Action of mefloquine/amitriptyline THN101 combination on neuropathic mechanical hypersensitivity in mice.
Fiche publication
Date publication
mars 2021
Journal
Pain
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GOUMON Yannick, Dr KREMER Mélanie, Dr YALCIN CHRISTMANN Ipek
Tous les auteurs :
Letellier B, Kremer M, Becker LJ, Andry V, Goumon Y, Leboulleux Q, Hener P, Inquimbert P, Couqueberg N, Waltisperger E, Yalcin I, Mouthon F, Droguerre M, Charvériat M, Barrot M
Lien Pubmed
Résumé
Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and, importantly, connexins - transmembrane proteins involved in cell-cell communication - contribute to these interactions. In a neuropathic pain model in rats, mefloquine, a connexin inhibitor, has been shown to potentiate the anti-hyperalgesic effect of amitriptyline, a widely used antidepressant. In the present study, we further investigated this improvement of amitriptyline action by mefloquine, using the cuff model of neuropathic pain in mice. We first observed that oral mefloquine co-treatment prolonged the effect of amitriptyline on mechanical hypersensitivity by 12 hours after administration. Additionally, we showed that this potentiation was not due to pharmacokinetic interactions between the two drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenergic receptors. Another connexin blocker, carbenoxolone, also improved amitriptyline action. Additional in vitro studies suggested that mefloquine may also directly act on serotonin transporters and on adenosine A1 and A2A receptors, but drugs acting on these other targets failed to amplify amitriptyline action. Together, our data indicate that pharmacological blockade of connexins potentiates the therapeutic effect of amitriptyline in neuropathic pain.
Référence
Pain. 2021 Mar 24;: