Peripheral sensory clocks drive nitroglycerin-induced rhythmic pain sensitivity

Mounting evidence has revealed circadian rhythms in pain sensitivity across multiple pain conditions, but the mechanisms that generate these rhythmic pain sensitivities remain unclear. We combined genetic models with tissue-specific knockout of the essential clock gene Bmal1 generated and a well-established nitroglycerin (NTG)–induced headache mouse model. Von Frey assays were performed to measure mechanical hypersensitivity at different times of the day. Circadian activity behavior, sleep and clock gene expression were also measured. Using trigeminal ganglion (TG) and dorsal root ganglion (DRG) sensory neuron–specific Bmal1 knockout mice, we show that, in both male and female mice, loss of Bmal1 completely abolishes the diurnal rhythm of pain sensitivity but does not perturb basal nociception of NTG-induced hypersensitivity. In contrast, suprachiasmatic nucleus (SCN)-specific Bmal1 deletion in male mice eliminates circadian locomotor rhythms without altering rhythmic pain sensitivity, demonstrating that the central pacemaker SCN is not required for circadian rhythms of pain sensitivity. Dual deletion of Bmal1 in both SCN and sensory neurons replicates the sensory neuron–specific phenotype, confirming the dominant role of the peripheral sensory neuron clocks in male mice. Although sensory neuron Bmal1 loss alters sleep architecture, the free-running circadian period length remains intact. Together, these findings reveal that local molecular clocks in the peripheral nervous system drive diurnal rhythmicity of NTG-induced pain independently of the SCN.