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International audience; Chronic postsurgical neuropathic pain (CPSNP) is frequent. While prevalence varies considerably according to type of operation and means of evaluation, it can reach 37% following breast surgery. Identification of risk factors related to the procedure and to the patient and taking into account the development of new, minimally invasive surgical techniques is increasingly nerve-sparing and reduces the likelihood of injury. CPSNP diagnosis in daily practice is facilitated by simple and quickly usable tools such as the NP4 4-question test. Management is based on pharmacological (analgesics, antiepileptics, antidepressants, local anesthetics) and non-pharmacological (kinesitherapy, neurostimulation, psychotherapy) approaches. In light of the present review of the literature, the authors, who constitute an expert group specialized in pain management, anesthesia and surgery, express their support for topical treatments (lidocaine, capsaicin) in treatment of localized postsurgical neuropathic pain in adults.

Background Mycolactone is a macrolide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and immunomodulatory properties. The latter were recently shown to result from mycolactone blocking the Sec61-dependent production of pro-inflammatory mediators by immune cells. Here we investigated whether mycolactone similarly affects the inflammatory responses of the nervous cell subsets involved in pain perception, transmission and maintenance. We also investigated the effects of mycolactone on the neuroinflammation that is associated with chronic pain in vivo. Methodology/ Principle findings Sensory neurons, Schwann cells and microglia were isolated from mice for ex vivo assessment of mycolactone cytotoxicity and immunomodulatory activity by measuring the production of proalgesic cytokines and chemokines. In all cell types studied, prolonged (>48h) exposure to mycolactone induced significant cell death at concentrations >10 ng/ml. Within the first 24h treatment, nanomolar concentrations of mycolactone efficiently suppressed the cell production of pro-inflammatory mediators, without affecting their viability. Notably, mycolactone also prevented the pro-inflammatory polarization of cortical microglia. Since these cells critically contribute to neuroinflammation, we next tested if mycolactone impacts this pathogenic process in vivo. We used a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. Here, mycolactone was injected daily for 3 days in the spinal canal, to ensure its proper delivery to spinal cord. While this treatment failed to prevent injury-induced neuroinflammation, it decreased significantly the local production of inflammatory cytokines without inducing detectable cytotoxicity. Conclusion/ Significance The present study provides in vitro and in vivo evidence that mycolactone suppresses the inflammatory responses of sensory neurons, Schwann cells and microglia, without affecting the cell viability. Together with previous studies using peripheral blood leukocytes, our work implies that mycolactone-mediated analgesia may, at least partially, be explained by its anti-inflammatory properties., Author summary Mycolactone is a complex macrolidic polyketide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and anti-inflammatory properties. Peripheral nerve destruction and activation of type 2 angiotensin II receptors on sensory neurons have been proposed to mediate bacteria-induced hypoesthesia in infected skin. In addition, mycolactone was recently shown to block the co-translational translocation of secretory proteins into the endoplasmic reticulum in host cells, leading to defective inflammatory responses. Here we examined if this last mechanism may also contribute to inhibit neuro-inflammation and particularly in the context of neuropathic pain. Using a representative panel of primary cells from the central and peripheral nervous systems, we found that indeed, mycolactone potently inhibits the production of pro-inflammatory mediators at non-cytotoxic concentrations. Notably, mycolactone prevented the polarization and pro-inflammatory functions of cortical microglia, which are critical inducers of neuroinflammation. Consistent with our in vitro findings, mycolactone had potent anti-inflammatory effects on the spinal cord of rats injected in the spinal canal, with no apparent side effects. Our data show that mycolactone suppresses inflammatory responses in the nervous system similarly as in the immune system, suggesting that mycolactone-mediated analgesia may, at least partially, be explained by its anti-inflammatory properties.

Objective:To investigate changes in body ownership and chronic neuropathic pain in patients with spinal cord injury (SCI) using multisensory own body illusions and virtual reality (VR).Methods:Twenty patients with SCI with paraplegia and 20 healthy control participants (HC) participated in 2 factorial, randomized, repeated-measures design studies. In the virtual leg illusion (VLI), we applied asynchronous or synchronous visuotactile stimulation to the participant's back (either immediately above the lesion level or at the shoulder) and to the virtual legs as seen on a VR head-mounted display. We tested the effect of the VLI on the sense of leg ownership (questionnaires) and on perceived neuropathic pain (visual analogue scale pain ratings). We compared illusory leg ownership with illusory global body ownership (induced in the full body illusion [FBI]), by applying asynchronous or synchronous visuotactile stimulation to the participant's back and the back of a virtual body as seen on a head-mounted display.Results:Our data show that patients with SCI are less sensitive to multisensory stimulations inducing illusory leg ownership (as compared to HC) and that leg ownership decreased with time since SCI. In contrast, we found no differences between groups in global body ownership as tested in the FBI. VLI and FBI were both associated with mild analgesia that was only during the VLI specific for synchronous visuotactile stimulation and the lower back position.Conclusions:The present findings show that VR exposure using multisensory stimulation differently affected leg vs body ownership, and is associated with mild analgesia with potential for SCI neurorehabilitation protocols.

