Abstract
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 ĸ-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.
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1999
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