Nociceptor circadian clock genes control excitability and pain perception in mice in a sex- and time-dependent manner

Nociception is critical for pain perception and survival and begins with the activation of nociceptors, specialized sensory neurons located in the dorsal root ganglia (DRGs). Both sex and circadian rhythms, governed by clock genes, seem to play a significant role in modulating pain perception. However, the potential interaction between circadian rhythms and sex differences in nociception at the peripheral level has been largely overlooked. Here, we first report that DRGs from mice express core clock genes in a time- and sex-dependent manner. Using whole-cell recordings in intact DRGs and optogenetic stimulation of Nav1.8-expressing neurons, we demonstrate that male nociceptors exhibit reduced excitability during the night, while female nociceptor excitability remains stable across time points. Disruption of the core clock gene Bmal1 in Nav1.8-expressing neurons not only diminished nociceptor activity but also abolished the nighttime reduction in heat sensitivity observed in males, highlighting a pivotal role for the molecular clock in regulating nociception. Transcriptomic and immunohistochemistry analyses, voltage-clamp recordings, and pharmacological experiments identified the voltage-gated chloride channel ClC-2 as a key mediator for the observed fluctuations in male nociceptor excitability and heat sensitivity. This work opens promising avenues for chronobiology-inspired strategies in pain management tailored to sex-specific mechanisms.