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      Glucocorticoid Regulation of Hypothalamic Proopiomelanocortin

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          Abstract

          Although glucocorticoids clearly inhibit proopiomelanocortin (POMC) gene transcription and peptide synthesis in the anterior pituitary, the effects of glucocorticoids on POMC in the hypothalamus are still unclear, even though most POMC neurons in the arcuate nucleus are known to have glucocorticoid receptors. In this study, we have therefore examined the effect of adrenalectomy (ADX) and glucocorticoid replacement on POMC mRNA and peptide (β-EP and α-MSH) levels in the medial basal hypothalamus (MBH) of the rat. POMC mRNA was measured by a sensitive solution hybridization S1 nuclease protection assay, and β-EP and α-MSH were measured by radioimmunoassay. In a first experiment, animals were studied 7 days after ADX or sham surgery. The mean POMC mRNA concentration was 1.01 ± 0.14 pg/µg RNA (means ± SE) in the intact animals and decreased to 0.55 ± 0.07 pg/µg RNA in the MBH of the ADX animals (p < 0.005). β-EP levels decreased in parallel from 4.30 ± 0.18 to 3.36 ± 0.11 ng/mg protein (p < 0.001); α-MSH levels decreased from 3.25 ± 0.21 to 2.41 ± 0.16 ng/mg protein (p < 0.005). In a second experiment, animals were studied 2 weeks after ADX. POMC mRNA levels again fell significantly from 1.15 ± 0.19 pg/µg RNA in the intact animals to 0.51 ± 0.06 pg/µg in the ADX animals (p < 0.01). β-EP levels fell also, but this was not significant. In a third experiment, all animals underwent ADX, and half of them received daily subcutaneous injections of dexamethasone (20 µg). Nine days after ADX, the mean POMC mRNA level was 0.66 ± 0.04 pg/µg RNA in the saline-treated animals and increased to 0.98 ± 0.08 pg/µg RNA in the dexamethasone-treated animals (p < 0.005). A parallel increase in β-EP levels from 5.03 ± 0.41 to 6.01 ± 0.53 ng/mg protein was also noted, but this was not statistically significant. We conclude that POMC gene expression is significantly inhibited in the MBH at 1 and 2 weeks after ADX. This effect was reversed by glucocorticoid replacement with doses close to the physiological range. The parallel changes in POMC mRNA and peptide levels strongly suggest that, in contrast to the anterior pituitary, low doses of glucocorticoids stimulate the biosynthesis of POMC in the MBH of ADX rats.

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          Most cited references 7

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          Cushing's syndrome.

           Jeffrey Orth (1995)
          Cushing's syndrome is usually caused by the secretion of corticotropin or cortisol by a pituitary or adrenal tumor, respectively, or by ectopic secretion of corticotropin. It is possible to determine the specific abnormality in most patients, but it can sometimes be difficult to decide whether the patient has hypercortisolism and whether it is primary or due to major depressive disorder or to the stress of other diseases. Determining the cause of the hypercortisolism involves performing multiple tests in a logical sequence; the results should all be consistent with the same diagnosis. Treatment should aim to cure the hypercortisolism and to eliminate any tumor that threatens the patient's health, while minimizing the chance of an endocrine deficiency or long-term dependence on medications.
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            Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis.

            A physiological role for beta-endorphin in endogenous pain inhibition was investigated by targeted mutagenesis of the proopiomelanocortin gene in mouse embryonic stem cells. The tyrosine codon at position 179 of the proopiomelanocortin gene was converted to a premature translational stop codon. The resulting transgenic mice display no overt developmental or behavioral alterations and have a normally functioning hypothalamic-pituitary-adrenal axis. Homozygous transgenic mice with a selective deficiency of beta-endorphin exhibit normal analgesia in response to morphine, indicating the presence of functional mu-opiate receptors. However, these mice lack the opioid (naloxone reversible) analgesia induced by mild swim stress. Mutant mice also display significantly greater nonopioid analgesia in response to cold water swim stress compared with controls and display paradoxical naloxone-induced analgesia. These changes may reflect compensatory upregulation of alternative pain inhibitory mechanisms.
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              alpha-Melanocyte stimulating hormone in the modulation of host reactions

               A. Catania (1993)
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                1998
                January 1998
                16 January 1998
                : 67
                : 1
                : 51-57
                Affiliations
                Department of Medicine, Columbia University College of Physicians & Surgeons, New York, N.Y., USA
                Article
                54298 Neuroendocrinology 1998;67:51–57
                10.1159/000054298
                9485169
                © 1998 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: 39, Pages: 7
                Categories
                Adrenal Steroids, Proopiomelanocortin and Stress

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