The interplay among circadian rhythm, pain and affective disorders and the underlying mechanisms

<p indent="0mm">Most organisms exhibit the phenomenon of circadian rhythm, which is driven by the self-sustained, endogenous oscillations generated by circadian clocks under the entrainment of external light. Pain perception and emotional states, and some of their corresponding pathological states such as chronic pain and affective disorders, can exhibit circadian rhythm. An increasing amount of evidence demonstrates that nociceptive threshold and mood states fluctuate across the 24-hour cycle. Conversely, circadian rhythm affects pain perception and affection. Sleep disorders resulting from circadian rhythm disruptions can increase the risk of developing affective disorders or chronic pain. Mutations in circadian clock genes, for example, <italic>Per2</italic> and <italic>Clock</italic>, can not only lead to disruptions in circadian rhythms and sleep disorders, but may also contribute to mood disorders such as winter depression and somatic sensory abnormality such as chronic pain. Clinically, there is a significant comorbidity among sleep disorders, chronic pain, and mood disorders, with underlying mechanisms linked to shared brain regions, cellular mechanisms, neurotransmitters, and the corresponding receptors. The raphe nucleus, a midbrain structure that is enriched in serotonergic neurons, projects to diverse brain regions, including cortical and subcortical areas. It serves as a hub modulating dopaminergic system and serotonergic system and we speculate that it may act as a “central brain region” regulating the comorbidity of circadian rhythm disorders, chronic pain, and mood disorders. The current paper elucidates the interrelationships among circadian rhythms, pain, and mood disorders, as well as the interactions among the three, and summarizes the potential critical brain regions and the underlying molecular mechanisms involved in the interactions. Based on the current research, we hypothesize that the raphe nucleus might serve as one of the critical brain regions mediating the interactions through its regulation on the serotonergic and dopaminergic systems, which provides a new theoretical framework for understanding the mechanisms of the comorbidity. In addition, we attempt to analyze the limitations in the current studies of the comorbidity of sleep disorder, mood disorder and chronic pain. Building upon these critical gaps, we provide an outlook on future research directions, aiming to promote the in-depth exploration of the mechanisms for the comorbidity of circadian rhythm disorders, chronic pain, and mood disorders, and offer new ideas for the clinical treatment of the related diseases. We hope to catalyze a paradigm shift from phenomenological observation to mechanism-driven therapeutics, ultimately enabling precision interventions that concurrently target pain, mood disorder and circadian rhythm disruption in treatment for refractory diseases.