[Circadian clock gene-mediated regulation of chronic pain pathophysiology]

Many physiological functions in humans and other mammals exhibit circadian rhythms with an approximate 24-hour period, enabling efficient adaptation to periodic environmental changes driven by the Earth's rotation. Clock genes generate circadian rhythms at the cellular level through transcription-translation feedback loops and contribute to the maintenance of physiological homeostasis. Accordingly, dysfunction of clock genes or chronic disruption of circadian rhythms has been implicated in increased disease risk and exacerbation of pathological conditions, and accumulating evidence indicates their involvement in the development and regulation of chronic pain disorders, including neuropathic pain and cancer-associated pain. For example, dysfunction of the clock gene Period2 circadian regulation of sleep-wake cycles and hormone secretion; however, Period2-defective mice do not develop neuropathic pain even after peripheral nerve injury. This phenotype is attributed to enhanced expression of adrenergic α1D receptors in the spinal dorsal horn, leading to increased endocannabinoid production, suggesting the existence of a previously unrecognized pain-inhibitory pathway. In addition, Rev-erbs, a class of nuclear receptors functioning as clock genes, are involved in circadian regulation and periodically suppress the expression of lipocalin-2 in the spinal cord. During the development of cancer-related pain, circadian control of lipocalin-2 expression contributes to daily fluctuations in pain thresholds. Artificial ligands targeting Rev-erbs are therefore suggested to alleviate cancer pain by suppressing lipocalin-2 expression. Collectively, functional analysis of clock genes in pain disorders is expected not only to deepen understanding of pathophysiology but also to facilitate identification of novel therapeutic targets and development of new analgesics from a chronobiological perspective.