Electrical low-frequency stimulation (LFS) of cutaneous afferents evokes long-term depression (LTD) of nociception. In vitro studies suggest a sole homosynaptic effect on the conditioned pathway. The present study addresses homotopy of LTD in human nociception and pain., Methods: In 30 healthy volunteers, nociceptive Adelta fibers were electrically stimulated by a concentric electrode. Test stimulation (0.125 Hz) was alternately applied unilateral to radial and ulnar side of right hand dorsum (ExpUni) or bilateral to radial side of right and left hand dorsum (ExpBi). Conditioning LFS (1 Hz, 1,200 pulses) was applied to radial side of right hand dorsum. Somatosensory evoked cortical vertex potentials (SEP) were recorded, and volunteers rated stimulus intensity., Results: After homotopic LFS, SEP amplitude (ExpUni: -34.6%; ExpBi: -33.6%) and pain rating (ExpUni: -44.1%; ExpBi: -29.1%) significantly decreased. Amplitude reduction after heterotopic LFS did not differ from habituation effects in Control experiment without LFS. Heterotopic pain perception was not affected., Conclusions: The electrophysiological and psychophysical study on synaptic plasticity in healthy man demonstrates homotopic organization of LTD., Significance: Homotopy is probably due to a homosynaptic effect at first nociceptive synapse, but descending inhibitory systems may also be involved. These experiments may help to judge the potency of LTD for future therapy in chronic pain.

Unlabelled: The objective of this study was to assess the impact of persistent inflammation on spinal gamma-aminobutyric acid-A (GABA-A) receptor-mediated modulation of evoked nociceptive behavior in the adult rat. Nocifensive threshold was assessed with von Frey filaments applied to the dorsal surface of the hind paw. The GABA-A receptor agonist muscimol, the antagonist gabazine, the benzodiazepine receptor agonist midazolam, and antagonists PK11195 and flumazenil were administered spinally in the presence and absence of complete Freund's adjuvant (CFA)-induced inflammation. In naive rats, muscimol increased and gabazine decreased nociceptive threshold. After CFA, the effects of these compounds were reversed: Low doses of muscimol exacerbated the inflammation-induced decrease in nociceptive threshold and gabazine increased nociceptive threshold. Midazolam increased nociceptive threshold both in the presence and absence of inflammation. Flumazenil but not PK11195 blocked the analgesic effects of midazolam. These findings indicate that inflammation-induced changes in GABA-A signaling are complex and are likely to involve several distinct mechanisms. Rectifying the changes in GABA-A signaling may provide effective relief from hypersensitivity observed in the presence of inflammation., Perspective: An inflammation-induced shift in spinal GABA-A receptor signaling from inhibition to excitation appears to underlie inflammatory pain and hypersensitivity. Use of GABA-A receptor selective general anesthetics in association with therapeutic interventions may be contraindicated. More importantly, rectifying the changes in GABA-A signaling may provide effective relief from inflammatory hypersensitivity.

Objective: The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor alpha (TNFalpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy., Methods: Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Adelta fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation)., Results: In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint., Conclusion: Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief.

Metabotropic glutamate 5 receptor (mGluR5) antagonists are effective in animal models of inflammatory and neuropathic pain. The involvement of mGluR5 in visceral pain pathways from the gastrointestinal tract is as yet unknown. We evaluated effects of mGluR5 antagonists on the colorectal distension (CRD)-evoked visceromotor (VMR) and cardiovascular responses in conscious rats, and on mechanosensory responses of mouse colorectal afferents in vitro. Sprague-Dawley rats were subjected to repeated, isobaric CRD (12 x 80 mmHg, for 30s with 5 min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1-10 micromol/kg, i.v.) and MTEP (1-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently with maximal inhibition of 52+/-8% (p<0.01) and 25+/-11% (p<0.05), respectively, without affecting colonic compliance. MPEP (10 micromol/kg, i.v.) reduced CRD-evoked increases in blood pressure and heart rate by 33+/-9% (p<0.01) and 35+/-8% (p<0.05), respectively. Single afferent recordings were made from mouse pelvic and splanchnic nerves of colorectal mechanoreceptors. Circumferential stretch (0-5 g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55-78% by 10 microM MTEP (p<0.05). Colonic probing (2g von Frey hair) activated serosal splanchnic afferents; their responses were reduced 50% by 10 microM MTEP (p<0.01). We conclude that mGluR5 antagonists inhibit CRD-evoked VMR and cardiovascular changes in conscious rats, through an effect, at least in part, at peripheral afferent endings. Thus, mGluR5 participates in mediating mechanically evoked visceral nociception in the gastrointestinal tract.

