Differential mechanisms of ovine fetal pituitary stimulation by a selective kappa-opioid agonist and by dynorphin.

Dynorphin has long been considered the putative endogenous ligand for the kappa-opioid receptor. The high density of kappa-opioid receptors in the hypothalamus and the high concentration of dynorphin peptides in the pituitary suggest that they may play an important role in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate this possibility in early development, we examined the effects of a highly selective kappa-opioid agonist, U50488H (trans- (+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide) and dynorphin A1-13 on plasma immunoreactive adrenocorticotropin (ir-ACTH) in the ovine fetus. Although both U50488H (1.0 mg/kg i.v.) and dynorphin A1-13 (0.5 mg/kg i.v.) evoked a similar robust increase in ir-ACTH levels, the response to dynorphin A1-13 peaked at 15 min while the maximal response to U50488H was not seen until 60 min following administration. In addition, the response to dynorphin A1-13, but not U50488H, was dependent upon the gestational age of the fetus. The response to U50488H was blocked by naloxone as well as antagonists of AVP and CRF indicating that U50488H is eliciting its effects via opioid receptors, most likely of the kappa receptor subtype, at the hypothalamus. Conversely, the dynorphin A1-13 response was not blocked by any of the aforementioned antagonist. Thus, it appears that dynorphin A1-13 may act as a direct mediator of ACTH release via nonopioid receptors at the level of the pituitary.