To examine the hypothesis that the increased adrenocortical activity during lactation induced the loss of the prolactin (PRL) -releasing effect of morphine, we studied the effect of morphine in adrenalectomized (ADX) and sham-operated primiparous lactating Wistar rats. Animals were adrenalectomized 4 days after delivery. On day 11 of lactation (7 days after ADX), pups were separated from their mother 2 h before morphine or haloperidol injection. Intravenous injection of 5 mg/kg morphine did not change plasma PRL levels in the sham-operated lactating rats, but it resulted in a significant increase of plasma PRL levels in ADX lactating animals, with or without corticosterone replacement. Catalepsy following 10 mg/kg i.v. morphine was also markedly enhanced in ADX lactating animals. The PRL response to 0.5 mg/kg haloperidol was higher in ADX lactating animals than that in the controls. Morphine given 2 h after haloperidol treatment resulted in a further increase of plasma PRL in ADX, but not in the sham-operated lactating animals. These results suggest that adrenal hyperfunction may lead to a loss of sensitivity to morphine during lactation.