Nociceptor circadian clock genes control excitability and pain perception in mice in a sex- and time-dependent manner
Source: Nature communications
Authors: Aurélie Brécier, Courtney A Bannerman, Yu-Feng Xie, Christopher Dedek, Amanda M Zacharias, Ciara D O’Connor, Aitana Rickert Llàcer, Steven D Miller, Vina W Li, Christina Meier, Laurel L Ballantyne, Justin Du Bois, Qingling Duan, Steven A Prescott, Nader Ghasemlou, Publication Date: Tue, 02 Jun 2026 06:00:00 -0400
Nat Commun. 2026 Jun 1. doi: 10.1038/s41467-026-73772-z. Online ahead of print.
ABSTRACT
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.
PMID:42230621 | DOI:10.1038/s41467-026-73772-z
Pubmed ID: pubmed:42230621
Identifiers: pmid:42230621, doi:10.1038/s41467-026-73772-z,
Paper chosen by Rajesh Khanna
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Pain perception is shaped by both sex and circadian rhythms, but whether the body clock and sex differences interact at the level of the peripheral sensory neurons that detect pain had been largely unexamined. Studying dorsal root ganglia (DRG) in mice, Brécier et al. found that nociceptors express core clock genes in patterns that vary by both time of day and sex. Using whole-cell recordings in intact DRG and optogenetic stimulation of NaV1.8-expressing neurons, they showed that male nociceptors become less excitable at night, whereas female nociceptor excitability stays constant across the day. Deleting the core clock gene Bmal1 in NaV1.8 neurons reduced nociceptor activity and erased the nighttime drop in heat sensitivity seen in males, confirming the molecular clock as a direct regulator of nociception. Transcriptomic, immunohistochemical, voltage-clamp, and pharmacological work identified the voltage-gated chloride channel ClC-2 as the mediator of these male-specific, time-dependent shifts in excitability.
Why this is exciting: it is the first demonstration that the circadian clock tunes pain sensitivity directly within peripheral nociceptors in a sex-specific way, linking a clock gene to a defined ion channel (ClC-2). This reframes pain as something that fluctuates by time of day differently in males and females, opening the door to chronobiology-informed treatment, where when a drug is given, and to whom, may matter as much as what is given.