TRPM8 is a non-canonical target of 7-nitrobenzodiazepines

Benzodiazepines are widely prescribed therapeutics whose actions are primarily attributed to the modulation of GABA_A receptors. Here, we identify a previously unrecognized target of a subset of benzodiazepines-the cold- and menthol-sensitive ion channel TRPM8 (transient receptor potential melastatin 8). Clonazepam and related 7-nitrobenzodiazepines act as potent TRPM8 agonists, eliciting calcium influx and membrane depolarization in heterologous expression systems, native human cells, and trigeminal sensory neurons. Pharmacological inhibition, genetic knockdown, and gene deletion of TRPM8 abolish clonazepam-evoked responses, establishing TRPM8 as the relevant molecular target. Mechanistically, clonazepam shares pharmacological features with icilin, a canonical TRPM8 agonist, and engages conserved determinants of channel activation. These findings expand the pharmacology of benzodiazepines beyond GABA_A receptors and suggest that TRPM8 activation may contribute to the clinical efficacy of clonazepam in burning mouth disorder and other sensory neuropathic conditions.