The antinociceptive effect of morphine (5 mg/kg body weight i.p.) in rats subjected to various experimental manipulations of the pituitary-adrenocortical system was studied. The absence of adrenal steroids increased the sensitivity to morphine. The following findings suggest that glucocorticosteroids have a long-lasting influence on opioid-induced antinociception, even when the steroids have been removed by adrenalectomy. First, when rats were adrenalectomized in the morning under basal conditions of pituitary-adrenocortical activity (plasma corticosterone level < 1 µg%), the subsequent hypersensitivity to morphine was more pronounced than when rats were adrenalectomized in the evening (plasma corticosterone level 18.4 µg%). This difference in hypersensitivity to morphine-induced antinociception following adrenalectomy either in the morning or in the evening persisted for at least 2 weeks. Second, exposure to a novel environment (stress of a new cage) or administration of corticosterone (10 mg/kg body weight s.c.) prior to morning adrenalectomy decreased the sensitivity to morphine measured 1 week later. Third, RU 38486, a glucocorticoid antagonist, injected in the lateral cerebral ventricle prior to the evening adrenalectomy increased subsequent morphine antinociception. In attempts to understand the long-term effect on morphine antinociception, the opioid receptor sites were quantified by an in vivo procedure. Quantitative autoradiography of binding sites labeled after intravenous administration of a tracer dose of [3H]-diprenorphine showed a decrease in retention of the labeled opioid in cortical and midbrain regions of rats adrenalectomized in the evening when compared with rats operated in the morning. In conclusion, the data suggest that a neuroen-docrine state invoked by the actual plasma corticosterone level at the time of adrenalectomy has a long-lasting influence on the degree of post-adrenalectomy opioid-induced antinociception. These long-term alterations of opioid responsiveness are reflected in altered binding to the opioid receptor system in the brai