We examined the effects of the neuropeptide nociceptin/orphanin FQ on activity of the limbic-hypothalamic-pituitary-adrenal axis (also known as the stress axis) in rats. This axis regulates important metabolic functions, and initiates critical neuroendocrine responses that cope with environmental threats and challenges to homeostatic functioning. Disregulation of the limbic-hypothalamic-pituitary-adrenal axis is associated with impaired physical and psychological health. In the present experiments, rats were treated with intracerebroventricular injections of nociceptin/orphanin FQ in the presence or absence of acute stressors. Plasma adrenocorticotrophic hormone and corticosterone concentrations were assayed 15 or 30min after injections. In the rats that were not exposed to stress, nociceptin/orphanin FQ produced dose-orderly elevations of circulating adrenocorticotrophic hormone and corticosterone concentrations. These effects were also found after administration of the nociceptin/orphanin FQ analogues, des-Phe orphanin FQ and [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin((1-13))NH(2). In rats that were exposed to the mild stress of a novel environment, nociceptin/orphanin FQ administration enhanced the stress-induced elevations of plasma adrenocorticotrophic hormone concentrations and prolonged the stress-induced elevations of plasma corticosterone concentrations. In rats that were exposed to restraint stress, nociceptin/orphanin FQ administration did not augment the stress-induced elevations in plasma hormones, perhaps because of a ceiling effect. We conclude that administration of nociceptin/orphanin FQ activates neuroendocrine activity of the limbic-hypothalamic-pituitary-adrenal axis even in the absence of a stressor, and may delay the shutdown of these physiological responses after exposure to acute mild stress. In light of the known functions of this axis, it appears that nociceptin/orphanin FQ participates in the regulation of important metabolic functions, and may be implicated in physiological responses to stress. This interaction between nociceptin/orphanin FQ and the limbic-hypothalamic-pituitary-adrenal axis implicates nociceptin/orphanin FQ in important aspects of physiological and psychological well-being.