Site and mechanism of action of dynorphin A-(1-13) and N-methyl-D-aspartate on ACTH release in fetal sheep.
Dynorphin A (Dyn A) stimulates the release of ACTH in fetal sheep, a response that involves N-methyl-D-aspartate (NMDA) receptors but not the secretogogues corticotropin-releasing hormone or arginine vasopressin. We now find that neither Dyn A-(1-13) (0.5 mg/kg, i.v.) nor NMDA (4 mg/kg, i.v.) elicits ACTH release in postnatal lambs. This led us to hypothesize that Dyn A-(1-13) and NMDA might act to release placental ACTH. However, the ability of Dyn A-(1-13), NMDA, and the kappa-opioid receptor agonist U-50488H (1 mg/kg, i.v.) to release ACTH was lost after either fetal hypophysectomy (n = 4) or hypothalamo-pituitary disconnection (n = 4). These results indicate that neither the placenta nor the fetal pituitary is the site of action for these agonists and suggest a hypothalamic or suprahypothalamic site of action. Furthermore, the release of ACTH by Dyn A-(1-13) and NMDA was abolished after pretreatment with indomethacin, suggesting that they might cause the release of a prostanoid, possibly from the placenta, that subsequently acts at the hypothalamus or serves as a permissive factor in the action of Dyn A-(1-13) and NMDA at the hypothalamus.
Nardo
Laura
L
Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
Soong
Yi
Y
Wu
Dunli
D
Young
I Ross
IR
Walker
David
D
Szeto
Hazel H
HH
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D017473:Receptors, Opioid, kappa / Q000819:agonists; D012756:Sheep
D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; D016202:N-Methylaspartate; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D004399:Dynorphins; D000324:Adrenocorticotropic Hormone; D007213:Indomethacin