Eric Salvat

The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the cuff model of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed.

The antiallodynic action of nortriptyline and terbutaline is mediated by β2 adrenoceptors and δ opioid receptors in the ob/ob model of diabetic polyneuropathy

Peripheral polyneuropathy is a frequent complication of diabetes. One of its consequences is neuropathic pain which is often chronic and difficult to treat. This pain management classically involves anticonvulsant drugs or tricyclic antidepressant drugs (TCA). We have previously shown that β2 adrenoceptors and δ opioid receptors are critical for TCA action in a traumatic model of neuropathic pain. In the present work, we used the obese leptin deficient mice (ob/ob) which are a genetic model of type 2 diabetes in order to study the treatment of diabetic polyneuropathy. ob/ob mice with hyperglycemia develop tactile bilateral allodynia. We investigated the action of the TCA nortriptyline and the β2 adrenoceptor agonist terbutaline on this neuropathic allodynia. The consequences of acute and chronic treatments were tested, and mechanical allodynia was assessed by using von Frey hairs. Chronic but not acute treatment with nortriptyline alleviates allodynia caused by the diabetic neuropathy. This effect depends on β2 adrenoceptors but not on α2 adrenoceptors, as shown by the blockade with repeated co-administration of the β2 adrenoceptor antagonist ICI118551 but not with repeated co-administration of the α2 adrenoceptor antagonist yohimbine. Direct stimulation of β2 adrenoceptors appears sufficient to relieve allodynia, as shown with chronic terbutaline treatment. δ but not mu opioid receptors seem important to these action since acute naltrindole, but not acute naloxonazine, reverses the effect of chronic nortriptyline or terbutaline treatment.

Neurophysiological responses to unpleasant stimuli (acute electrical stimulations and emotional pictures) are increased in patients with schizophrenia

Patients with schizophrenia have often been described as insensitive to nociceptive signals, but objective evidence is sparse. We address this question by combining subjective behavioral and objective neurochemical and neurophysiological measures. The present study involved 21 stabilized and mildly symptomatic patients with schizophrenia and 21 control subjects. We applied electrical stimulations below the pain threshold and assessed sensations of pain and unpleasantness with rating scales, and Somatosensory Evoked Potentials (SEPs/EEG). We also measured attention, two neurochemical stress indices (ACTH/cortisol), and subjective VEPs/EEG responses to visual emotional stimuli. Our results revealed that, subjectively, patients’ evaluations do not differ from controls. However, the amplitude of EEG evoked potentials was greater in patients than controls as early as 50u2009ms after electrical stimulations and beyond one second after visual processing of emotional pictures. Such responses could not be linked to the stress induced by the stimulations, since stress hormone levels were stable. Nor was there a difference between patients and controls in respect of attention performance and tactile sensitivity. Taken together, all indices measured in patients in our study were either heightened or equivalent relative to healthy volunteers.

A comparison of early and late treatments on allodynia and its chronification in experimental neuropathic pain

Background Surgeries causing nerve injury can result in chronic neuropathic pain, which is clinically managed by using antidepressant or anticonvulsant drugs. Currently, there is a growing interest for investigating preemptive treatments that would prevent this long-term development of neuropathic pain. Our aim was to compare analgesic drugs using two distinct treatment modalities: either treatment onset at surgery time or following a couple of weeks of neuropathic pain. Methods In male C57BL/6J mice, neuropathic pain was induced by cuffing the sciatic nerve, and allodynia was assessed using von Frey filaments. We tested the effect of anticonvulsants (gabapentin 10u2009mg/kg and carbamazepine 40u2009mg/kg), antidepressants (desipramine 5u2009mg/kg, duloxetine 10u2009mg/kg, and fluoxetine 10u2009mg/kg), dexamethasone (2u2009mg/kg), and ketamine (15u2009mg/kg). Drugs were injected daily or twice a day, starting either at surgery time or on day 25 postsurgery (15 days of treatment for antidepressants and 10 days for other drugs). Results Ketamine was the only effective treatment during the early postsurgical period. Although early anticonvulsant treatment was not immediately effective, it prevented chronification of allodynia. When treatments started at day 25 postsurgery, desipramine, duloxetine, and anticonvulsants suppressed the mechanical allodynia. Conclusions Our data show that allodynia measured in experimental neuropathic pain model likely results from a combination of different processes (early vs. late allodynia) that display different sensitivity to treatments. We also propose that early anticonvulsant treatment with gabapentin or carbamazepine may have a prophylactic effect on the chronification of allodynia following nerve injury.

Tests and Models to Study Pain in Animal-Based Translational Research

Nociceptive reflexes are predominant in traditional “pain” tests using rodents. However, pain is not a nociceptive reflex, but an unpleasant personal experience associated with a complex sensory, emotional and cognitive phenomenology. Modern research methods in behavioral neuroscience have now enabled preclinical pain researchers to develop procedures which differentially combine reflex and non-reflex based measures, thus making various aspects of pain experience experimentally accessible in rodents. These aspects include the aversive component, anxiodepressive and cognitive consequences of pain as well as pain empathy. Rodents are also highly sensitive to their environmental context, and can accordingly attribute different contextual meaning to different experimental situations. This chapter summarizes classically used nociceptive tests, but mainly focuses on the recent developments highlighting the possibility to address the complex experience of pain in rodents.

Phenylpyridine-2-ylguanidines and rigid mimetics as novel inhibitors of TNFα overproduction: Beneficial action in models of neuropathic pain and of acute lung inflammation

4-phenylpyridin-2-yl-guanidine (5b): a new inhibitor of the overproduction of pro-inflammatory cytokines (TNFα and Il1β) was identified from a high-throughput screening of a chemical library on human peripheral blood mononuclear cells (PBMCs) after LPS stimulation. Derivatives, homologues and rigid mimetics of 5b were designed and synthesized, and their cytotoxicity and ability to inhibit TNFα overproduction were evaluated. Among them, compound 5b and its mimetic 12 (2-aminodihydroquinazoline) showed similar inhibitory activities, and were evaluated in vivo in models of lung inflammation and neuropathic pain in mice. In particular, compound 12 proved to be active (5u202fmg/kg, ip) in both models.

Médecine factuelle (EBM) et traitement des douleurs

L’EBM ou medecine factuelle est l’utilisation judicieuse chez un patient donne des meilleures preuves disponibles pour traiter la pathologie qu’il presente. Ces preuves sont obtenues a partir de l’analyse de la litterature de qualite publiee a propos de la pathologie en question. En matiere de douleurs chroniques, plusieurs ecueils viennent contrecarrer les bonnes intentions de l’EBM : l’imprecision de bon nombre de cadres nosographiques, avec, de fait, bien souvent, une meconnaissance de la physiopathologie correspondante ; la notion de plasticite des voies nociceptives qui fait qu’une douleur chronique peut modifier les « circuits neuronaux » et leur reponse aux traitements actifs dans une douleur aigue ; la plainte douloureuse depasse largement le fait physiologique et inclut dans ses determinants des facteurs personnels et environnementaux ; ce qui fait que la litterature de qualite est rare. A cote de therapeutiques validees (alcoolisation splanchnique dans la douleur solaire d’origine cancereuse, psychotropes dans les douleurs neuropathiques), d’autres paraissent efficaces, mais il manque des preuves (peridurale aux corticoides dans les radiculalgies, stimulation electrique dans les douleurs neuropathiques, etc.), et d’autres encore sont, a defaut d’essais bien conduits, a considerer comme equivalentes au placebo.