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Papers of the Week

Papers: 27 Mar 2021 - 2 Apr 2021

Animal Studies, Pharmacology/Drug Development

2021 Mar 24


Action of mefloquine/amitriptyline THN101 combination on neuropathic mechanical hypersensitivity in mice.


Letellier B, Kremer M, Becker Léa J, Andry V, Goumon Y, Leboulleux Q, Hener P, Inquimbert P, Couqueberg N, Waltisperger E, Yalcin I, Mouthon F, Droguerre M, Charvériat M, Barrot M
Pain. 2021 Mar 24.
PMID: 33769363.


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.