Cryptochrome Stabilization Ameliorates Chronic Pain

Physiological and pathological pain exhibits striking diurnal variation, but the underlying mechanisms are largely unknown. We now describe an independent molecular clock in peripheral sensory neurons and satellite glial cells of sensory ganglia. We show that it is the sensory neuron transcription-translation feedback loops (TTFLs) that are responsible for diurnal pain behaviors. This clock regulates diurnal neurophysiological responses to a range of ligands, as well as synaptic activities of primary nociceptors. Furthermore, we find that loss of Cry1 and Cry2 , the repressive arm of the core TTFLs, intensifies pain responses associated with increased voltage-gated sodium channel currents. Conversely, stabilization of CRY1 and CRY2 using the small molecule KL001, reduces pain sensitivity. Our results highlight novel opportunities to address chronic pain by directly harnessing circadian mechanisms. One-Sentence Summary A peripheral pain clock governs daily pain fluctuations, which can be harnessed for treating pain disorders.