The widely used antihistamine mepyramine causes topical pain relief through direct blockade of nociceptor sodium channels.

Autor: Hao J; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Brosse L; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Bonnet C; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Ducrocq M; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Padilla F; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Penalba V; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Desplat A; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Ruel J; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France., Delmas P; Laboratoire de Neurosciences Cognitives, UMR 7291, CNRS, Aix-Marseille-Université, Marseille Cedex 15, France.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Dec; Vol. 35 (12), pp. e22025.
DOI: 10.1096/fj.202100976RR
Abstrakt: Mepyramine, a first-generation antihistamine targeting the histamine H(1) receptor, was extensively prescribed to patients suffering from allergic reactions and urticaria. Serious adverse effects, especially in case of overdose, were frequently reported, including drowsiness, impaired thinking, convulsion, and coma. Many of these side effects were associated with the blockade of histaminergic or cholinergic receptors. Here we show that mepyramine directly inhibits a variety of voltage-gated sodium channels, including the Tetrodotoxin-sensitive isoforms and the main isoforms (Nav1.7, Nav1.8, and Nav1.9) of nociceptors. Estimated IC 50 were within the range of drug concentrations detected in poisoned patients. Mepyramine inhibited sodium channels through fast- or slow-inactivated state preference depending on the isoform. Moreover, mepyramine inhibited the firing responses of C- and Aβ-type nerve fibers in ex vivo skin-nerve preparations. Locally applied mepyramine had analgesic effects on the scorpion toxin-induced excruciating pain and produced pain relief in acute, inflammatory, and chronic pain models. Collectively, these data provide evidence that mepyramine has the potential to be developed as a topical analgesic agent.
(© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
Externí odkaz: