Alain Eschalier

CYCLOPHOSPHAMIDE-INDUCED CYSTITIS IN FREELY-MOVING CONSCIOUS RATS: BEHAVIORAL APPROACH TO A NEW MODEL OF VISCERAL PAIN

PURPOSEnTo develop a model of visceral pain in rats using a behavioral approach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic effects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis.nnnMATERIALS AND METHODSnCP was administered at doses of 50, 100 and 200 mg./kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addition, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examination. Finally, to show that the bladder is essential for the CP-induced behavioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v.nnnRESULTSnCP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specific postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pretreatment with naloxone. At the time of administration of morphine, histological modifications of the bladder wall, such as chorionic and muscle layer edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the same marked behavioral modifications as those observed in male rats. Administered at the dose of 20 mg. intravesically, CP did not produce any behavioral effects, whereas acrolein at 0.5 mg. intravesically induced behavioral modifications identical to those under CP 200 mg./kg. i.p., with the same maximal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavioral effects at all.nnnCONCLUSIONSnOverall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.

Blockade of supraspinal 5-HT1A receptors potentiates the inhibitory effect of venlafaxine on wind-up activity in mononeuropathic rats

In mononeuropathic rats submitted to a C-fiber reflex responses paradigm, repeated administration (five successive injections every half-life) of 10 mg/kg, s.c. of venlafaxine, but not of 2.5 mg/kg, s.c., a mixed monoamine reuptake inhibitor with preferential inhibitory activity in 5-HT reuptake, induced a progressive reduction of spinal wind-up. Repeated co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 i.c.v. (50 microg/injection) significantly increased the effect of venlafaxine s.c., indicating that venlafaxine-induced inhibition of spinal wind-up in mononeuropathic rats is potentiated by blockade of central 5-HT1A receptors.

Paracetamol: Update on its Analgesic Mechanism of Action

Paracetamol is the most widely used over-the-counter medication in the world. The mechanism of action of its analgesic effect was often considered as based on the mobilization of the cyclooxygenases and more recently on serotonergic pathways. A new metabolic pathway involving the generation of an active metabolite, AM404 (N-(4Hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), in the brain by the fatty acid amide hydrolase (FAAH) enzyme, was recently identified. This chapter describes experimental data that have shown the involvement of this metabolic pathway in the analgesic action of paracetamol and its relationship with the cyclooxygenase and serotonergic systems. It also explains how new targets and systems, such as the cannabinoid and vanilloid systems and the calcium channel receptor Cav3.2, play a role in the action of paracetamol. Finally, it suggests how research on the mechanism of the clinically relevant effects of this long-established analgesic could lead to new therapeutic pain strategies.

Implication des canaux ioniques dans l'hypersensibilité au froid induite par l'oxaliplatine

Loxaliplatine, largement utilise dans le traitement du cancer colorectal, se singularise par la survenue tres precoce, des le debut du protocole de chimiotherapie de troubles douloureux associes a la perception du froid (hypersensibilite au froid). De nombreux traitements ont ete testes pour ces symptomes sans grand succes, cest pourquoi le developpement de nouveaux analgesiques est necessaire. Le but de ce travail est de developper un modele souris reproduisant cette hypersensibilite au froid et den rechercher les mecanismes physiopathologiques. Comme chez les patients, ladministration aigue doxaliplatine entraine une amplification importante de la perception du froid chez la souris. Nous montrons que ces symptomes sont medies par les nocicepteurs exprimant le thermorecepteur TRPM8. Sur le plan du mecanisme physiopathologique, loxaliplatine favorise lexcitabilite de ces nocicepteurs en diminuant de maniere drastique lexpression des plusieurs canaux potassiques (TREK1 et TRAAK en particulier), et en augmentant lexpression de canaux proexcitateurs tels que les canaux cationiques actives par lhyperpolarisation (HCN1 notamment). Ces constatations sont confortees au niveau comportemental par lanalyse de la lignee de souris double KO pour TREK1 et TRAAK, et par lutilisation de lIvabradine, un inhibiteur pharmacologique specifique des canaux HCNs. Livabradine, deja utilise en clinique pour le traitement de linsuffisance cardiaque, entraine une disparition de lhypersensibilite au froid induite par loxaliplatine. Collectivement, ces resultats suggerent que loxaliplatine exacerbe la perception du froid en remodelant le patron dexpression de plusieurs canaux ioniques qui coordonnent la reponse au froid. Livabradine peut ainsi representer un traitement sur mesure pour les neuropathies induites par loxaliplatine.