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

Abstract

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 IC50 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.

Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor

“…Like many other first-generation antihistamines, mepyramine can cross the blood‒brain barrier and often causes serious side effects, such as drowsiness. Recently, mepyramine has been shown to bind to a variety of voltage-gated sodium channels and directly inhibit their activity, so mepyramine has the potential to be developed as a topical analgesic agent 33 . Deciphering the recognition details of mepyramine by each individual target receptor will provide valuable clues for further optimization of the drug for improved specificity and efficacy.…”