International audience; OBJECTIVES: Conduct a literature review on the organization models for the chronic neuropathic pain management of spinal cord injury (SCI) patients. METHODS: Bibliographical research on Medline based on the following keywords: chronic neuropathic pain in spinal cord injury-comprehensive management-multidisciplinary approaches. RESULTS AND DISCUSSION: No data was found in the literature on this specific topic. We took the option to report the data from the French laws regarding chronic non-cancer pain management. Chronic pain in SCI patients needs a specific and rigorous approach, justifying the role of the physical medicine and rehabilitation (PM&R) physician within specialized pain management centers as a key referent physician and coordinator for this type of patient. Furthermore, SCI pain is a chronic pain and as such requires a global care management; engulfing its emotional, affective, cognitive and behavioral aspects. These particular aspects need to be evaluated within specialized centers dedicated to chronic pain that provide specific therapies such as behavioral and cognitive therapies. CONCLUSION: Specific pain management centers or hospital units remain the benchmark place for chronic pain in SCI patients. PM&R physicians play a key role in the care management of chronic SCI pain. The partnership PM&R-Pain management center aims to provide the most efficient and coordinated care for SCI patient.

International audience; ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Nauclea latifolia Smith (Rubiaceae) popularly known as "koumkouma" is used in traditional Cameroonian medicine as neuropathic pain remedy and for the treatment of headache, inflammatory pain and convulsion. This study was conducted to evaluate the antinociceptive effects of the alkaloid fraction isolated from Nauclea latifolia in neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rat. MATERIALS AND METHODS: Bioactive-guided fractionation of the root extracts of Nauclea latifolia using the Von Frey in a rat model of neuropathic pain (Benett model), afforded a potent anti-hyperalgesic fraction IV. Further fractionation of this fraction was performed by high-performance liquid chromatography (HPLC), yielded eight sub-fractions (F1-F8) which were tested for antinociceptive effects. The alkaloid fraction (F3) collected by HPLC, exhibited potent antinociceptive effects, and the anti-allodynic and anti-hyperalgesic effects of this fraction (8, 16, 40 and 80 mg/kg) were determined using the von Frey and acetone tests respectively in a rat model of neuropathic pain. Rota-rod performance and catalepsy tests were used for the assessment of motor coordination. RESULTS: The alkaloid fraction (80 mg/kg) administered intraperitoneally induced a completely decreased hyperalgesia 90 min post-dosing. In the acetone test, the Nauclea latifolia fraction at 80mg/kg showed its maximal anti-allodynic effects 120 min post-injection. The areas under the curve (AUC) of the anti-allodynic or anti-hyperalgesic effects produced by the alkaloid fraction at 80 mg/kg were significantly (p

International audience; We conducted a postal survey to assess the prevalence and characteristics of neuropathic pain and migraine in a cohort of multiple sclerosis (MS) patients. Of the 1300 questionnaires sent, 673 could be used for statistical analysis. Among the respondents, the overall pain prevalence in the previous month was 79%, with 51% experiencing pain with neuropathic characteristics (NCs) and 46% migraine. MS patients with both migraine and NC pain (32% of the respondents) reported more severe pain and had lower health-related quality of life than MS patients with either migraine or NC pain. Pain intensity in MS patients with migraine was moderate (6.0 ± 0.1). Migraine was mostly episodic, but headaches were occurring on ≥15 days per month in 15% of those with migraine. MS patients with migraine were younger and had shorter disease durations than those with NC pain. NC pain was most often located in the extremities, back and head, and was frequently described as tingling and pins-and-needles. The intensity of NC pain was low to moderate (4.9 ± 0.1), but positively correlated with the number of painful body sites. Nonetheless, patients with NC pain were more disabled (with a higher Expanded Disability Status Scale and pain interference index) than patients with migraine. Migraine, but not NC pain, was associated with age, disease duration, relapsing-remitting course, and interferon-beta treatment. This suggests that NC pain and migraine are mediated by different mechanisms. Therefore, pain mechanisms that specifically operate in MS patients need to be characterized to design optimal treatments for these individuals.

