INHIBITION OF NEUROENDOCRINE STRESS RESPONSES TO IMMUNE CHALLENGE IN PREGNANCY IS INDUCED BY ALLOPREGNANOLONE

Research output: Contribution to conferenceAbstract

Abstract

The hypothalamus-pituitary-adrenal (HPA) axis is the major neuroendocrine stress response system and is activated by immune signals that indicate infection. Corticotropin-releasing hormone (CRH) neurones in the parvocellular paraventricular nucleus (pPVN) play a key role in co-ordinating responses of this system to stressors. Systemic administration of the cytokine interleukin-1 (IL-1) robustly activates these CRH neurones via a noradrenergic pathway arising in the nucleus tractus solitarii (NTS). In late pregnancy, HPA responses to IL-1 are essentially absent due to reduced stimulation of the pPVN CRH neurones1. This is not a result of a failure of IL-1β to activate brainstem afferents to the PVN, as systemic IL-1 still activates NTS neurones in pregnancy (measured by Fos expression). However microdialysis experiments reveal that noradrenaline release after IL-1 is increased in the PVN of only virgin rats1. This difference is explained by the emergence of an endogenous opioid mechanism which acts presynaptically to block IL-1-induced noradrenaline release in the PVN1. Hence, in pregnant rats, antagonising opioids with naloxone restores HPA responses to IL-1 and when applied directly into the PVN, naloxone restores IL-1β-evoked noradrenaline release within the PVN1. The source of the opioid peptide and receptor is evidently the NTS neurones that project to the PVN as mRNA expression for proenkephalin-A (pENK-A), and the mu-opioid receptor is increased in the NTS A2 region in late pregnancy1.

We have sought to identify the pregnancy signal that induces opioid inhibition over HPA axis responses. The female sex steroids, estradiol and progesterone, are produced in increasing amounts in pregnancy, but mimicking the levels found in pregnancy in virgin rats does not attenuate HPA axis stress responses2. However, allopregnanolone (5α-pregnan-3α-ol-20-one), the neuroactive steroid metabolite of progesterone, is abundant in the brain in pregnancy3 and is a putative candidate. Allopregnanolone is produced by the sequential action of 5-reductase and 3-hydroxysteroid dehydrogenase (3-HSD), both of which are expressed in the brain4. Allopregnanolone acts as an allosteric modulator at GABAA receptors to enhance the effectiveness of GABA actions5 and, moreover has been shown to reduce stress-induced HPA axis activity in male rats6.

We have blocked allopregnanolone production with a 5-reductase inhibitor (finasteride), and found this restored HPA axis responses to IL-1 in pregnant rats (rapidly increased pPVN CRH mRNA expression, ACTH and corticosterone secretion)7. Conversely, in virgin rats allopregnanolone attenuated HPA responses to IL-17. Neither of the allopregnanolone precursors, progesterone nor dihydroprogesterone, reduced HPA responses to IL-1β in virgin rats, indicating ineffective conversion to allopregnanolone. Indeed, compared with non-pregnant females, we found the activity of the allopregnanolone-synthesising enzymes, 5-reductase and 3-hydroxysteroid dehydrogenase was increased in the hypothalamus in late pregnancy, as was mRNA expression in the NTS and PVN7.

Allopregnanolone appears to depend upon the actions of endogenous opioids to exert its suppressive effects on HPA axis activity. While naloxone restores HPA axis responses to IL-1 in pregnancy, it has no further effect when given in combination with finasteride7. Moreover the attenuated HPA response to IL-1 seen in virgins treated with allopregnanolone is reversed by naloxone7 suggesting allopregnanolone induces opioid inhibition over HPA responses to IL-1 in virgin rats. In pregnancy, proenkephalin-A mRNA expression is up-regulated in the NTS1. This effect can be reversed in pregnant rats with finasteride treatment and mimicked in virgin rats with allopregnanolone treatment7.

Thus, in pregnancy allopregnanolone induces inhibitory opioid mechanisms that restrain HPA responses to IL-1. This novel opioid-mediated mechanism may explain other neuroendocrine adaptations that ensure a successful pregnancy outcome. Furthermore these adaptations in HPA axis responsiveness may play an important role in altered metabolic and immune balance in pregnancy, and in protecting fetuses from adverse early life programming.
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References:
1Brunton, P.J. et al (2005) J Neurosci 25: 5117-26.
2Douglas, A.J. et al (2000) J Neuroendocrinol 12: 343-50.
3Concas, A. et al (1998) Proc Natl Acad Sci USA 95:13284-89.
4Compagnone, N. A.& Mellon, S. H. (2000) Front Neuroendocrinol 21: 1-56.
5Herd, M. B. et al (2007) Pharmacol Ther 116: 20-34.
6Patchev, V. K et al (1996) Neuropsychopharmacology 15: 533-540.
7Brunton, P.J. et al (2009) J Neurosci 29: 6449-60.

Financial Support: BBSRC
Original languageEnglish
Publication statusUnpublished - 2011
Event6th International Meeting Steroids and Nervous System - Turin, Italy
Duration: 19 Feb 201123 Feb 2011

Conference

Conference6th International Meeting Steroids and Nervous System
Country/TerritoryItaly
CityTurin
Period19/02/1123/02/11

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