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Orexins are hypothalamic neuropeptides that stimulate arousal and food intake but also activate the hypothalamic-pituitary-adrenal (HPA) axis. During late pregnancy in the rat, the responsiveness of the HPA axis to stressors is attenuated, and thus we investigated HPA axis responses to centrally administered orexin-A during pregnancy. Intracerebroventricular injection of orexin-A (0.5 μg, 140 pmol) significantly increased plasma adrenocorticotropic hormone and corticosterone concentration within 10 min in virgin female Sprague-Dawley rats, but had no effect in day 21 pregnant rats. Orexin-A significantly increased corticotropin-releasing hormone (CRH) mRNA expression, measured by in situ hybridization, in the paraventricular nucleus (PVN) of the virgin group but not in the pregnant group. Thus, the responsiveness of PVN CRH neurones to orexin-A, and hence the pituitary-adrenal axis, is markedly reduced in pregnancy. This may favour anabolic adaptations in pregnancy.