International audience; We conducted a postal survey to assess the prevalence and characteristics of neuropathic pain and migraine in a cohort of multiple sclerosis (MS) patients. Of the 1300 questionnaires sent, 673 could be used for statistical analysis. Among the respondents, the overall pain prevalence in the previous month was 79%, with 51% experiencing pain with neuropathic characteristics (NCs) and 46% migraine. MS patients with both migraine and NC pain (32% of the respondents) reported more severe pain and had lower health-related quality of life than MS patients with either migraine or NC pain. Pain intensity in MS patients with migraine was moderate (6.0 ± 0.1). Migraine was mostly episodic, but headaches were occurring on ≥15 days per month in 15% of those with migraine. MS patients with migraine were younger and had shorter disease durations than those with NC pain. NC pain was most often located in the extremities, back and head, and was frequently described as tingling and pins-and-needles. The intensity of NC pain was low to moderate (4.9 ± 0.1), but positively correlated with the number of painful body sites. Nonetheless, patients with NC pain were more disabled (with a higher Expanded Disability Status Scale and pain interference index) than patients with migraine. Migraine, but not NC pain, was associated with age, disease duration, relapsing-remitting course, and interferon-beta treatment. This suggests that NC pain and migraine are mediated by different mechanisms. Therefore, pain mechanisms that specifically operate in MS patients need to be characterized to design optimal treatments for these individuals.

International audience; Background: Pathological pain states are often associated with neuronal hyperexcitability in the spinal cord. Reducing this excitability could theoretically be achieved by amplifying the existing spinal inhibitory control mediated by GABAA receptors (GABAARs). In this study, we used the non-benzodiazepine anxiolytic etifoxine (EFX) to characterize its interest as pain killer and spinal mechanisms of action. EFX potentiates GABAAR function but can also increase its function by stimulating the local synthesis of 3α-reduced neurosteroids (3αNS), the most potent endogenous modulators of this receptor.Methods: The efficacy of EFX analgesia and the contribution of 3αNS were evaluated in a rat model of mononeuropathy. Spinal contribution of EFX was characterized through changes in pain symptoms after intrathecal injections, spinal content of EFX and 3αNS, and expression of FosB-related genes, a marker of long-term plasticity.Results: We found that a 2-week treatment with EFX (>5 mg/kg, i.p.) fully suppressed neuropathic pain symptoms. This effect was fully mediated by 3αNS and probably by allopregnanolone, which was found at a high concentration in the spinal cord. In good agreement, the level of EFX analgesia after intrathecal injections confirmed that the spinal cord is a privileged target as well as the limited expression of FosB/ΔFosB gene products that are highly expressed in persistent pain states.Conclusions: This preclinical study shows that stimulating the production of endogenous analgesics such as 3αNS represents an interesting strategy to reduce neuropathic pain symptoms. Since EFX is already prescribed as an anxiolytic in several countries, a translation to the human clinic needs to be rapidly evaluated.

International audience; We conducted a postal survey to assess the prevalence and characteristics of neuropathic pain and migraine in a cohort of multiple sclerosis (MS) patients. Of the 1300 questionnaires sent, 673 could be used for statistical analysis. Among the respondents, the overall pain prevalence in the previous month was 79%, with 51% experiencing pain with neuropathic characteristics (NCs) and 46% migraine. MS patients with both migraine and NC pain (32% of the respondents) reported more severe pain and had lower health-related quality of life than MS patients with either migraine or NC pain. Pain intensity in MS patients with migraine was moderate (6.0 ± 0.1). Migraine was mostly episodic, but headaches were occurring on ≥15 days per month in 15% of those with migraine. MS patients with migraine were younger and had shorter disease durations than those with NC pain. NC pain was most often located in the extremities, back and head, and was frequently described as tingling and pins-and-needles. The intensity of NC pain was low to moderate (4.9 ± 0.1), but positively correlated with the number of painful body sites. Nonetheless, patients with NC pain were more disabled (with a higher Expanded Disability Status Scale and pain interference index) than patients with migraine. Migraine, but not NC pain, was associated with age, disease duration, relapsing-remitting course, and interferon-beta treatment. This suggests that NC pain and migraine are mediated by different mechanisms. Therefore, pain mechanisms that specifically operate in MS patients need to be characterized to design optimal treatments for these individuals.

International audience; Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5-HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose-dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5-fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages.

