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Les récepteurs des protons et de la capsaïcine: Contribution à la physiologie et la physiopathologie de la douleur

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Douleur et Analgésie

Résumé

Les structures moléculaires de deux canaux ioniques activés par des ligands et présents dans les terminaisons nerveuses sensorielles nociceptives, le récepteur des protons ASIC et le récepteur de la capsaicine VR1, ont été récemment élucidées. Les canaux ASIC sont des canaux cationiques plutôt sélectifs pour le Na+ qui sont activés directement par une diminution du pH extracellulaire. Ils appartiennent à la superfamille des canaux Na+ sensibles à l’amiloride. Ils sont formés de plusieurs sous-unités homologues dont certaines sont aussi présentes dans le système nerveux central et qui peuvent s’assembler en homo- ou en hétéro-multiméres. Une combinaison particulière spécifique des neurones sensoriels (ASIC2b et ASIC3) a des propriétés proches de celles du cannal natif qui a été impliqué dans la perception de la douleur associée à une acidose tissulaire. VR1 est un canal cationique non sélectif très perméable au Ca2+ qui possède une structure différente de celle des canaux ASIC mais semblable à celle des canaux activés par la déplétion des stocks intracellulaires de Ca2+ VR1 est spécifiquement exprimé dans les neurones sensoriels et il est activé directement par les vanilliques comme la capsaicine. Il est surtout activé par la chaleur dans une gamme de températures douloureuses (à partir de 43°C). Ce seuil est considérablement abaissé par une diminution du pH extracellulaire et VR1 peut être activé à des températures physiologiques dans certaines conditions d’acidose. L’obtention de ces nouveaux outils moléculaires devrait permettre de mieux comprendre les mécanismes de la douleur associés à ces deux récepteurs et d’envisager le développement de nouveaux analgésiques capables de moduler leur activité.

Summary

The molecular cloning of two ligand-gated ion channels present in the primary afferent nociceptor terminal, i.e., the acid sensing ion channel ASIC and the capsaicin receptor VR1, was recently completed. ASICs are cationic channels rather selective for Na+ that are directly activated by a drop in the extracellular pH. They belong to the superfamily of amiloride-sensitive Na+ channels. They are composed of several homologous subunits, some of them being also present in the central nervous system, that can assemble in homo- or heteromultimers. A particular combination in the sensory neurons (ASIC2b and ASIC3) displays properties very close to that of the native channel involved in the perception of the non-adaptive pain associated with tissue acidosis. VR1 is a non-selective cationic channel that displays a high selectivity for Ca2+ and possess a structure different from that of ASIC but similar to that of store-operated channels (SOC). VR1 is specifically expressed in sensory neurons and is directly activated by vanilloid compounds like capsaicin. VR1 is also activated by noxious heat. The threshold for heat-evoked response is lowered by a decrease in the extracellular pH and VR1 is activated at normal physiological temperatures in the presence of low pH. The availability of these novel molecular probes will be important to study the pain mechanisms associated with these receptors and to develop new analgesic drugs that can modulate their activity.

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  1. CR2 INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UPR 411, 660, route des Lucioles, F-06560, Valbonne

    E. Lingueglia

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Texte présenté d’un cours de perfectionnement, intitulé «Douleur et Canaux loniques» qui s’est tenu dans le cadre de la 22e réunion annuelle de la SFD, le 19 novembre 1998 à Versailles.

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Lingueglia, E. Les récepteurs des protons et de la capsaïcine: Contribution à la physiologie et la physiopathologie de la douleur. Doul. et Analg. 12, 243–249 (1999). https://doi.org/10.1007/BF03008489

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