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The Journal of Neuroscience, May 20, 2009, 29(20):6449-6460; doi:10.1523/JNEUROSCI.0708-09.2009

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Behavioral/Systems/Cognitive
Central Opioid Inhibition of Neuroendocrine Stress Responses in Pregnancy in the Rat Is Induced by the Neurosteroid Allopregnanolone

Paula J. Brunton,¹ Ailsa J. McKay,¹ Tomasz Ochedalski,² Agnieszka Piastowska,² Elbieta Rebas,³ Agnieszka Lachowicz,²  and John A. Russell¹

¹Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, and Departments of ²Comparative Endocrinology and ³Molecular Neurochemistry, Medical University of ód, 91-425 ód, Poland

Correspondence should be addressed to Paula J. Brunton, Centre for Integrative Physiology, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh EH8 9XD, UK. Email: p.j.brunton{at}ed.ac.uk

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-1β (IL-1β), 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-1β, 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-1β in pregnancy. In late pregnancy, inhibition of 5-reductase (an allopregnanolone-synthesizing enzyme) with finasteride restored HPA axis responses (rapidly increased pPVN CRH mRNA expression, ACTH, and corticosterone secretion) to IL-1β. Conversely, allopregnanolone reduced HPA responses in virgin rats. In late pregnancy, activity of the allopregnanolone-synthesizing enzymes (5-reductase and 3-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-1β 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-1β 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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Received Feb. 6, 2009; revised April 8, 2009; accepted April 9, 2009.

Correspondence should be addressed to Paula J. Brunton, Centre for Integrative Physiology, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh EH8 9XD, UK. Email: p.j.brunton{at}ed.ac.uk

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