International audience; Trigeminal neuropathic pain is due to lesion or dysfunction of the nervous system. Dynamic mechanical allodynia is a widespread symptom of neuropathic pain for which mechanisms are still poorly understood. Recent studies demonstrate that forebrain neurons, including neurons in the medial prefrontal cortex (mPFC) are important for the perception of acute and chronic pain. Using the phosphorylation of the extracellular-signal regulated kinase (pERK-1/2) as an anatomical marker of neuronal activation, the present study investigated how dynamic mechanical allodynia is processed in the rat ventral mPFC (prelimbic and infralimbic cortex) after chronic constriction injury to the infraorbital nerve (IoN-CCI). Two weeks after unilateral IoN-CCI, rats showed a dramatic bilateral trigeminal dynamic mechanical allodynia. Light, moving stroking of the infraorbital skin resulted in strong, bilateral upregulation of pERK-1/2 in the ventral mPFC of IoN-CCI animals. pERK-1/2 was located in neuronal cells only. Stimulus-evoked pERK-1/2 immunopositive cell bodies displayed a rostrocaudal gradient and layer-selective distribution in the ventral mPFC, being predominant in the rostral ventral mPFC and in layers II-III and V-VI of the ventral mPFC. In layers II-III, intense pERK-1/2 also extended into distal dendrites, up to layer I. These results demonstrate that trigeminal nerve injury induces a significant alteration in the ventral mPFC processing of tactile stimuli and suggest that ERK phosphorylation contributes to the mechanisms underlying abnormal pain perception under this condition.

International audience; PURPOSE: About forty percent of the patients with primary Sjögren's syndrome (pSS) experience chronic neuropathic pain with normal electrodiagnostic studies. Two previous studies suggest that chronic neuropathic pain in pSS is due to small fiber neuropathy (SFN). Quantification of epidermal nerve fiber density after skin biopsy has been validated to diagnose small fiber neuropathy. METHODS: Skin biopsy was performed in 14 consecutive pSS patients (satisfying the american-european classification criteria) with chronic neuropathic pain and normal electrodiagnostic studies suggesting SFN. RéSULTS: Fourteen female pSS patients exhibited chronic neuropathic pain [burning sensation (n=14), prickling (n=4), dysesthesia (n=8)] with paroxystic exacerbations (n=10) and allodynia (n=13), for a mean period of 18.4±12.4 months. Neuropathic pain involved mostly hands and feet (n=13), with a distal (n=9) and leg (n=4) predominant distribution. Neurological examination disclosed normal deep tendon responses and absence of motor weakness (n=14). Small fiber neuropathy was confirmed by skin biopsy in 13 cases. Epidermal nerve fiber density was decreased in distal [(n=12), mean 3.5±1.7 fibers/mm (N>6.9)] and proximal site of biopsy [(n=9), mean 7.04±2.63 fibers/mm (N>9.3)]. CONCLUSION: Small fiber neuropathy is commonly responsible of chronic neuropathic pain in pSS. Prevalence, physiopathology and neurological evolution of such neuropathies still remain unknown.

MMNP; International audience; OBJECTIVE: Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, possibly by acting on neurogenic inflammation. Such a mechanism may be involved in peripheral neuropathic pain. METHODS: A possible direct analgesic effect of BTX-A pain processing was investigated in 29 patients with focal painful neuropathies and mechanical allodynia using a randomized, double-blind, placebo-controlled design. Patients received a one-time intradermal administration of BTX-A (20-190 units) into the painful area. Outcome measures, evaluated at baseline, then at 4, 12, and 24 weeks, included average spontaneous pain intensity, quantified testing of thermal and mechanical perception and pain, allodynia to brushing (area, intensity), neuropathic symptoms, clinical global impression, and quality of life. RESULTS: BTX-A treatment, relative to placebo, was associated with persistent effects on spontaneous pain intensity from 2 weeks after the injection to 14 weeks. These effects correlated with the preservation of thermal sensation at baseline (p < 0.05). BTX also improved allodynia to brush and decreased pain thresholds to cold, without affecting perception thresholds. There were sustained improvements in the proportion of responders (number needed to treat for 50% pain relief: 3.03 at 12 weeks), neuropathic symptoms, and general activity. Most patients reported pain during the injections, but there were no further local or systemic side effects. INTERPRETATION: These results indicate for the first time that BTX-A may induce direct analgesic effects in patients with chronic neuropathic pain independent of its effects on muscle tone and suggest novel indications for BTX-A in analgesia.