This study was undertaken to investigate any relationship between sensory features and neck pain in female office workers using quantitative sensory measures to better understand neck pain in this group. Office workers who used a visual display monitor for more than four hours per day with varying levels of neck pain and disability were eligible for inclusion. There were 85 participants categorized according to their scores on the neck disability index (NDI): 33 with no pain (NDI<8); 38 with mild levels of pain and disability (NDI 9-29); 14 with moderate levels of pain (NDI30). A fourth group of women without neck pain (n=22) who did not work formed the control group. Measures included: thermal pain thresholds over the posterior cervical spine; pressure pain thresholds over the posterior neck, trapezius, levator scapulae and tibialis anterior muscles, and the median nerve trunk; sensitivity to vibrotactile stimulus over areas of the hand innervated by the median, ulnar and radial nerves; sympathetic vasoconstrictor response. All tests were conducted bilaterally. ANCOVA models were used to determine group differences between the means for each sensory measure. Office workers with greater self-reported neck pain demonstrated hyperalgesia to thermal stimuli over the neck, hyperalgesia to pressure stimulation over several sites tested; hypoaesthesia to vibration stimulation but no changes in the sympathetic vasoconstrictor response. There is evidence of multiple peripheral nerve dysfunction with widespread sensitivity most likely due to altered central nociceptive processing initiated and sustained by nociceptive input from the periphery.

Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.

A pharmacological model of migraine is described using ultrasound vocalization (USV) of rats following central inflammation-induced sensitization to tactile stimulation. Central inflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS) increased USV induced by an air current focused on the head and this was abolished by morphine and ketorolac, suggesting a nociceptive component. USV in naive rats were unaffected. Diazepam reduced USV in both inflamed and naive rats. The triptans, zolmitriptan and sumatriptan, both reduced USV in inflamed but not in naive rats, as did dihydroergotamine, and the calcitonin gene-related peptide (CGRP) antagonists alphaCGRP(8-37) and BIBN4096BS. The neurokinin-1 antagonist L-733-060 had no effect in either inflamed or naive rats when given after induction of inflammation, but when given with the LPS it prevented the augmentation of USV. This profile of activity of agents proven to be effective in the clinic suggests this model can be used to predict novel therapeutic agents for migraine.

Purpose of Review: Chronic visceral pain is one of the most common causes of morbidity in the general population. Despite a gargantuan effort from academia and the pharmaceutical industry, an integrated understanding of the pathophysiological mechanisms of chronic visceral pain, particularly with respect to functional gastrointestinal disorders, remains incomplete., Recent Findings: Advances in our understanding of the structure and function of the microanatomy of nociception has led to the identification of a number of ion channels, neurotransmitter receptors and trophic factors that may be intimately involved in chronic visceral pain. These advances have been paralleled with those in the fields of genetics, neurophysiology and functional neuroimaging. These advances have allowed the objective assessment of central processing of visceral sensation and furthermore the factors that may modulate this process in health and disease., Summary: These findings have important implications for the future direction of research. The real challenge for the future progress is to further characterize patients with chronic visceral pain in terms of their clinical phenotype, genotyping and nociceptive physiology on an individual basis towards the development of more efficacious therapeutic strategies.

Purpose of Review: To review key mechanisms underlying the transmission of nociceptive information from the periphery to the central nervous system implicated in different acute pain states., Recent Findings: Advances in molecular and transgenic approaches have helped to identify novel therapeutic targets for the treatment of pain from tissue and nerve damage such as acid-sensing ion channels, transient receptor potential and NaV channels. The subsequent development of selective pharmacological ligands has also strengthened the role of other receptors such as hyperpolarization-activated cyclic nucleotide-gated channels and the further development of subunit specific antagonists, such as those available for NR2B, will further advance our understanding of the mechanisms involved in nociceptive transmission., Summary: Inflammatory and neuropathic pain differ considerably in their peripheral mechanisms but certain central spinal and brain mechanisms are common to both. The mechanisms of pain are not fully established but are thought to be underpinned by changes in the expression of receptors (nociceptive plasticity), central spinal hyperexcitability (central sensitization) and alterations in descending control from the midbrain. This review considers these mechanisms and highlights recent advances in the understanding of pain perception.

To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor alpha (TNFalpha) antagonist etanercept. In naive mice, exogenous TNFalpha evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFalpha enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNFalpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.

