The Type 2 Corticotrophin-Releasing Hormone Receptor Mediates Orexin A-Induced Luteinising Hormone Suppression in Ovariectomised Rats

Orexins are thought to be regulatory factors of the arousal and sleep patterns. They also affect immune, feeding, autonomic and neuroendocrine systems. We have previously shown that intracerebroventricular (i.c.v.) injection of orexin decreases pulsatile luteinising hormone (LH) secretion in ovariectomised (OVX) rats. However, the details of this mechanism have not been fully examined. Intracerebroventricular injection of orexin A also stimulates corticotrophin-releasing hormone (CRH) systems, which have been implicated in the stress-induced suppression of reproductive function. In the present study, we investigated the role of CRH systems in orexin-induced LH suppression. OVX rats were implanted with i.c.v. and intravenous (i.v.) cannulae. After i.c.v. injection of orexin and/or CRH receptor antagonists, blood samples were collected through the i.v. cannula at 6-min intervals for 120 min for LH measurement. Intracerebroventricular injection of orexin A or B (3 nmol/2.5 μl) suppressed pulsatile LH secretion. Coadministration of orexin A and α-helical corticotrophic-releasing factor (CRF), a nonselective CRH receptor antagonist (13 nmol/2.5 μl), or astressin 2 B, a selective type2 (CRH-R2) CRH receptor antagonist (28 nmol/2.5 μl), partly restored pulsatile LH secretion. Orexin B-induced LH suppression was not restored by α-helical CRF. In addition, i.c.v. injection of orexin A increased CRH and urocortin II (Ucnll), but not Ucn mRNA levels, in the hypothalamus. These findings suggest that CRH-R2 mediates orexin A-induced LH suppression and it is possible that CRH and Ucnll in the hypothalamus are involved in this pathway.