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Neuronal rhythmogenesis in the spinal cord is correlated with variations in extracellular K + levels ([K + ] e ). Astrocytes play important role in [K + ] e homeostasis and compute neuronal information. Yet it is unclear how neuronal oscillations are regulated by astrocytic K + homeostasis. Here we identify the astrocytic inward-rectifying K + channel Kir4.1 (a.k.a. Kcnj10) as a key molecular player for neuronal rhythmicity in the spinal central pattern generator (CPG). By combining two-photon calcium imaging with electrophysiology, immunohistochemistry and genetic tools, we report that astrocytes display Ca 2+ transients before and during oscillations of neighboring neurons. Inhibition of astrocytic Ca 2+-transients with BAPTA decreases the barium-sensitive Kir4.1 current responsible of K + clearance. Finally, we show in mice that Kir4.1 knockdown in astrocytes progressively prevents neuronal oscillations and alters the locomotor pattern resulting in lower motor performances in challenging tasks. These data identify astroglial Kir4.1 channels as key regulators of neuronal rhythmogenesis in the CPG driving locomotion.

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.