CONSEQUENCES OF PRENATAL MORPHINE EXPOSURE ON THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS IN THE NEWBORN RAT - EFFECT OF MATERNAL ADRENALECTOMY

The hypothalamo-pituitary-adrenal axis is already functional in rat fe tuses in late gestation. We have reported previously that prenatal mor phine exposure induced a severe atrophy of the adrenals and a decrease of corticosterone release in newborn rats at birth and during the ear ly postnatal period. The first aim of the present study was to determi ne the effects of prenatal morphine exposure (1) on corticotrophin rel easing factor (CRF) content of the hypothalamus, CRF immunofluorescenc e in the median eminence, CRF mRNA in the paraventricular nucleus (PVN ) and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary gland ; (2) on CRF-induced ACTH release from the anterior pituitary gland in vitro; and (3) on ACTH-induced corticosterone release by the adrenals in vitro. Moreover, as morphine is a hepatotoxic factor, we determine d the effects of prenatal morphine on liver weight and plasma corticos teroid binding globulin (CBG) binding capacity in newborn rats. Since acute administration of morphine stimulates corticosterone secretion i n adult rats and since maternal corticosterone can cross the placental barrier, we also measured both adrenal weight and glucocorticoid acti vity in newborns from adrenalectomized mothers treated with morphine. The present results show that prenatal morphine given to intact mother s induced adrenal atrophy and hypoactivity in newborns but did not aff ect the responsiveness of the anterior pituitary gland to CRF or that of the adrenal gland to ACTH, Prenatal morphine reduced both CRF conte nt in the newborn hypothalamus and CRF immunofluorescence in the media n eminence without a significant effect on CRF mRNA expression in the PVN. Moreover, morphine induced a significant decrease of POMC mRNA in the anterior pituitary gland. However, morphine did not significantly affect the weight of the liver, or the plasma CBG binding capacity fo r corticosterone, in rat pups. In contrast, morphine treatment of the adrenalectomized mothers did not induce adrenal atrophy in newborns an d did not impair adrenal activation during the early postnatal period. Maternal adrenalectomy also prevented the effects of prenatal morphin e on hypothalamic content of CRF, CRF immunofluorescence in the median eminence, and POMC mRNA in the anterior pituitary gland. However, adr enal atrophy was observed at term in newborns of adrenalectomized moth ers treated with both morphine and corticosterone or only corticostero ne, In conclusion, morphine given to pregnant rats induced inhibition of the hypothalamo-pituitary-adrenal axis in pups at term. As maternal adrenalectomy prevented these effects, we speculate that an adrenal f actor of maternal origin, probably corticosterone, mediated these drug effects on newborns.