title: Allopregnanolone and induction of endogenous opioid inhibition of oxytocin responses to immune stress in pregnant rats.
abstract: In virgin rats, systemic administration of interleukin (IL)-1β (i.e. to mimic infection), increases oxytocin secretion and the firing rate of oxytocin neurones in the supraoptic nucleus (SON). However, in late pregnancy, stimulated oxytocin secretion is inhibited by an endogenous opioid mechanism, preserving the expanded neurohypophysial oxytocin stores for parturition and minimising the risk of preterm labour. Central levels of the neuroactive metabolite of progesterone, allopregnanolone, increase during pregnancy and allopregnanolone acting on GABA(A)  receptors on oxytocin neurones enhances inhibitory transmission. In the present study, we tested whether allopregnanolone induces opioid inhibition of the oxytocin system in response to IL-1β in late pregnancy. Inhibition of 5α-reductase (an allopregnanolone-synthesising enzyme) with finasteride potentiated IL-1β-evoked oxytocin secretion in late pregnant rats, whereas allopregnanolone reduced the oxytocin response in virgin rats. IL-1β increased the number of magnocellular neurones in the SON and paraventricular nucleus (PVN) expressing Fos (an indicator of neuronal activation) in virgin but not pregnant rats. In immunoreactive oxytocin neurones in the SON and PVN, finasteride increased IL-1β-induced Fos expression in pregnant rats. Conversely, allopregnanolone reduced the number of magnocellular oxytocin neurones activated by IL-1β in virgin rats. Treatment with naloxone (an opioid antagonist) greatly enhanced the oxytocin response to IL-1β in pregnancy, and finasteride did not enhance this effect, indicating that allopregnanolone and the endogenous opioid mechanisms do not act independently. Indeed, allopregnanolone induced opioid inhibition over oxytocin responses to IL-1β in virgin rats. Thus, in late pregnancy, allopregnanolone induces opioid inhibition over magnocellular oxytocin neurones and hence on oxytocin secretion in response to immune challenge. This mechanism will minimise the risk of preterm labour and prevent the depletion of neurohypophysial oxytocin stores, which are required for parturition.
authors.affiliation: Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK. p.j.brunton@ed.ac.uk
authors.forename: P J
authors.initials: PJ
authors.lastname: Brunton
authors.forename: J
authors.initials: J
authors.lastname: Bales
authors.forename: J A
authors.initials: JA
authors.lastname: Russell
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D010121:Oxytocin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D010904:Pituitary Gland, Posterior / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000187:drug effects / Q000502:physiology*; D011280:Pregnanolone / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D013495:Supraoptic Nucleus / Q000187:drug effects / Q000502:physiology
chemical_list: D058891:5-alpha Reductase Inhibitors; D053583:Interleukin-1beta; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D009270:Naloxone; D010121:Oxytocin; D018120:Finasteride; D011280:Pregnanolone