Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone
Open accessAbstract
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.
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Allopregnanolone induces GABAergic inhibition of HPA axis activation in female rats and pregnant women.
“Allopregnanolone has induced the GABAergic inhibition of HPA axis activation in female rats [93,94] and pregnant women [95].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [95]
The Results and Discussion report that allopregnanolone attenuated HPA-axis responses to an immune challenge in pregnant and nonpregnant female rats. The “Role of allopregnanolone” section proposes that it might enhance GABA action; it does not establish GABAergic inhibition as the mechanism. Pregnant women are cited separately as [95] in the citing sentence, so that part is not attributed to this rat study. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTetrahydrodeoxycorticosterone (TH-DOC) attenuates HPA axis function.
“another potent GABAA receptor modulator and deoxycorticosterone-derived steroid, tetrahydrodeoxycorticosterone (TH-DOC), also attenuates the HPA axis function (77, 82, 83).”
From Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis (2020) · cites this paper as [77]
The Allopregnanolone-synthesizing enzymes section (page unavailable) identifies TH-DOC as a deoxycorticosterone-derived neurosteroid acting like allopregnanolone. The paper reports that allopregnanolone reduces HPA responses, but does not show that TH-DOC does so; it says reduced TH-DOC formation is unlikely to explain the effects observed in this study. (LLM, conf=0.83)
Experimental — accuracy not yet measuredStudies in rodents show an inhibitory effect of allopregnanolone on the function of the HPA axis.
“Studies in rodents show an inhibitory effect of allopregnanolone on the function of the HPA axis (77–79).”
From Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis (2020) · cites this paper as [77]
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- Authors
- Brunton, P. J., McKay, A. J., Ochędalski, T., Piastowska, A., Rębas, E., Lachowicz, A., & Russell, J. A.
- Affiliations
- University of Edinburgh (GB)
- Medical University of Lodz (PL)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-05-20
- Volume
- 29
- Issue
- 20
- Pages
- 6449-6460
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665894
- OpenAlex
- W1980099277
- Cited by
- 126
- References
- 57
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 5 · 2016: 9 · 2015: 13 · 2014: 10 · 2013: 11 · 2012: 3
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ERA (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- allopregnanolone, pregnancy, hypothalamic-pituitary-adrenal axis, corticotropin-releasing factor, paraventricular nucleus, IL-1β, 5α-reductase, finasteride, nucleus tractus solitarius, noradrenaline release, proenkephalin A, neurosteroids, progesterone metabolites, stress response, naloxone
- MeSH terms
- Adrenocorticotropic Hormone, Analgesics, Opioid, Analysis of Variance, Anesthetics, Animals, Chromatography, Thin Layer, Corticosterone, Corticotropin-Releasing Hormone, 20-alpha-Dihydroprogesterone, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Female, Hypothalamo-Hypophyseal System, Neural Inhibition, Neurons, Oxidoreductases, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, Pregnancy, Pregnancy, Animal, Pregnanolone, Progestins, Progesterone, RNA, Messenger, Stress, Physiological, Time Factors, Rats, Sprague-Dawley, Finasteride, Rats, Interleukin-1beta
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