International audience; BACKGROUND: The therapeutic effect of antidepressant drugs against depression usually necessitates a chronic treatment. A large body of clinical evidence indicates that antidepressant drugs can also be highly effective against chronic neuropathic pain. However, the mechanism by which these drugs alleviate pain is still unclear. METHODS: We used a murine model of neuropathic pain induced by sciatic nerve constriction to study the antiallodynic properties of a chronic treatment with the tricyclic antidepressants nortriptyline and amitriptyline. Using knockout and pharmacological approaches in mice, we determined the influence of delta-opioid receptors in the therapeutic action of chronic antidepressant treatment. RESULTS: In our model, a chronic treatment by tricyclic antidepressant drugs totally suppresses the mechanical allodynia in neuropathic C57Bl/6J mice. This therapeutic effect can be acutely reversed by an injection of the delta-opioid receptor antagonist naltrindole. Moreover, the antiallodynic property of antidepressant treatment is absent in mice deficient for the delta-opioid receptor gene. CONCLUSIONS: The antiallodynic effect of chronic antidepressant treatment is mediated by a recruitment of the endogenous opioid system acting through delta-opioid receptors.

International audience; Entrapment of the pudendal nerve may be at the origin of chronic perineal pain. This syndrome must be diagnosed because this can result in the indication of surgical decompression of the entrapped nerve for pain relief. Electroneuromyographic (ENMG) investigation is often performed in this context, based on needle electromyography and the study of sacral reflex and pudendal nerve motor latencies. The limits of ENMG investigation, owing to various pathophysiological and technical considerations, should be known. The employed techniques do not assess directly the pathophysiological mechanisms of pain but rather correlate to structural alterations of the pudendal nerve (demyelination or axonal loss). In addition, only direct or reflex motor innervation is investigated, whereas sensory nerve conduction studies should be more sensitive to detect nerve compression. Finally, ENMG cannot differentiate entrapment from other causes of pudendal nerve lesion (stretch induced by surgical procedures, obstetrical damage, chronic constipation...). Thus, perineal ENMG has a limited sensitivity and specificity in the diagnosis of pudendal nerve entrapment syndrome and does not give direct information about pain mechanisms. Pudendal neuralgia related to nerve entrapment is mainly suspected on specific clinical features and perineal ENMG examination provides additional, but no definitive clues, for the diagnosis or the localization of the site of compression. In fact, the main value of ENMG is to assess objectively pudendal motor innervation when a surgical decompression is considered. Perineal ENMG might predict the outcome of surgery but is of no value for intraoperative monitoring.

International audience; We conducted a large nationwide postal survey to estimate the prevalence of chronic pain with or without neuropathic characteristics in the French general population. A questionnaire aimed at identifying chronic pain (defined as daily pain for at least 3 months), evaluating its intensity, duration and body locations, was sent to a representative sample of 30,155 subjects. The DN4 questionnaire was used to identify neuropathic characteristics. Of the questionnaires, 24,497 (81.2%) were returned and 23,712 (96.8%) could be assessed. Seven thousand five hundred and twenty-two respondents reported chronic pain (prevalence=31.7%; [95%CI: 31.1-32.3]) and 4709 said the pain intensity was moderate to severe (prevalence=19.9%; [95%CI: 19.5-20.4]). Neuropathic characteristics were reported by 1631 respondents with chronic pain (prevalence=6.9%; [95%CI: 6.6-7.2]), which was moderate to severe in 1209 (prevalence=5.1% [95%CI: 4.8-5.4]). A higher prevalence of chronic pain with neuropathic characteristics was associated with middle age (50-64 years), manual professions and those living in rural areas. It was more frequently located in the lower limbs and its intensity and duration were higher in comparison with chronic pain without neuropathic characteristics. This large national population-based study indicates that a significant proportion of chronic pain patients report neuropathic characteristics. We identified distinctive socio-demographic profile and clinical features indicating that chronic pain with neuropathic characteristics is a specific health problem.

International audience; Neurolytic blockade is one of the therapeutic possibilities to treat spasticity of various muscles. In patients with spasticity of the adductor thigh muscles, a percutaneous approach to the obturator nerve is often difficult. We describe a new approach to the obturator nerve and we examine its feasibility. The second objective was to assess the efficacy of obturator neurolysis for the management of adductor thigh muscle pain and spasticity associated with hemiplegia or paraplegia. Nerve blocks were performed via a combined approach using fluoroscopy and nerve stimulation to identify the obturator nerve. Neurolysis was performed by injection of 65% ethanol. We performed 27 blocks in 23 patients. Technical evaluation was achieved in terms of number of attempted needle insertions, time to accurate location of the nerve and success rate. The efficacy of the block was assessed using four scores: degree of alleviation of muscle spasm and triple flexion of the lower limb, improvement of gait and facilitation of hygienic care. Success rate of the technique was 100% with a time to accurate nerve location of 130+/-35 s. Compared with scores measured immediately before the block, all studied parameters were significantly improved. Efficiency was significant on adductor muscle spasticity (p