We have previously demonstrated that gabapentin supraspinally activates the descending noradrenergic system to ameliorate pain hypersensitivity in mice with partial nerve ligation. To clarify the supraspinal mechanism of action of gabapentin, whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury or mice subjected to a sham-operation, and the effects of gabapentin in the modulation of synaptic transmission were studied. Bath application of gabapentin (10, 30 and 100 muM) in a concentration-dependent manner reduced the GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs) in slices prepared from partially nerve-ligated mice, whereas glutamate-mediated excitatory post-synaptic currents were hardly affected. By contrast, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Although gabapentin altered neither the amplitude nor the frequency of miniature IPSCs, it reduced IPSCs together with an increase in the paired-pulse ratio, suggesting that gabapentin acts on the pre-synaptic GABAergic nerve terminals in the LC. As the protein kinase A (PKA) inhibitor H-89 but not the protein kinase C inhibitor chelerythrine abolished the inhibitory action of gabapentin on IPSCs, PKA-mediated phosphorylation seems to be important for supraspinal gabapentin responsiveness in neuropathic conditions. Together, gabapentin generates PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission, and thereby removes the inhibitory influence on LC neurons only under neuropathic pain states. These findings provide crucial evidence of how supraspinally acting gabapentin recruits the descending noradrenergic system.

In the elderly patient, the barriers to effective treatment of pain are substantial. Even the perception of pain may differ from that in those of less advanced years. Of course, many other factors impinge on the presence of, and treatment of, pain in elderly patients. Issues of physical accessibility to treatment, cost of drugs, the presence of coexisting illness, the use of concomitant medication, and even the ability to understand the complaints of the patient who has cognitive impairment are only some of those factors that contribute to the complexity of the situation.

Unlabelled: The pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC(1)-R) is a member of the 7-transmembrane domain, group 2 G-protein coupled receptor family. PAC(1)-Rs modulate neurotransmission and neurotrophic actions and have been implicated in both pronociception and antinociception. To better understand the role of PAC(1)-Rs in pain, PACAP 6-38, a PAC(1)-R antagonist, was evaluated in several inflammatory and neuropathic pain models after intrathecal (i.t.) administration. PACAP 6-38 potently reduced mechanical allodynia in a neuropathic spinal nerve ligation model (77% +/- 15% maximal effect at 12 nmol, P < .01) and was also effective in reducing thermal hyperalgesia in the carrageenan model of inflammatory pain (89% +/- 17% maximal effect at 12 nmol, P < .01). Although nociceptive responses were also attenuated with PACAP 6-38 in a dose-dependent manner in models of chronic inflammatory and persistent pain, no effects on motor performance were observed at analgesic doses. Taken together, these data demonstrate that blockade of the PAC(1)-R/PACAP complex by PACAP 6-38 can effectively attenuate thermal hyperalgesia and mechanical allodynia associated with inflammatory and neuropathic pain states. These results further emphasize that at the level of the spinal cord, PAC(1)-R activation is pronociceptive., Perspective: This article presents the analgesic profile generated by the blockade, at the spinal cord level, of the PAC-1 receptor by a potent peptide antagonist. This comprehensive data set demonstrates that if small molecule PAC-1 receptor antagonists could be identified, they would potentially produce broad-spectrum analgesia in both inflammatory and neuropathic pain states.

Unlabelled: Skeletal muscle injuries can induce chronic pain, but the underlying mechanism is unknown. One possible cause has been suggested to be an increased sensitivity to inflammatory mediators. We demonstrate that self-limited inflammatory hyperalgesia induced by intramuscular carrageenan (lasting approximately 5 days) results in a state of chronic-latent hyperalgesia, revealed by injection of prostaglandin E(2) (PGE(2)) 10 days after carrageenan at the same site. In carrageenan-pretreated muscle, PGE(2) produced hyperalgesia that was unattenuated even 14 days after injection, markedly longer than the 4-hour hyperalgesia induced by PGE(2) in naive rats. This chronic-latent hyperalgesia was reversed as well as prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cepsilon, a second messenger implicated in long-lasting plasticity in cutaneous nociceptors., Perspective: We describe a novel experimental model for chronic muscle pain, produced by mild acute muscle inflammation, that has clinical significance since it has the potential to reveal cellular processes by which acute inflammation or muscle trauma underlies chronic muscle pain.

The purpose of this brief review is to present evidence from experimental and clinical neck pain studies of pain-induced neuromuscular adaptations. It has been shown that clinical neck pain is associated with a substantial reorganization in the control strategies of cervical muscles during static and dynamic tasks. Experimental neck pain models allow local elicitation of nociceptive afferents, mimicking the sensory aspects of clinical pain, without major changes in muscle properties. These models may help understand the physiological mechanisms underlying the observations from clinical neck pain studies. The knowledge obtained from the interpretation of clinical findings with experimental pain models has relevance for the development of therapeutic interventions for the rehabilitation of patients with neck pain disorders.

