Document Detail

Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone.
MedLine Citation:
PMID:  19458216     Owner:  NLM     Status:  MEDLINE    
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.
Paula J Brunton; Ailsa J McKay; Tomasz Ochedalski; Agnieszka Piastowska; Elzbieta Rebas; Agnieszka Lachowicz; John A Russell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
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:
Created Date:  2009-05-21     Completed Date:  2009-06-08     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6449-60     Citation Subset:  IM    
Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
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MeSH Terms
20-alpha-Dihydroprogesterone / pharmacology
Adrenocorticotropic Hormone / metabolism
Analgesics, Opioid / metabolism*
Analysis of Variance
Anesthetics / pharmacology*
Chromatography, Thin Layer / methods
Corticosterone / metabolism
Corticotropin-Releasing Hormone / genetics,  metabolism
Enzyme Inhibitors / pharmacology
Enzyme-Linked Immunosorbent Assay / methods
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, Animal / drug effects
Pregnanolone / pharmacology*
Progesterone / pharmacology
Progestins / pharmacology
RNA, Messenger / metabolism
Rats, Sprague-Dawley
Stress, Physiological / drug effects*
Time Factors
Grant Support
//Biotechnology and Biological Sciences Research Council
Reg. No./Substance:
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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