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      The Role of N-Methyl-D-Aspartate Receptors in the Release of Adrenocorticotropin by Dynorphin A 1–13

      , ,

      Neuroendocrinology

      S. Karger AG

      Corticotropin, Excitatory amino acid receptors, Opioid peptides, Development

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          Abstract

          We previously reported that dynorphin A<sub>1–13</sub> 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 A<sub>1–13</sub> may release ACTH via N-methyl-D-aspartate (NMDA) receptors. To test this hypothesis, we have compared the ACTH response to dynorphin A<sub>1–13</sub> and NMDA in the chronically-instrumented ovine fetus. Our data show that both dynorphin A<sub>1–13</sub> (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 A<sub>1–13</sub>. The response to both dynorphin A<sub>1–13</sub> 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 A<sub>1–13</sub> and NMDA were inhibited by dexamethasone. The results of this study indicate a role for NMDA receptors in the action of dynorphin A<sub>1–13</sub>, 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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          Most cited references 6

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          Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus.

          Although anatomical and neurochemical studies suggest that endogenous opioids act as neurotransmitters, their roles in normal and pathophysiological regulation of synaptic transmission are not defined. Here we examine the actions of prodynorphin-derived opioid peptides in the guinea-pig hippocampus and show that physiological stimulation of the dynorphin-containing dentate granule cells can release endogenous dynorphins, which then activate kappa 1 opioid receptors present in the molecular layer of the dentate gyrus. Activation of kappa 1 receptors by either pharmacologically applied agonist or endogenously released peptide reduces excitatory transmission in the dentate gyrus, as shown by a reduction in the excitatory postsynaptic currents evoked by stimulation of the perforant path, a principal excitatory afferent. In addition, released dynorphin peptides were found to block the induction of long-term potentiation (LTP) at the granule cell-perforant path synapse. The results indicate that endogenous dynorphins function in this hippocampal circuit as retrograde, inhibitory neurotransmitters.
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            MK-801 blocks dynorphin A (1-13)-induced loss of the tail-flick reflex in the rat.

            Dynorphin A (1-13) administered intrathecally to rats results in a dose-dependent loss of the tail-flick reflex. This effect is mediated, at least in part, by N-methyl-D-aspartate receptors. We examined the influence of pretreatment or post-treatment with MK-801 on this behavioral response. MK-801 administered i.p. 30 min prior to dynorphin provided dose-dependent protection against loss of the tail-flick reflex with an ED50 of 0.06 mg/kg. MK-801 administered after dynorphin had a dose- and time-dependent protective action. The dose of 0.06 mg/kg protected 63% of the animals from loss of the tail-flick reflex when injected 15 min after dynorphin. In contrast, 3 mg/kg did not protect animals when injected 15 min after dynorphin, but did protect 50% of the animals when injected 30 min post-dynorphin. Although we cannot exclude other effects mediated by MK-801, these data support our previous findings that dynorphin-induced loss of the tail-flick reflex involves the N-methyl-D-aspartate-receptor complex and support the contention that the process(es) initiated by dynorphin injection proceed rapidly (minutes rather than hours).
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              • Abstract: not found
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              A direct non-opiate interaction of dynorphin-(1-13) with the N-methyl-D-aspartate (NMDA) receptor.

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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                1999
                January 1999
                27 January 1999
                : 69
                : 1
                : 28-33
                Affiliations
                Department of Pharmacology, Cornell University Medical College, New York, N.Y., USA
                Article
                54400 Neuroendocrinology 1999;69:28–33
                10.1159/000054400
                9892848
                © 1999 S. Karger AG, Basel

                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.

                Page count
                Figures: 4, References: 33, Pages: 6
                Categories
                Corticotropin and Stress

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