The effects of acute and chronic treatment with morphine and stadol on the functional activity of the hypothalamo-pituitary-adrenocortical (HPA) system in the rat were studied by investigating their effects on the secretion of adrenocorticotrophin (ACTH) by the pituitary gland and corticotrophin-releasing hormone (CRH) by the hypothalamus. The acute injection of morphine or stadol (3.5 mg/100 g body weight i.p.) caused a rise at 5 and 25 min followed by a fall at 90 and 120 min in the concentrations of ACTH in the plasma and adenohypophysis and in hypothalamic CRH content. It appears that, in the rat, the response of HPA system to acute morphine or stadol administration could change depending upon the time of courses. In addition, chronic morphine or stadol (0.5 mg/100 g body weight i.p. daily) administration for a period of 7 days have little effect on plasma and adenohypophysis ACTH concentrations and hypothalamic CRH content. This may indicate that drug tolerance might have developed. Conversely, repeated daily doses of morphine or stadol (2 mg/ 100 g body weight i.p.) for 7 days cause a significant lowering of plasma and pituitary ACTH concentrations and hypothalamic CRH content. These data suggest that the effect of both drugs is dose related. Overall, the present results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine or stadol treatment for a short-term, and with a decreased release of these peptides in chronic treatment. However, the results indicate that morphine and stadol change HPA activity by acting on specific receptors in the hypothalamus and raise the possibility that opioid peptides and their receptors are physiologically important in the control of the secretion of CRH.