Ontogeny of mu- and kappa-opiate receptor control of the hypothalamo-pituitary-adrenal axis in rats.

The purpose of the present study was to determine the relative ontogeny of mu- and kappa-opiate receptor control of the hypothalamo-pituitary-adrenal (HPA) axis in rats. The ability of the mu-agonist morphine and the kappa-agonist U-50,488 to stimulate the HPA axis was determined by evaluating ACTH and corticosterone (CS) secretion in developing rat pups. Morphine elicited marked rises in both ACTH and CS secretion in 10-day-old rats, and these increases were maximal from 30-60 min after drug administration. Both morphine and U50,488H caused a dose-related rise in CS secretion that was blocked by the synthetic glucocorticoid dexamethasone. The mu-opiate antagonist beta-funaltrexamine blocked the morphine-induced rise in CS secretion, and the kappa-antagonist norbinaltorphimine blocked the action of U50,488H. While a maximal dose of U50,488H (1 mg/kg) elicited a significant rise in CS secretion as early as postnatal day 2, significant effects of a maximal dose of morphine (5 mg/kg) were not observed until day 5. The effects of both drugs were significantly blunted during the stress-hyporesponsive period from days 5-15. The results of this study demonstrate that significant opiate receptor control of HPA function can be demonstrated early in postnatal development, even before the onset of the stress-hyporesponsive period. In addition, these data suggest that kappa-receptor control is functional before mu-receptor control of HPA function.