Selective Inhibition of Orexin-2 Receptors Prevents Stress-Induced ACTH Release in Mice

Abstract

Orexins peptides exert a prominent role in arousal-related processes including stress responding, by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptors located widely throughout the brain. Stress or orexin administration stimulates hyperarousal, adrenocorticotropic hormone (ACTH) and corticosterone release, and selective OX1R blockade can attenuate several stress-induced behavioral and cardiovascular responses but not the hypothalamic-pituitary-adrenal (HPA) axis activation. As opposed to OX1R, OX2R are preferentially expressed in the paraventricular hypothalamic nucleus which is involved in the HPA axis regulation. In the present study, we investigated the effects of a psychological stress elicited by cage exchange (CE) on ACTH release in two murine models (genetic and pharmacological) of selective OX2R inhibition. CE-induced stress produced a significant increase in ACTH serum levels. Mice lacking the OX2R exhibited a blunted stress response. Stress-induced ACTH release was absent in mice pre-treated with the selective OX2R antagonist JNJ-42847922 (30 mg/kg po), whereas pre-treatment with the dual OX1/2R antagonist SB-649868 (30 mg/kg po) only partially attenuated the increase of ACTH. To assess whether the intrinsic and distinct sleep-promoting properties of each antagonist could account for the differential stress response, a separate group of mice implanted with electrodes for standard sleep recording were orally dosed with JNJ-42847922 or SB-649868 during the light phase. While both compounds reduced the latency to non-rapid eye movement (NREM) sleep without affecting its duration, a prevalent REM-sleep promoting effect was observed only in mice treated with the dual OX1/2R antagonist. These data indicate that in a psychological stress model, genetic or pharmacological inhibition of OX2R markedly attenuated stress-induced ACTH secretion, as a separately mediated effect from the NREM sleep induction of OX2R antagonism.

The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder

“…Lateral hypothalamic orexinergic neurons have previously been demonstrated to be involved in maintaining wakefulness 18 and show high neuronal activity during wake state while they are virtually silent during sleep 19,20 . OX activates both OX1R and OX2R during stress 21 , resulting in HPA activation which can be prevented selectively by OX2R antagonists 22 and increased blood pressure and heart rate 23,24 , which can be prevented by OX1R antagonists 25 . In rodents OX antagonists ameliorated behavioral consequences of chronic unpredictable stress, normalized HPA axis function 26 , and attenuated an OX-induced increase in adrenocorticotropic hormone levels 27 .…”

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia

“…Seltorexant blocks OX2Rs which are present in the paraventricular nucleus of the hypothalamus (Yun et al, 2017). As a result, HPA-axis function and therefore hyperarousal can theoretically be attenuated.…”

Orexins, Sleep, and Blood Pressure

“…Yun and colleagues recently demonstrated that the involvement of the orexin system in stress response is even more profound. A typical hormonal reaction to stress—an increase in serum levels of adrenocorticotropic hormone (ACTH)—was absent in stress-exposed mice pretreated with selective OX2R antagonist [ 55 ].…”