Unlabelled: Peripheral nerve injury has been associated with changes in the modulatory action of noradrenergic pathways on nociceptive traffic through the spinal cord. Thus, the purpose of this study was to assess whether endogenous noradrenergic descending inhibition, acting via spinal alpha(2)-receptors, is altered after peripheral nerve damage. We investigated the effects of spinal administration of a selective alpha(2)-adrenoceptor antagonist, atipamezole, on the evoked activity of deep dorsal horn neurons in animals with selective spinal nerve ligation (SNL) compared with a sham-operated group. Intrathecal administration of atipamezole (1, 10, and 100 microg) did not produce any significant effects on the electrically evoked neuronal responses in either animal group, with the exception of a small but significant enhancement of the postdischarge in the sham control group only. Similarly, no significant effects were observed with the heat-evoked neuronal responses in either group. Interestingly, atipamezole significantly increased the evoked responses of neurons to low-intensity mechanical stimuli in the sham control group but was without effect in the SNL group. Thus, our findings suggest that peripheral nerve injury can result in the suppression of noradrenergic spinal alpha(2)-adrenoceptor-mediated inhibition of spinal dorsal horn neuronal activity evoked by low-intensity mechanical stimuli., Perspective: These results suggest that a tonically active noradrenergic inhibition of mechanically evoked spinal dorsal horn neuronal responses is lost after nerve injury. This shift in the balance of noradrenergic controls may be one of the many underlying mechanisms by which behavioral symptoms of hypersensitivity develop after nerve damage.

Cancer patients treated with antimitotic drugs in the taxane and vinca alkaloid classes sometimes develop a chronic painful peripheral neuropathy whose cause is not understood. In animal models of painful peripheral neuropathy due to nerve trauma or diabetes there is obvious axonal degeneration accompanied by an abnormal incidence of spontaneous discharge in A-fiber and C-fiber nociceptors. But animals with paclitaxel- and vincristine-evoked neuropathic pain do not have axonal degeneration at the level of the peripheral nerve. However, recent data show that they do have a partial degeneration of the primary afferent neurons' terminal arbors in the epidermis. It is not clear as to whether this relatively minor degeneration is accompanied by abnormal spontaneous discharge. We surveyed primary afferent axonal activity in the sural nerve of rats with the paclitaxel- and vincristine-evoked pain syndromes at the time of peak pain severity. Compared to vehicle-injected controls, we find a significant increase in spontaneously discharging A-fibers and C-fibers. Moreover, we show that prophylactic treatment with acetyl-l-carnitine (ALC), which blocks the development of the paclitaxel-evoked pain, causes a significant decrease (ca. 50%) in the incidence of A-fibers and C-fibers with spontaneous discharge. These results suggest that abnormal spontaneous afferent discharge is likely to be a factor in the pathogenesis of chemotherapy-evoked painful peripheral neuropathy, and that the therapeutic effects of ALC may be due to the suppression of this discharge.

Under physiological conditions, nociceptive information is mainly processed in superficial laminae of the spinal dorsal horn, whereas non-nociceptive information is processed in deeper laminae. Neuropathic pain patients often suffer from touch-evoked pain (allodynia), suggesting that modality borders are disrupted in their nervous system. We studied whether excitation evoked in deep dorsal horn neurons either via stimulation of primary afferent Abeta-fibres, by direct electrical stimulation or via glutamate microinjection leads to activation of neurons in the superficial dorsal horn. We used Ca(2+)-imaging in transversal spinal cord slices of neuropathic and control animals to monitor spread of excitation from the deep to the superficial spinal dorsal horn. In neuropathic but not control animals, a spread of excitation occurred from the deep to the superficial dorsal horn. The spread of excitation was synaptically mediated as it was blocked by the AMPA receptor antagonist CNQX. In contrast, block of NMDA receptors was ineffective. In control animals, the violation of modality borders could be reproduced by bath application of GABA(A) and glycine receptor antagonists. Furthermore, we could show that neuropathic animals were more prone to synchronous network activity than control animals. Thus, following peripheral nerve injury, excitation generated in dorsal horn areas which process non-nociceptive information can invade superficial dorsal horn areas which normally receive nociceptive input. This may be a spinal mechanism of touch-evoked pain.

The present study aims to investigate changes of spinal cord AMPA receptor GluR1 and its phosphorylation in inflammatory and neuropathic pain. Complete Freund's adjuvant (CFA) injection into the hind paw produced inflammatory thermal hyperalgesia that was assessed by decreased response latency to radiant heat; spinal nerve ligation (SNL) was used to induce mechanical allodynia that was evaluated with von Frey hairs. By method of Western blot, expression of GluR1 (the main subunit of the AMPA receptor) and its phosphorylated forms at serine 845 (pGluR1-Ser845) and at serine 831 (pGluR1-Ser831) in the spinal dorsal horn was observed. It was found that the expression of pGluR1-Ser845 and pGluR1-Ser831 increased significantly at 1 h after CFA injection, reached peak at 4 h and returned to the normal control level at 24 h, while no significant change was detected in GluR1 itself. In contrast, neither GluR1 nor pGluR1 showed any significant change in rats following SNL. These results suggest that phosphorylated GluR1 (pGluR1-Ser845 and pGluR1-Ser831) might play a role in the induction of inflammatory but not neuropathic pain.

Background & Aims: Visceral hypersensitivity is a hallmark of irritable bowel syndrome (IBS), but the relationship with clinical symptoms and psychological factors has not been fully established. We aimed to (1) evaluate these variables in a large cohort of IBS patients, recruited from both hospital and general practice, and in healthy controls and (2) assess which of these factors predicts the occurrence of visceral hypersensitivity in IBS., Methods: Rectal compliance and perception (intensity, perception thresholds; visual analogue scale, 0-100 mm) were assessed by a rectal barostat study (ramp distention) in 101 IBS patients and 40 healthy volunteers. IBS symptom severity was scored by using a 14-day 5-item diary. Anxiety, depression, somatization, vigilance, pain coping, dysfunctional cognitions, psychoneuroticism, and quality of life were assessed with psychometric questionnaires., Results: Rectal compliance was significantly reduced in IBS patients compared with controls (P < .01), as were thresholds for pain (27 +/- 15 vs 35 +/- 8 mm Hg; P < .01) and urge (P < .05). Levels of anxiety, depression, neuroticism, somatization, and dysfunctional cognitions were significantly increased in IBS patients versus controls, whereas pain coping and quality of life were significantly worse. Hypersensitivity to rectal distention occurred in 33% of patients and was associated with increased symptom severity (P = .016), but not with demographic characteristics or psychological disturbances., Conclusions: Hypersensitivity to balloon distention occurs in 33% of IBS patients and is predicted by symptom severity but not by psychological or demographic characteristics.

Background: Abdominal pain related to irritable bowel syndrome (IBS) and functional abdominal pain (FAP) is frequent in children and can be of variable severity. Both IBS and FAP are associated with rectal hypersensitivity. We hypothesized that in children with IBS and FAP, the rectal sensory threshold for pain (RSTP) is associated with symptom severity., Patients and Methods: A total of 47 patients (34 girls; median age, 14.2 years) with IBS (n = 29) and FAP (n = 18), according to the Rome II criteria, underwent a rectal barostat examination to determine their RSTP. Gastrointestinal symptom severity was assessed by validated questionnaires. During the rectal barostat exam, symptoms were documented using a visual analog scale and by measuring the area coloured on a human body diagram corresponding to painful sensations., Results: The median RSTP was 16 mmHg and was similar in IBS and FAP patients. Eighty-three percent of the patients had rectal hypersensitivity (RSTP < or = 30.8 mmHg, the 5th percentile of control children studied in our laboratory). Fifty-one percent and 36%, respectively, reported missing school and social activities at least once per week. Increased frequency of pain, missed days of school, missed social activities, and pain during the barostat examination were not associated with lower RSTP values in either the whole group or in the subset of children with rectal hypersensitivity., Conclusions: Rectal hypersensitivity is not proportional to the severity of symptoms in children with IBS and FAP, indicating that symptom severity is influenced by other factors in addition to visceral hypersensitivity.

Neuropeptide FF (NPFF) precursors from different species contain at least three known neuropeptides, i.e. FF (FLFQPQRF-NH(2)), AF (AGEGLSSPFWSLAAPQR-NH(2)) and SF (SLAAPQRF-NH(2)). We demonstrate that the rat NPFF precursor contains another bioactive sequence, NAWGPWSKEQLSPQA, spanning between positions 85 and 99. Synthetic NPFF precursor (85-99) (10 and 20 nmol, i.c.v.) blocked the expression of conditioned place preference induced by morphine (5 mg/kg, s.c.). This peptide alone (10 and 20 nmol, i.c.v.) had no influence on the baseline latency of a nociceptive reaction but reversed the antinociceptive activity of morphine (5 mg/kg, s.c.) in the tail-immersion test in rats. These data suggest the existence of a novel bioactive cryptic peptide within an already known NPFF precursor.

Neuropathic pain, following a lesion of the peripheral or primary nervous system, is characterized by a set of pathophysiologic mechanisms and a clinical expression that distinguishes it from other chronic pain, especially inflammatory pain. These two types of pain are nonetheless frequently found in the same patient. It is important to be able to recognize neuropathic pain, either isolated or associated with other chronic pain, because it requires appropriate management.

