The role of N-methyl-D-aspartate receptors in the release of adrenocorticotropin by dynorphin A1-13.
We previously reported that dynorphin A1-13 evokes a significant increase in plasma adrenocorticotropin (ACTH) after intravenous administration in the ovine fetus. This response was not sensitive to naloxone and was regulated differently from the response to U50, 488H, a selective kappa-opioid agonist. NMDA appears to play a role in many of the nonopioid actions of dynorphin. We therefore hypothesized that dynorphin A1-13 may release ACTH via N-methyl-D-aspartate (NMDA) receptors. To test this hypothesis, we have compared the ACTH response to dynorphin A1-13 and NMDA in the chronically-instrumented ovine fetus. Our data show that both dynorphin A1-13 (0.5 mg/kg) and NMDA (4 mg/kg) induced a significant release of immunoreactive ACTH in the late-term ovine fetus. The ACTH response to NMDA was of a smaller magnitude, but of longer duration, when compared to dynorphin A1-13. The response to both dynorphin A1-13 and NMDA was significantly attenuated by pretreatment with the noncompetitive NMDA antagonist, MK-801, but was not affected by antagonists of corticotropin-releasing hormone and arginine vasopressin. Finally, the ACTH response to both dynorphin A1-13 and NMDA were inhibited by dexamethasone. The results of this study indicate a role for NMDA receptors in the action of dynorphin A1-13, and suggest that NMDA may act directly at the level of the pituitary to release ACTH without the involvement of hypothalamic secretagogues.
Szeto
H H
HH
Department of Pharmacology, Cornell University Medical College, New York, N.Y., USA. hhszeto@mail.med.cornell.edu
Soong
Y
Y
Wu
D
D
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005312:Fetal Blood / Q000378:metabolism; D005333:Fetus / Q000187:drug effects / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology; D007700:Kinetics; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012756:Sheep
D018691:Excitatory Amino Acid Antagonists; D005938:Glucocorticoids; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C026843:dynorphin (1-13); D004399:Dynorphins; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone