DEVELOPMENTAL REGULATION OF PREPROENKEPHALIN MESSENGER-RNA IN THE OVINE PARAVENTRICULAR NUCLEUS - EFFECTS OF STRESS AND GLUCOCORTICOIDS

The opioid peptides have profound effects at several levels within the hypothalamo-pituitary-adrenal (HPA) axis. Activation of fetal HPA fun ction occurs during late gestation, and as part of the fetal adaptive response to stress. Changes in the relative levels, localization and d istribution of hypothalamic preproenkephalin (PENK) mRNA in the ovine hypothalamic paraventricular nucleus (PVN) during development were exa mined by in situ hybridization histochemistry. The effects of fetal hy poxemia applied in the presence or absence of concomitant cortisol, to establish negative feedback potential in late gestation were also inv estigated. PENK mRNA was present at low levels within the PVN, by d60 (term d147). During mid to late gestation, there was an increase in PE NK mRNA levels from d60-80 to d100-120, then reaching a peak at d130-1 40. Levels then decreased dramatically during the last 5-7 days prior to parturition, but increased again in the newborn lamb. Throughout ge station, PENK mRNA was confined exclusively to the parvocellular regio n of the PVN. Cortisol infusion induced significant decreases (P < 0.0 5) in PENK mRNA, in normoxemic fetuses at d135 of gestation. The hypox emic insult, which is known to stimulate plasma ACTH and cortisol, in these fetuses, did not significantly affect PENK mRNA. There was no si gnificant difference in PENK mRNA between saline or cortisol infused h ypoxemic fetuses. However, the combination of cortisol infusion and hy poxemia significantly decreased PENK mRNA compared to the saline-infus ed normoxemic fetuses. Together, these results indicate that the eleva tion of endogenous fetal cortisol, that occurs at the end of gestation , may act to inhibit expression of the PENK gene in the hypothalamic P VN of the developing ovine fetus.