DYNORPHIN A(1-13) STIMULATES OVINE FETAL PITUITARY-ADRENAL-FUNCTION THROUGH A NOVEL NONOPIOID MECHANISM

We previously reported that U50488H, a kappa-selective opioid agonist, stimulates the release of adrenocorticotropin (ACTH) in the ovine fet us via the release of hypothalamic arginine vasopressin and corticotro pin releasing factor. In this study we examined the effects of the end ogenous kappa-preferring opioid peptide, dynorphin A(1-13), on fetal A CTH release using the unanesthetized, chronically catheterized fetal l amb model. Fetal plasma samples were collected at timed intervals afte r fetal administration od dynorphin A(1-13), (0.5 mg/kg, i.v.) and sub sequently analyzed by radioimmunoassay for immunoreactive-ACTH and imm unoreactive-cortisol. Dynorphin A(1-13) produced a highly significant and rapid increase in immunoreactive-ACTH (P = .002) and immunoreactiv e-cortisol (P = .002) with peak levels of 383.3 +/- 43.8 pg/ml and 32. 8 +/- 9.0 ng/ml, respectively, at 15 min after administration. A simil ar increase in plasma immunoreactive-ACTH was seen after the same dose of dynorphin A(1-17) (P = .02) but not dynorphin A(2-17). This ACTH r esponse to dynorphin A(1-13) was shown to be insensitive to the opioid antagonist, naloxone (12 mg/hr), as well as antagonists of corticotro pin releasing factor and arginine vasopressin. These data suggest that dynorphin A(1-13) in the ovine fetus may be acting through a mechanis m distinct from the kappa-opioid system and that the dynorphins may se rve as secretagogues of ACTH directly at the anterior pituitary throug h nonopioid receptors.