Examining the role of endogenous orexins in hypothalamus-pituitary-adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat

The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus-pituitary-adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge.