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

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-1 beta (IL-1 beta), to investigate the underlying mechanisms. Intravenous IL-1 beta 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-1 beta in virgin and in late pregnant rats, pPVN CRH neurones are activated only in virgin rats. As a consequence IL-1 beta 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-1 beta 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.