The effects of morphine and naloxone on hypothalamo-pituitary-adrenocortical (HPA) activity and blood pressure were studied in rats in which adrenergic transmission had been impaired pharmacologically. The alpha 1-adrenoceptor antagonist, prazosin and the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (alpha-MPT), increased the hypothalamic corticotrophin releasing factor (CRF) content and the plasma corticotrophin (ACTH) concentration and exaggerated the HPA response to stress. In addition, the spontaneous secretion of CRF by hypothalami in vitro was increased by alpha-MPT-treatment. Morphine enhanced the basal and stress-induced activity of the HPA system in vivo. It also stimulated the secretion of CRF by hypothalami in vitro. Naloxone did not affect resting HPA activity but reduced markedly the stress-induced release of corticotrophin. The effects of morphine and naloxone on the HPA axis, in vivo, were reduced by pretreatment with alpha-MPT and prazosin, respectively. The HPA responses could not be correlated with the changes in blood pressure which the drugs caused. The results suggest that opioid substances stimulate HPA activity by depressing the activity of the adrenergic pathways which inhibit the secretion of CRF.