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

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      S. Karger AG

      Corticotropin, Excitatory amino acid receptors, Opioid peptides, Development

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          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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              A direct non-opiate interaction of dynorphin-(1-13) with the N-methyl-D-aspartate (NMDA) receptor.


                Author and article information

                S. Karger AG
                January 1999
                27 January 1999
                : 69
                : 1
                : 28-33
                Department of Pharmacology, Cornell University Medical College, New York, N.Y., USA
                54400 Neuroendocrinology 1999;69:28–33
                © 1999 S. Karger AG, Basel

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


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