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 axis plays an important role in the development of several vital organs and in the onset of parturition, an understanding of the role of opioid receptor subtypes on the fetal HPA axis is important in the design of new obstetrical analgesics. In these studies, we examined the effects of highly selective mu, delta and kappa opioid agonists on plasma immunoreactive adrenocorticotropin (ir-ACTH) and immunoreactive cortisol (ir-cortisol) in the ovine fetus. Intravenous administration of the mu selective agonist [D-Ala2-N-Me-Phe4,Gly-ol]-enkephalin resulted in a 92% increase in ir-ACTH (P = .005) and ir-cortisol. The delta selective agonist, [D-Pen2,D-Pen5]-enkephalin, elicited a much smaller increase (52%) in ir-ACTH (P = .01). In contrast, there was a 7-fold increase in ir-ACTH (P < .001) and a significant increase in ir-cortisol (P = .02) with the kappa selective U50,488H. When the same agonists were administered intracerebroventricularly, there was no change in ir-ACTH or ir-cortisol. These data suggest that the kappa opioid receptor may be more important in the modulation of the fetal HPA axis and that the distribution of these opioid agonists from the lateral ventricle to the hypothalamus and pituitary is very limited.