Objectives: To explore clinical findings in men with chronic pain after falanga torture as compared with controls, and to try to understand the nature of the pain mechanisms responsible., Methods: Eleven male torture victims from the Middle East with chronic pain after falanga, and 11 age, sex, and ethnically matched controls with no history of torture were recruited. All participants were interviewed regarding pain characteristics in the feet and lower legs at rest and when walking. Structural changes and motor and sensory function were clinically assessed according to a standardized protocol. The walking pattern was observed for compensatory gait patterns., Results: The torture victims had pain in their feet and lower legs and a compensated gait pattern, usually with severe pain during walking. Reduced light touch and thermal sensation, tactile dysesthesia, allodynia, and tenderness on palpation were common findings. Structural changes in the feet were found in more than half of the victims, but did not correlate with pain reports. These clinical findings were nonexistent or seen only rarely in controls., Discussion: We found clear clinical signs of nerve injury in the feet. The sensory findings indicated 2 neuropathic pain mechanisms, one dominated by a peripheral pain generator and other by irritative phenomena (dysesthesia, allodynia), indicating central sensitization. It is reasonable to assume that these changes are due to the falanga exposure. A nociceptive contribution cannot be excluded. It is important to perform an individual diagnostic analysis to facilitate adequate treatment.

The reeler gene encodes Reelin, a secreted glycoprotein that binds to the very-low-density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (Apoer 2), and induces Src- and Fyn-mediated tyrosine phosphorylation of the intracellular adaptor protein Disabled-1 (Dab1). This Reelin-Dab1 signaling pathway regulates neuronal positioning during development. A second Reelin pathway acts through Apoer 2-exon 19 to modulate synaptic plasticity in adult mice. We recently reported positioning errors in reeler dorsal horn laminae I-II and V, and the lateral spinal nucleus. Behavioral correlates of these positioning errors include a decreased mechanical and increased thermal sensitivity in reeler mice. Here we examined mice with deletions or modifications of both the Reelin-Dab1 signaling pathway and the Reelin-Apoer 2-exon 19 pathway on a Vldlr-deficient background. We detected reeler-like dorsal horn positioning errors only in Dab1 mutant and Apoer 2/Vldlr double mutant mice. Although Dab1 mutants, like reeler, showed decreased mechanical and increased thermal sensitivity, neither the single Vldlr or Apoer 2 knockouts, nor the Apoer 2-exon 19 mutants differed in their acute pain sensitivity from controls. However, despite the dramatic alterations in acute 'pain' processing in reeler and Dab1 mutants, the exacerbation of pain processing after tissue injury (hindpaw carrageenan injection) was preserved. Finally, we recapitulated the reeler dorsal horn positioning errors by inhibiting Dab1 phosphorylation in organotypic cultures. We conclude that the Reelin-Dab1 pathway differentially contributes to acute and persistent pain, and that the plasticity associated with the Reelin-Apoer 2-exon 19 pathway is distinct from that which contributes to injury-induced enhancement of 'pain' processing.

Changes in expression and function of voltage-gated sodium channels (VGSC) in dorsal root ganglion (DRG) neurons may play a major role in the genesis of peripheral hyperexcitability that occurs in neuropathic pain. We present here the first description of changes induced by spared nerve injury (SNI) to Na(v)1 mRNA levels and tetrodotoxin-sensitive and -resistant (TTX-S/TTX-R) Na(+) currents in injured and adjacent non-injured small DRG neurons. VGSC transcripts were down-regulated in injured neurons except for Na(v)1.3, which increased, while they were either unchanged or increased in non-injured neurons. TTX-R current densities were reduced in injured neurons and the voltage dependence of steady-state inactivation for TTX-R was positively shifted in injured and non-injured neurons. TTX-S current densities were not affected by SNI, while the rate of recovery from inactivation was accelerated in injured neurons. Our results describe altered neuronal electrogenesis following SNI that is likely induced by a complex regulation of VGSCs.

Primary hyperalgesia to mechanical and thermal stimuli are major clinical symptoms of inflammatory pain and can be induced experimentally by ultraviolet-B (UV-B) irradiation in humans. We set-up a pig model in order to have more options for pharmacological intervention on primary hyperalgesia. Pig skin was irradiated with a dose one- to threefold higher than the minimum erythema dose (MED) and investigated for mechanical and heat responsiveness 24 and 48 h post UV-B treatment. C-fiber activation upon mechanical and thermal stimulation was assessed indirectly by extent of the axon reflex erythema (flare) measured by laser Doppler imaging. Mechanical stimulation with von Frey filaments (100 mN) induced flare responses in UV-B treated skin at 24 and 48 h, but no effect was measured in normal untreated skin. Increased mechanical stimulation (600 mN) elicited a small flare response in normal skin in an area of 1.8 cm(2) on average that was extending about 2.5 cm(2) in the UV-B irradiated sites. Thermal stimuli provoked in normal pig skin flare areas of approximately 2 cm(2) (45 degrees C, 10 s) and 4.5 cm(2) (47 degrees C, 10 s) which increased to about 3.5 cm(2) (45 degrees C) and 5.5 cm(2) (47 degrees C) following UV-B irradiation at 24 and 48 h. No significant differences of mechanically or thermally induced hypersensitivity were seen between 24 and 48 h after irradiation. We conclude that UV-B induced mechanical and heat sensitization of primary afferent nociceptors can be assessed in pig skin, providing a new human-like model of primary hyperalgesia. Sensitization of primarily mechano-insensitive (silent) nociceptors, which are underlying the flare response in humans, most probably contributes to the observation presented here.

