OPIOID MODULATION OF THE FETAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS - THE ROLE OF RECEPTOR SUBTYPES AND ROUTE OF ADMINISTRATION

The role of receptor subtypes in opioid modulation of the hypothalamic -pituitary-adrenal (HPA) axis is well understood in the adult but has not been investigated in the developing fetus. Because the fetal HPA a xis plays an important role in the development of several vital organs and in the onset of parturition, an understanding of the role of opio id receptor subtypes on the fetal HPA axis is important in the design of new obstetrical analgesics. In these studies, we examined the effec ts of highly selective mu, delta and kappa opioid agonists on plasma i mmunoreactive adrenocorticotropin (ir-ACTH) and immunoreactive cortiso l (ir-cortisol) in the ovine fetus. Intravenous administration of the mu selective agonist [D-Ala(2)-N-Me-Phe(4),Gly-ol]-enkephalin resulted in a 92% increase in ir-ACTH (P = .005) and ir-cortisol. The delta se lective agonist, [D-Pen(2),D-Pen(5)]-enkephalin, elicited a much small er increase (52%) in ir-ACTH (P = .01). In contrast, there was a 7-fol d increase in ir-ACTH (P < .001) and a significant increase in ir-cort isol (P = .02) with the kappa selective U50,488H. When the same agonis ts were administered intracerebroventricularly, there was no change in ir-ACTH or ir-cortisol. These data suggest that the kappa opioid rece ptor may be more important in the modulation of the fetal HPA axis and that the distribution of these opioid agonists from the lateral ventr icle to the hypothalamus and pituitary is very limited.