1. Action of mefloquine/amitriptyline THN101 combination on neuropathic mechanical hypersensitivity in mice
- Author
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Franck Mouthon, Nolwenn Couqueberg, Virginie Andry, Perrine Inquimbert, Quentin Leboulleux, Marine Droguerre, Baptiste Letellier, Pierre Hener, Michel Barrot, Ipek Yalcin, Mathieu Charvériat, Mélanie Kremer, Yannick Goumon, Elisabeth Waltisperger, Léa J. Becker, Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Yalcin, Ipek, and Theranexus [Lyon]
- Subjects
Amitriptyline ,[SDV]Life Sciences [q-bio] ,Carbenoxolone ,Antidepressive Agents, Tricyclic ,Pharmacology ,Neuropathic pain ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Mefloquine ,business.industry ,Long-term potentiation ,Antidepressive Agents ,Rats ,3. Good health ,[SDV] Life Sciences [q-bio] ,Anesthesiology and Pain Medicine ,Neurology ,chemistry ,Neuralgia ,Antidepressant ,Neurology (clinical) ,Serotonin ,business ,030217 neurology & neurosurgery ,Research Paper ,Tricyclic ,medicine.drug - Abstract
Supplemental Digital Content is Available in the Text. Mefloquine/amitriptyline THN101 combination reduces cuff-induced neuropathic hypersensitivity by recruiting noradrenergic descending pathways and α2 adrenoceptors and by blocking connexin in mice., 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 antihyperalgesic effect of amitriptyline, a widely used antidepressant. In this 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. In addition, we showed that this potentiation was not due to pharmacokinetic interactions between the 2 drugs. Besides, lesional and pharmacological approaches showed that the prolonged effect was induced through noradrenergic descending pathways and the recruitment of α2 adrenoceptors. 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.
- Published
- 2021