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

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.