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.

Goldstein A, Fischli W, Lowney LI, et al: Porcine pituitary dynorphin: Complete amino acid sequence of the biologically active heptapeptide. Proc Natl Acad Sci USA 1981;78:7219–7223.
Mansour A, Fox CA, Burke S, et al: Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: An in situ hybridization study. J Comp Neurol 1994;350:412–438.
Hollt V, Haarmann I, Bovermann K, Jerlicz M, Herz A: Dynorphin-related immunoreactive peptides in rat brain and pituitary. Neurosci Lett 1980;18:149–153.
Taylor CC, Wu DL, Soong Y, Yee JS, Szeto HH: Kappa-opioid agonist, U50,488H, stimulates ovine fetal pituitary-adrenal function via hypothalamic arginine-vasopressin and corticotrophin-releasing factor. J Pharmacol Exp Ther 1996;277:877–884.
Taylor CC, Wu DL, Soong Y, Yee J, Szeto HH: Dynorphin A1–13 stimulates ovine fetal pituitary-adrenal function through a novel nonopioid mechanism. J Pharmacol Exp Ther 1997;280:416–421.
Walker JM, Moises HC, Coy DH, Baldrighi G, Akil H: Nonopiate effects of dynorphin and des-Tyr-dynorphin. Science 1982;218:1136–1138.
Takemori AE, Loh HH, Lee NM: Suppression by dynorphin A and [des-tyr1]dynorphin A peptides of the expression of opiate withdrawal and tolerance in morphine-dependent mice. J Pharmacol Exp Ther 1993;266:121–124.
Hooke LP, He L, Lee NM: [Des-Tyr1]dynorphin A-(2–17) has naloxone-insensitive antinociceptive effect in the writhing assay. J Pharmacol Exp Ther 1995;273:802–807.
Shukla VK, Lemaire S: Non-opioid effects of dynorphins: Possible role of the NMDA receptor: Trends Pharmacol Sci 1994;15:420–424.
Brann DW, Mahesh VB: Excitatory amino acid neurotransmission: Evidence for a role in neuroendocrine regulation. Trends Endocrinol Metab 1992;3:122–126.
Farah JM Jr, Rao TS, Mick SJ, Coyne KE, Iyengar S: N-methyl-D-aspartate treatment increases circulating adrenocorticotropin and luteinizing hormone in the rat. Endocrinology 1991;128:1875–1880.
Jezova D, Oliver C, Jurcovicova J: Stimulation of adrenocorticotropin but not prolactin and catecholamine release by n-methyl-aspartic acid. Neuroendocrinology 1991;54:488–492.
Brooks AN, Howe DC: Adrenocorticotrophin and luteinizing hormone responses to N-methyl-D-aspartate during fetal development in sheep. J Neuroendocrinol 1996;8:315–321.
Taylor CC, Wu DL, Soong Y, Yee J, Szeto HH: Differential mechanisms of ovine fetal pituitary stimulation by a selective kappa-opioid agonist and by dynorphin. Neuroendocrinology 1996;64:419–424.
Szeto HH, Zhu YS, Cai LQ: Central opioid modulation of fetal cardiovascular function: Role of µ- and δ-receptors. Am J Physiol 1990;258:R1453–R1458.
Bakshi R, Faden AI: Competitive and non-competitive NMDA antagonists limit dynorphin A-induced rat hindlimb paralysis. Brain Res 1990;507:1–5.
Laughlin TM, Vanderah TW, Lashbrook J, et al: Spinally administered dynorphin A produces long-lasting allodynia: Involvement of NMDA but not opioid receptors. Pain 1997;72:253–260.
Vanderah TW, Laughlin T, Lashbrook JM, et al: Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: Blockade by MK-801 but not naloxone. Pain 1996;68:275–281.
Norman LJ, Challis JR: Synergism between systemic corticotropin-releasing factor and arginine vasopressin on adrenocorticotropin release in vivo varies as a function of gestational age in the ovine fetus. Endocrinology 1987;120:1052–1058.
Sucher N, Awobuluyi M, Choi YB, Lipton SA: NMDA receptors: From genes to channels. Trends Pharmacol Sci 1996;17:348–355.
Faden AI: Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism. J Neurosci 1992;12:425–429.
Wagner JJ, Terman GW, Chavkin C: Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature 1993;363:451–454.
Massadier D, Hunt PF: A direct non-opiate interaction of dynorphin (1–13) with the N-methyl-D-aspartate receptor. Eur J Pharmacol 1989;170:125–126.
Bakshi R, Faden AI: Blockade of the glycine modulatory site of NMDA receptors modifies dynorphin-induced behavioral effects. Neurosci Lett 1990;110:113–117.
Isaac L, Van Zandt OT, Ristic H, Stewart P: MK-801 blocks dynorphin A (1–13)-induced loss of the tail-flick reflex in the rat. Brain Res 1990;531:83–87.
Chen L, Gu Y, Huang L-YM: The opioid peptide dynorphin directly blocks NMDA receptor channels in the rat. J Physiol Lond 1995;482:575–581.
Meeker RB, Greenwood RS, Hayward JN: Glutamate receptors in the rat hypothalamus and pituitary. Endocrinology 1994;134:621–629.
Patchev VK, Karalis K, Chrousos GP: Effects of excitatory amino acid transmitters on hypothalamic corticotropin-releasing hormone and arginine-vasopressin release in vitro: Implications in pituitary-adrenal regulation. Brain Res 1994;633:312–316.
Costa A, Yasin SA, Hucks D, Forsling ML, Besser M, Grossman A: Differential effects of neuroexcitatory amino acids on corticotropin-releasing hormone-41 and vasopressin release from rat hypothalamic explants. Endocrinology 1992;131:2595–2602.
Currie IS, Gillies G, Brooks AN: Modulation of arginine vasopressin secretion from cultured ovine hypothalamic cells by glucocorticoids and opioid peptides. Neuroendocrinology 1994;60:360–367.
Apostolakis EM, Longo LD, Yellon SM: Cortisol feedback regulation of pulsatile ACTH secretion in fetal sheep during late gestation. Am J Physiol Endocrinol Metab 1994;267:E521–E527.
Rose JC, Hargrave BY, Dix PM, Meis PJ, LaFave M, Torpe B: Corticotropin-releasing factor-induced adrenocorticotrophic hormone release in the sheep fetus: Blockade by cortisol. Am J Obstet Gynecol 1985;151:1128–1133.
Norman LJ, Challis JR: Dexamethasone inhibits ovine corticotrophin-releasing factor (oCRF), arginine vasopressin (AVP), and oCRF + AVP stimulated release of ACTH during the last third of pregnancy in the sheep fetus. Can J Physiol Pharmacol 1987;65:1186–1192.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.