Pain intensity fluctuates across the day in patients, yet the cellular clock mechanisms that generate pain rhythmicity and their therapeutic potential remain poorly defined. Prior studies have established circadian variation in nociception and a requirement for intact clock function, but it has remained unclear the neurophysiological mechanisms which translate clock state into time-of-day changes in pain. The goal of this study was to define the clock component(s) and effector pathway(s) that drive pain rhythmicity and to test whether this axis can be exploited for analgesia. We combined behavioural analyses under circadian conditions with genetic dissection of clock components in sensory neurons, electrophysiological interrogation of nociceptor excitability, and pharmacological modulation of the clock machinery. To establish translational relevance, we used human iPSC-derived nociceptors, including a human pain disease model, to test whether the same clock-excitability coupling operates in human cells. We show that nociceptive behaviours exhibit robust circadian rhythmicity and that this rhythmicity depends on the molecular clock within peripheral sensory neurons. Loss of cryptochromes CRY1/CRY2 disrupts time-of-day differences in nociceptor excitability, identifying cryptochromes as essential clock effectors in the pain pathway. Mechanistically, cryptochrome state controls voltage-gated sodium channel function, providing a direct link from clock machinery to nociceptor responsiveness. Pharmacological stabilisation of cryptochromes using a small-molecule modulator suppresses sodium currents and reduces nociceptive responses across distinct pain paradigms, and this effect is abrogated when cryptochrome function is absent. In synchronised human iPSC-derived nociceptors, we observe concordant clock-state-dependent changes in excitability, and cryptochrome stabilisation reduces hyperexcitability. These findings identify a peripheral sensory neuron clock mechanism that drives pain rhythmicity through cryptochrome-dependent control of sodium channel function and highlight cryptochrome stabilisation as a non-opioid therapeutic strategy for pain disorders with diurnal symptom variation.
