| Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone. | |
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MedLine Citation:
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PMID: 19458216 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The hypothalamus-pituitary-adrenal (HPA) axis is the major neuroendocrine stress response system. Corticotropin-releasing hormone (CRH) neurons in the parvocellular paraventricular nucleus (pPVN) play a key role in coordinating responses of this system to stressors. The cytokine interleukin-1beta (IL-1beta), mimicking infection, robustly activates these CRH neurons via a noradrenergic input arising from the nucleus tractus solitarii (NTS). In late pregnancy, HPA axis responses to stressors, including IL-1beta, are attenuated by a central opioid mechanism that auto-inhibits noradrenaline release in the PVN. Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in HPA responsiveness to IL-1beta in pregnancy. In late pregnancy, inhibition of 5alpha-reductase (an allopregnanolone-synthesizing enzyme) with finasteride restored HPA axis responses (rapidly increased pPVN CRH mRNA expression, ACTH, and corticosterone secretion) to IL-1beta. Conversely, allopregnanolone reduced HPA responses in virgin rats. In late pregnancy, activity of the allopregnanolone-synthesizing enzymes (5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase) was increased in the hypothalamus as was mRNA expression in the NTS and PVN. Naloxone, an opioid antagonist, restores HPA axis responses to IL-1beta in pregnancy but had no additional effect after finasteride, indicating a causal connection between allopregnanolone and the endogenous opioid mechanism. Indeed, allopregnanolone induced opioid inhibition over HPA responses to IL-1beta in virgin rats. Furthermore, in virgin rats, allopregnanolone treatment increased, whereas in pregnant rats finasteride decreased proenkephalin-A mRNA expression in the NTS. Thus, in pregnancy, allopregnanolone induces opioid inhibition over HPA axis responses to immune challenge. This novel opioid-mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy. |
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Authors:
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Paula J Brunton; Ailsa J McKay; Tomasz Ochedalski; Agnieszka Piastowska; Elzbieta Rebas; Agnieszka Lachowicz; John A Russell |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 29 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-05-21 Completed Date: 2009-06-08 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 6449-60 Citation Subset: IM |
Affiliation:
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Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom. p.j.brunton@ed.ac.uk |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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20-alpha-Dihydroprogesterone
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pharmacology Adrenocorticotropic Hormone / metabolism Analgesics, Opioid / metabolism* Analysis of Variance Anesthetics / pharmacology* Animals Chromatography, Thin Layer / methods Corticosterone / metabolism Corticotropin-Releasing Hormone / genetics, metabolism Enzyme Inhibitors / pharmacology Enzyme-Linked Immunosorbent Assay / methods Female Finasteride / pharmacology Hypothalamo-Hypophyseal System / drug effects* Interleukin-1beta / pharmacology Neural Inhibition / drug effects* Neurons / drug effects, metabolism Oxidoreductases / metabolism Paraventricular Hypothalamic Nucleus / cytology Pituitary-Adrenal System / drug effects* Pregnancy Pregnancy, Animal / drug effects Pregnanolone / pharmacology* Progesterone / pharmacology Progestins / pharmacology RNA, Messenger / metabolism Rats Rats, Sprague-Dawley Stress, Physiological / drug effects* Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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//Biotechnology and Biological Sciences Research Council |
| Chemical | |
Reg. No./Substance:
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0/Analgesics, Opioid; 0/Anesthetics; 0/Enzyme Inhibitors; 0/Interleukin-1beta; 0/Progestins; 0/RNA, Messenger; 128-20-1/Pregnanolone; 145-14-2/20-alpha-Dihydroprogesterone; 50-22-6/Corticosterone; 57-83-0/Progesterone; 9002-60-2/Adrenocorticotropic Hormone; 9015-71-8/Corticotropin-Releasing Hormone; 98319-26-7/Finasteride; EC 1.-/Oxidoreductases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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