Inflammatory Cytokine-Mediated Interactions Between Pain and Insomnia: Mechanisms and Therapeutic Implications.

Inflammatory cytokines, as key signaling molecules linking the immune, nervous, and endocrine systems, may contribute to the interaction between pain and insomnia. This narrative review summarizes recent research on the mechanisms underlying inflammatory cytokine-mediated interactions between pain and insomnia, with a focus on the roles of inflammatory cytokines in insomnia-related inflammatory responses, pain sensitization, and the bidirectional regulatory loop between pain and insomnia. Current evidence indicates that chronic insomnia may promote a low-grade inflammatory state through mechanisms involving hypothalamic-pituitary-adrenal (HPA) axis dysfunction, sympathetic nervous system dysregulation, and circadian rhythm disturbances. It is also associated with alterations in pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Chronic pain, in turn, may affect the sleep-wake regulatory network through sustained nociceptive input, peripheral inflammatory signaling, central sensitization, and glial cell activation, thereby further exacerbating sleep disturbances. With the involvement of inflammatory cytokines, pain and insomnia may form a mutually reinforcing pathological loop. However, current evidence regarding inflammatory cytokine-mediated interactions between pain and insomnia is primarily derived from preclinical and observational studies. The validation of these mechanisms in humans and their clinical translational relevance require further clarification through well-designed clinical studies. Future research should further elucidate the temporal relationships among inflammatory cytokines, sleep disturbances, and pain sensitization, establish inflammation-based patient stratification approaches, and explore the potential value of inflammation-targeted and neuroimmune regulatory strategies in the management of pain-insomnia comorbidity.