Inhibitory effects of an orexin-2 receptor antagonist on orexin A- and stress-induced ACTH responses in conscious rats.

Orexins, recognized for their diverse functions in sleep/wakefulness/arousal and appetite regulation, may play provocative roles in stress response. Although the PVN of the hypothalamus expresses an abundance of orexin-2 receptor (OX-2R), the involvement of OX-2R in regulating ACTH response to stress remains unclear. To address this, we examined effects of a selective antagonist to OX-2R (N-{(1S)-1-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]carbonyl}-2,2-dimethylpropyl)-N-{4-pyridinylmethyl}amine upon plasma ACTH concentrations after administration of orexin A and swimming stress. Increases in ACTH levels with orexin A or swimming stress were attenuated with prior administration of an OX-2R antagonist. These results suggest that swimming stress facilitates ACTH release, at least in part via activation of OX-2R.