KAPPA-OPIOID AGONIST, U50,488H, STIMULATES OVINE FETAL PITUITARY-ADRENAL-FUNCTION VIA HYPOTHALAMIC ARGININE-VASOPRESSIN AND CORTICOTROPIN-RELEASING FACTOR

The fetal hypothalamic-pituitary-adrenal axis is regulated by such fac tors as corticotrophin releasing factor, arginine vasopressin and the endogenous opioid peptides. The goal of this study was to determine wh ether activation of the kappa-opioid system can modulate ovine fetal p ituitary-adrenal function. The highly selective kappa-opioid agonist, U50,488H {trans-(+/-)-3,4-dichloro-N-methyl-[2-(1 -pyrrolidinyl)-cyclo hexyl]benzeneacetamide} (1 mg/kg, i.v.), was administered directly to the ovine fetus in utero and fetal plasma levels of immunoreactive adr enocorticotrophin (ir-ACTH) and cortisol (ir-cortisol) were measured v ia radioimmunoassay. U50,488H resulted in an immediate and highly sign ificant (P = .00005) increase in ir-ACTH, with a concomitant, signific ant (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 naloxo ne (12 mg/hr, i.v.) administration, indicating that U50,488H is acting at classical opioid receptors to elicit this effect. Pretreatment wit h antagonists of arginine vasopressin or corticotrophin releasing fact or attenuated the U50,488H response and it was therefore concluded tha t U50,488H is most likely acting to modulate ir-ACTH and ir-cortisol l evels through regulation of arginine vasopressin and corticotrophin re leasing factor release via hypothalamic kappa-opioid receptors. The re sults of this study should aid in the design of obstetrical analgesics that will not alter the fetal stress response.