Opiates are widely used as obstetrical analgesics during pregnancy and, as such, their interactions with the fetal endocrine system may have important consequences. In this study, the effects of morphine administration to fetal sheepin uteroon fetal plasma immunoreactive (ir)-ACTH and ir-cortisol were examined. At the lowest dose administered (0.6 mg/h, i.v.) morphine reduced, although not significantly, plasma ir-cortisol levels. A dose-dependent stimulation of cortisol release was observed with higher doses of morphine. Doses of 2.5 and 5.0 mg/h morphine resulted in a significant increase in ir-cortisol with a change from control levels equal to 9.6± 1.1 ng/mL (p= 0.03) and 17.6 ± 5.1 ng/mL(p= 0.03), respectively. This increase in plasma ir-cortisol was associated with a significant increase in ir-ACTH (111.8 ± 23.2 pg/mLversus42.8 ± 5.1 pg/mL;p= 0.02) that was naloxone-reversible. These effects of morphine were observed in fetal lambs only >125 d of gestation, suggesting a maturation of functional opioid receptors in the ovine fetal hypothalamic-pituitary-adrenal axis after this time.Abbreviations: CRF,corticotropin-releasing factor;HPA,hypothalamic-pituitary-adrenal;ir,immunoreactive