Neuropathic pain can be conceptualized as the result of an "aberrant learning" process, associated with maladaptive plasticity of the nervous system. A number of modifications of the peripheral nervous system have been described in animal models of neuropathic pain, but their relation with different symptoms in humans is far from fully understood. We note in particular ectopic discharges in damaged myelinated fibers, abnormal activity in undamaged fibers, overexpression of calcium channels increasing the release of excitatory neurotransmitters, and sympathetic sprouting towards the spinal ganglia. Spinal mechanisms involve central sensitization, kindling and potentiation phenomena. Underlying these phenomena may be connectivity changes--still controversial--of non-nociceptive terminals and variations in the sensitivity of postsynaptic receptors. Also contributing to these pathophysiologic modifications are attenuation of spinal inhibition by selective neuronal loss and the development of inflammatory phenomena, including cytokine secretion by macrophages and glial cells. Changes in the dorsal horn modify the activity of projections towards the brainstem and increase spinal hyperactivity still further by feedback loops. These effects are delayed, suggesting that maintenance of spinal sensitization requires the involvement of mechanisms of descending facilitation involving the brainstem. These phenomena induce changes in the activity of thalamocortical networks, which develop autonomous processes that maintain the pain. The cortical representation of body areas change after nervous lesions, and these changes may correlate with the emergence of pain. Neuropathic allodynia and hyperalgesia are supported by cortical modifications that experimental models reproduce very incompletely. Experimental allodynia and neuropathic allodynia share the activation of the cortical pain matrix as well as the bilateralization of insular activity. However, although experimental allodynia tends to increase the activity of limbic and affective networks of the perigenual and orbitofrontal cortex, in neuropathic allodynia, analgesic procedures lead to increased activity in these structures. This suggests that their role in experimental allodynia would likely be reactive and protective, and that inability to generate their activation may contribute to the clinical expression of neuropathic pain.

A pain model for screening analgesics was established in anesthetized rats. The omenta of urethane-anesthetized rats were exteriorized, fixed in a plastic chamber, and superfused with Tyrode solution. Administration of bradykinin (BK) in the chamber elicited the reflex hypertensive response (RHR). Modification of the RHR was tested by topical (in the chamber) or intravenous administration of drugs. The BK dose-response curve was shifted to the right by topical indomethacin. The RHR by BK was inhibited by topical application of a BK B(2) antagonist, (Thi(5,8)-D-Phe(7)-BK), a local anesthetic (2% carbocaine), and by intravenous administration of a ganglion blocker (hexamethonium) or an alpha-adrenergic blocker (dibenamine). The RHR by topical BK was almost completely inhibited by morphine and the suppression was largely reversed by naloxone. The RHR, induced by a threshold dose of BK and inhibited by indomethacin, was potentiated by pretreatment of the omentum with prostaglandin (PG) E(2) or PGI(2). PGE(2) was less potent, but the effect lasted longer than that of PGI(2). Topical administration of a non-acidic analgesic, mepirizole, inhibited the RHR by topical BK by only 20%, but intravenous mepirizole inhibited topical BK by 96.2%, indicating its major central action. This model may be useful for studying analgesics.

Migraine headache originates from the stimulation of nerve terminals of trigeminal ganglion neurons that innervate meninges. Characteristic features of migraine pain are not only its delayed onset but also its persistent duration. Current theories propose that endogenous substances released during a migraine attack (the neuropeptide calcitonin gene-related peptide [CGRP] and the neurotrophin nerve growth factor [NGF]) sensitize trigeminal neurons to transmit nociceptive signals to the brainstem, though the mechanisms remain poorly understood. Recent studies indicate that acute, long-lasting sensitization of trigeminal nociceptive neurons occurs via distinct processes involving enhanced expression and function of adenosine triphosphate (ATP)-gated P2X3 receptors known to play a role in chronic pain. In particular, on cultured trigeminal neurons, CGRP (via protein kinase A-dependent signaling) induces a slowly developing upregulation of the ionic currents mediated by P2X3 receptors by enhancing receptor trafficking to the neuronal membrane and activating their gene transcription. Such upregulated receptors acquire the ability to respond repeatedly to extracellular ATP, thus enabling long-lasting signaling of painful stimuli. In contrast, NGF induces rapid, reversible upregulation of P2X3 receptor function via protein kinase C phosphorylation, an effect counteracted by anti-NGF antibodies. The diverse intracellular signaling pathways used by CGRP and NGF show that the sensitization of P2X3 receptor function persists if the action of only one of these migraine mediators is blocked. These findings imply that inhibiting a migraine attack might be most efficient by a combinatorial approach. The different time domains of P2X3 receptor modulation by NGF and CGRP suggest that the therapeutic efficacy of novel antimigraine drugs depends on the time of administration.

