The fetal hypothalamic-pituitary-adrenal axis is regulated by such factors as corticotrophin releasing factor, arginine vasopressin and the endogenous opioid peptides. The goal of this study was to determine whether activation of the kappa-opioid system can modulate ovine fetal pituitary-adrenal function. The highly selective kappa-opioid agonist, U50,488H ¿trans-(+/-)-3, 4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexy]benzeneacetamide ¿ (1 mg/kg, i.v.), was administered directly to the ovine fetus in utero and fetal plasma levels of immunoreactive adrenocorticotrophin (ir-ACTH) and cortisol (ir-cortisol) were measured via radioimmunoassay. U50,488H resulted in an immediate and highly significant (P = .00005) increase in ir-ACTH, with a concomitant, significant (P = .02) increase in ir-cortisol. The peak increase was 312.1 +/- 31.2 pg/ml and 17.9 +/- 5.4 ng/ml from predrug control values for ir-ACTH and ir-cortisol, respectively, at 60 min after administration of U50,488H. This stimulation was completely blocked by concurrent naloxone (12 mg/hr, i.v.) administration, indicating that U50,488H is acting at classical opioid receptors to elicit this effect. Pretreatment with antagonists of arginine vasopressin or corticotrophin releasing factor attenuated the U50,488H response and it was therefore concluded that U50,488H is most likely acting to modulate ir-ACTH and ir-cortisol levels through regulation of arginine vasopressin and corticotrophin releasing factor release via hypothalamic kappa-opioid receptors. The results of this study should aid in the design of obstetrical analgesics that will not alter the fetal stress response.