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The Journal of Neuroscience, May 25, 2005, 25(21):5117-5126; doi:10.1523/JNEUROSCI.0866-05.2005

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Behavioral/Systems/Cognitive
Endogenous Opioids and Attenuated Hypothalamic-Pituitary-Adrenal Axis Responses to Immune Challenge in Pregnant Rats

Paula J. Brunton,¹ Simone L. Meddle,¹ Shuaike Ma,² Tomasz Ochedalski,³ Alison J. Douglas,¹ and John A. Russell¹

¹Laboratory of Neuroendocrinology, Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom, ²Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, and ³Institute of Gynecology and Obstetrics, Medical University of Lodz, 94-029 Lodz, Poland

In late pregnant rats, the hypothalamic-pituitary-adrenal (HPA) axis is hyporesponsive to psychogenic stressors. Here, we investigated attenuated HPA responses to an immune challenge and a role for endogenous opioids. ACTH and corticosterone were assayed in blood samples from virgin and 21 d pregnant rats before and after endotoxin [lipopolysaccharide (LPS); 1 µg/kg, i.v.], interleukin-1 (IL-1; 500 ng/kg, i.v.), or vehicle. In virgins, plasma ACTH concentrations increased 1 h after LPS and 15 min after IL-1, as did corticosterone, with no responses in pregnant rats. In situ hybridization revealed increased corticotrophin releasing hormone (CRH) mRNA expression in the dorsomedial parvocellular paraventricular nucleus (pPVN) and increased anterior pituitary pro-opiomelanocortin mRNA expression 4 h after IL-1 in virgins; these responses were absent in pregnant rats. In contrast, immunocytochemistry showed that Fos expression was similarly increased in the nucleus tractus solitarius (NTS) A2 region in virgin and pregnant rats 90 min and 4 h after IL-1. Naloxone pretreatment (5 mg/kg, i.v.) restored ACTH and pPVN CRH mRNA responses after IL-1 in pregnant rats but reduced the CRH mRNA response in virgins without affecting ACTH. Proenkephalin-A and µ-opioid receptor mRNA expression in the NTS was significantly increased in the pregnant rats, indicating upregulated brainstem opioid mechanisms. IL-1 increased noradrenaline release in the PVN of virgin, but not pregnant, rats. However, naloxone infused directly into the PVN increased noradrenaline release after IL-1 in pregnant rats. Thus, the HPA axis responses to immune signals are suppressed in pregnancy at the level of pPVN CRH neurons through an opioid mechanism, possibly acting by preterminal autoinhibition of NTS projections to the pPVN.

Key words: ACTH; CRH mRNA; IL-1; µ-opioid receptor mRNA; noradrenaline; nucleus tractus solitarius; proenkephalin-A mRNA

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Received March 10, 2004; revised April 11, 2005; accepted April 14, 2005.

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