Objective: To develop and validate a questionnaire for assessing cutaneous allodynia (CA), and to estimate the prevalence and severity of CA in the migraine population., Methods: Migraineurs (n = 11,388) completed the Allodynia Symptom Checklist, assessing the frequency of allodynia symptoms during headache. Response options were never (0), rarely (0), less than 50% of the time (1), > or = 50% of the time (2), and none (0). We used item response theory to explore how well each item discriminated CA. The relations of CA to headache features were examined., Results: All 12 questions had excellent item properties. The greatest discrimination occurred with CA during "taking a shower" (discrimination = 2.54), wearing a necklace (2.39) or ring (2.31), and exposure to heat (2.1) or cold (2.0). The factor analysis demonstrated three factors: thermal, mechanical static, and mechanical dynamic. Based on the psychometrics, we developed a scale distinguishing no CA (scores 0-2), mild (3-5), moderate (6-8), and severe (> or = 9). The prevalence of allodynia among migraineurs was 63.2%. Severe CA occurred in 20.4% of migraineurs. CA was associated with migraine defining features (eg, unilateral pain: odds ratio, 2.3; 95% confidence interval, 2.0-2.4; throbbing pain: odds ratio, 2.3; 95% confidence interval, 2.1-2.6; nausea: odds ratio, 2.3; 95% confidence interval, 2.1-2.6), as well as illness duration, attack frequency, and disability., Interpretation: The Allodynia Symptom Checklist measures overall allodynia and subtypes. CA affects 63% of migraineurs in the population and is associated with frequency, severity, disability, and associated symptoms of migraine. CA maps onto migraine biology.

Injury to the spinal cord (SCI) can produce a constellation of problems including chronic pain, autonomic dysreflexia, and motor dysfunction. Neuroplasticity in the form of fiber sprouting or the lack thereof is an important phenomenon that can contribute to the deleterious effects of SCI. Aberrant sprouting of primary afferent fibers and synaptogenesis within incorrect dorsal horn laminae leads to the development and maintenance of chronic pain as well as autonomic dysreflexia. At the same time, interruption of connections between supraspinal motor control centers and spinal cord output cells, due to lack of successful regenerative sprouting of injured descending fiber tracts, contributes to motor deficits. Similarities in the molecular control of axonal growth of motor and sensory fibers have made the development of cogent therapies difficult. In this study, we discuss recent findings related to the degradation of inhibitory barriers and promotion of sprouting of motor fibers as a strategy for the restoration of motor function and note that this may induce primary afferent fiber sprouting that can contribute to chronic pain. We highlight the importance of careful attentiveness to off-target molecular- and circuit-level modulation of nociceptive processing while moving forward with the development of therapies that will restore motor function after SCI.

Objectives: Sensory hypersensitivity, central hyperexcitability [lowered nociceptive flexion reflex (NFR) thresholds], and psychologic distress are features of chronic whiplash. However, relationships between these substrates are not clear. This study tested the hypothesis that psychologic distress and catastrophization are correlated with sensory hypersensitivity and NFR responses in chronic whiplash., Methods: Pressure and thermal pain thresholds (mean values across 3 body sites), NFR threshold, and pain at threshold Visual Analog Scale were measured in 30 participants with chronic whiplash and 30 asymptomatic controls. Pain and disability levels Neck Disability Index, psychologic distress (GHQ-28), and catastrophization (PCS) were also measured in the whiplash group., Results: Whiplash injured participants demonstrated lowered pain thresholds to pressure and cold (P<0.05); lowered NFR thresholds (P=0.003), and demonstrated above threshold levels of psychologic distress (GHQ-28) and levels of catastrophization comparable with other musculoskeletal conditions. There were no group differences for heat pain thresholds or pain at NFR threshold. In the whiplash group, PCS scores correlated moderately with cold pain threshold (r=0.51, P=0.01). In contrast, there were no significant correlations between GHQ-28 scores and pain threshold measures or between psychologic factors and NFR responses in whiplash participants. There were no significant correlations between psychologic factors and pain thresholds or NFR responses in controls., Discussion: We have demonstrated that psychologic factors have some association with sensory hypersensitivity (cold pain threshold measures) in chronic whiplash but do not seem to influence spinal cord excitability. This suggests that psychologic disorders are important, but not the only, determinants of central hypersensitivity in whiplash patients.