The orexin system as a pharmacological target in inflammation: peripheral mechanisms and safety implications

The orexin (hypocretin) system, composed of the neuropeptides orexin A and orexin B and their receptors OX1R and OX2R, is primarily known for its role in sleep-wake regulation and energy homeostasis. Increasing evidence indicates that orexin signaling also participates in the regulation of inflammatory processes. This review examines the pharmacological relevance of the orexin system in immune modulation, with particular emphasis on potential peripheral mechanisms that may represent novel therapeutic targets. Current evidence suggests that orexins may influence inflammatory responses through both central and peripheral pathways, including modulation of the hypothalamic-pituitary-adrenal axis, autonomic nervous system activity, regulation of adrenal corticosteroid secretion, reduction of oxidative stress, and potential direct effects on immune cells expressing orexin receptors. A major unresolved question is the origin and function of circulating orexin peptides detected in human plasma despite their predominantly central production. We also review the limited pharmacokinetic data available for orexin peptides and evaluate reported plasma concentrations, highlighting substantial methodological variability that complicates interpretation of circulating levels and their potential peripheral sources. Distinguishing between central and peripheral orexin actions is pharmacologically important. While orexin receptor antagonists are already approved for insomnia and agonists are being developed for narcolepsy, their potential effects on immune function warrant further consideration. Conversely, peripheral or immune-specific variants of orexin signaling could represent promising therapeutic targets with reduced central nervous system effects.