Attenuated hypothalamo-pituitary-adrenal axis responses to immune challenge during pregnancy: the neurosteroid opioid connection

Abstract

In late pregnancy maternal hypothalamo-pituitary-adrenal (HPA) axis responses to emotional and physical stressors are attenuated. This is expected to minimize the detrimental programming effects of glucocorticoid exposure on the fetuses. We have utilized a model of immune challenge, systemic administration of interleukin-1beta (IL-1beta), to investigate the underlying mechanisms. Intravenous IL-1beta activates corticotropin-releasing hormone (CRH) neurones in the parvocellular division of the paraventricular nucleus (pPVN) via noradrenergic (A2 cell group) neurones in the nucleus tractus solitarii (NTS). Despite comparable activation of these brainstem neurones by IL-1beta in virgin and in late pregnant rats, pPVN CRH neurones are activated only in virgin rats. As a consequence IL-1beta fails to evoke ACTH and corticosterone secretion in late pregnant rats, in contrast to virgin rats. Suppressed responsiveness of the CRH neurones, and hence the HPA axis, following IL-1beta in late pregnancy is explained by presynaptic inhibition of noradrenaline release in the pPVN, due to increased endogenous enkephalin and mu-opioid receptor production in brainstem NTS neurones. The factor that signals to the brain the pregnancy status of the animal and stimulates opioid production in the brainstem is allopregnanolone, a neurosteroid metabolite of progesterone. The supporting evidence for these mechanisms is discussed.

Figure 1. Responsiveness of the HPA axis in late pregnancy

The mean increase in ACTH secretion (expressed relative to basal (dotted line) plasma concentrations). A, 15 min after the onset of a 30 min period of restraint (a psychological stressor) in conscious virgin (n = 4) and day 21 pregnant (n = 5) rats. B, 15 min after administration of interleukin-1β (a physical stressor; 500 ng kg⁻¹i.v.) in conscious virgin (n = 8) and day 21 pregnant (n = 7) rats. Values are group means ± s.e.m.*P < 0.001 Student's t test. Blood was collected from rats via a chronic jugular vein cannula implanted 5 days prior to the experiment under inhalation of halothane anaesthesia (2–3% in 600 ml min⁻¹ each of oxygen and nitrous oxide) in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986 and local (University of Edinburgh) ethics guidelines. Data in B from Brunton et al. (2005). C, schematic diagram representing the timescale of the change in HPA axis responsiveness during pregnancy. In early pregnancy (days 0–10) ACTH secretory responses to stressors (elevated plus maze, forced swimming, restraint) are indistinguishable from those observed in virgin rats. Between days 11 and 15 the mechanisms that restrain the HPA axis in late pregnancy emerge resulting in a progressive reduction in HPA axis responsiveness until term when ACTH responses are minimal.

Figure 2. How circulating IL-1β signals to the HPA axis

Circulating interleukin-1β (IL-1β) binds to IL-1 receptors (IL-1R) on the endothelium of brain blood vessels, stimulating (+) cyclo-oxygenase (COX) and local production of prostaglandins. Prostaglandins activate A2 noradrenergic neurones (via EP receptors) in the nucleus tractus solitarii (NTS) which project directly to the parvocellular division of the paraventricular nucleus (pPVN). Noradrenaline released from the nerve terminals in the pPVN acts via α-adrenoreceptors to activate CRH neurones. CRH released at the median eminence enters the hypothalamo-hypophysial portal system and acts on CRH type 1 receptors on anterior pituitary corticotropes to trigger ACTH secretion, which in turn stimulates corticosterone secretion from the cortex of the adrenal glands. Other neural circuitry involving the parabrachial nucleus (PB), central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) is also involved in signalling to the CRH neurones following systemic IL-1β.

Figure 3. Proposed mechanism of suppressed HPA axis responses in late pregnancy

Central and circulating levels of allopregnanolone are increased (↑) in pregnancy. Allopregnanolone increases the expression of mRNA for proenkephalin-A (and perhaps for μ-opioid receptor) in the A2 cell region of the nucleus tractus solitarii (NTS). NTS noradrenergic A2 neurones innervate CRH neurones in the parvocellular division of the paraventricular nucleus (pPVN) and are activated (+) following systemic administration of interleukin-1β (IL-1β; see Fig. 2). However, in late pregnancy, increased opioid (enkephalin) inhibition prevents IL-1β from stimulating noradrenaline release in the PVN. Enkephalin acts presynaptically on μ-opioid receptors (MOR) to inhibit noradrenaline release from nerve terminals in the PVN. The opioid receptor antagonist, naloxone, restores HPA axis responses to IL-1β when administered systemically, and when infused directly into the PVN reinstates noradrenaline release evoked by IL-1β. Induction of this inhibitory (−) opioid mechanism by allopregnanolone in late pregnancy prevents activation of the CRH neurones and consequently HPA axis responses to IL-1β are suppressed (↓).