Exogenous opioid regulation of the hypothalamic-pituitary-adrenal axis in fetal sheep

To test the hypothesis that endogenous opioids participate in the regulation of the ontogenic development of the hypothalamic-pituitary-adrenal axis in fetal sheep, we measured changes in immunoreactive (ir) ACTH and cortisol concentrations in response to bolus injections of either the [Met]-enkephalin analogue, [D-Ala2,N-Phe4,Met(0)ol5]-enkephalin (FK 33-824; 25 micrograms), the opioid antagonist naloxone (1 mg), a combination of both, or saline vehicle, administered to chronically catheterized fetal sheep through late gestation. There were no effects of either FK 33-824, naloxone or saline on the release of ir-ACTH and cortisol at the earliest stage of gestation studied (days 110-115). By days 125-130, FK 33-824 caused a rapid but short-lived (30 min) increase in plasma ir-ACTH (P less than 0.05) which was accompanied by a smaller but nonsignificant increase in cortisol. Naloxone given concurrently with FK 33-824 abolished this response, thus providing evidence for a specific effect through opioid receptors. Naloxone given alone was without effect. At days 135-140, FK 33-824 caused a significant increase in ir-ACTH which was of similar duration and magnitude to that which occurred at days 125-130. There was a larger basal variation in plasma concentrations of cortisol than at days, 125-130, and a greater increase in cortisol after FK 33-824, although this did not reach statistical significance. Naloxone again reversed the effects of FK 33-824 but was without effect when given alone.(ABSTRACT TRUNCATED AT 250 WORDS)