Orexin Receptor Antagonism Improves Sleep Quality and Mitigates Lipopolysaccharide‐Induced Inflammatory Responses in a Mouse Model

Alterations in the immune system, stemming from sleep/wakefulness disorders, increase the risk of inflammatory pathologies. Orexin, a hypothalamic neuropeptide, regulates sleep and wakefulness. However, the role of orexin in inflammatory responses-whether it is protective or pathological-is still unclear. In this study, our aim was to elucidate the role of orexin in sleep and inflammatory states through the examination of a lipopolysaccharide (LPS)-induced systemic inflammatory model and the effects of daridorexant, a dual orexin receptor antagonist. Intraperitoneal LPS administration significantly decreased rapid eye-movement (REM) sleep and wakefulness while increasing non-REM sleep. Pretreatment with daridorexant enhanced REM sleep recovery in LPS-induced systemic inflammation, evidenced by extended duration and increased episode frequency. Transcriptomic profiling demonstrated a rise in the expression of pro-inflammatory cytokines (Cxcl1, Ccl2, Ccl7, and Tnf) within the hypothalamus of LPS-challenged mice, which was mitigated by daridorexant administration. In addition, daridorexant mitigated LPS-induced acute lung inflammation. These findings suggest that by reducing pro-inflammatory cytokine expression, the inhibition of orexin activity mitigates the lethargy associated with systemic inflammation, while also improving sleep quality. This study explores the potential of orexin receptor antagonists as strategic options for inflammatory pathologies and their associated sleep disorders.