title: Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone.
abstract: 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.
authors.affiliation: Laboratory of Neuroendocrinology, Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom. p.j.brunton@ed.ac.uk
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Brunton
authors.forename: Ailsa J
authors.initials: AJ
authors.lastname: McKay
authors.forename: Tomasz
authors.initials: T
authors.lastname: Ochedalski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Piastowska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Rebas
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lachowicz
authors.forename: John A
authors.initials: JA
authors.lastname: Russell
mesh_terms: D004092:20-alpha-Dihydroprogesterone / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000701:Analgesics, Opioid / Q000378:metabolism*; D000704:Analysis of Variance; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D002855:Chromatography, Thin Layer / Q000379:methods; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D053583:Interleukin-1beta / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D000777:Anesthetics; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D011372:Progestins; D012333:RNA, Messenger; D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone; D018120:Finasteride; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D011280:Pregnanolone; D010088:Oxidoreductases; D003345:Corticosterone