I.p. injection of morphine-HCl (MOR; 80 mg/kg) stimulated corticosteroid production of adrenal glands in vitro and caused a decrease of noradrenaline (NA) content in the hypothalamus of rats. A negative correlation was found between corticosteroid production rate in vitro and the level of hypothalamic NA in MOR-treated animals. The NA-depleting effect of MOR was mainly located in the medial basal hypothalamus. The NA-depleting effect of MOR was potentiated in adrenalectomized (ADX) animals maintained on 1 mg/kg corticosterone (B), while MOR-induced NA depletion was abolished in ADX rats maintained on 10 mg/kg B. The same B treatment in intact animals still resulted in MOR-induced NA depletion, while the enhanced corticosteroid production in vitro was suppressed in a dose-dependent manner. Intraventricular administration of L-dopa or dops (dl-treo-3,4-dihydroxyphenylserine) did not prevent MOR-induced ACTH release or NA depletion in the hypothalamus. 3H-NA accumulation from 3H-tyrosine (T) in vitro was stimulated by MOR in several parts of the hypothalamus. This was most pronounced in the arcuate nucleus area; dopamine (DA) accumulation was not affected. The results suggest that MOR elicits ACTH release through interfering with an inhibitory noradrenergic control mechanism in the hypothalamus, presumably located in the arcuate nucleus.