|Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone.|
|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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|Type: Journal Article; Research Support, Non-U.S. Gov't|
|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|
|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|
|Languages: eng Pagination: 6449-60 Citation Subset: IM|
|Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom. firstname.lastname@example.org|
|APA/MLA Format Download EndNote Download BibTex|
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
Stress, Physiological / drug effects*
|//Biotechnology and Biological Sciences Research Council|
|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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