Allopregnanolone and suppressed hypothalamo–pituitary–adrenal axis stress responses in late pregnancy in the rat

In rats, late pregnancy is associated with suppressed hypothalamo-pituitary-adrenal (HPA) axis responses to a variety of stressful stimuli. The result is reduced corticosterone secretion following stress, which is considered to give some protection to the fetuses from adverse glucocorticoid programming and limits the catabolic effect of corticosterone, hence minimizing maternal energy expenditure. We have used a model of immune challenge in which systemic administration of the cytokine, interleukin-1β (IL-1β), allows study of the mechanisms underlying HPA axis hyporesponsiveness in late pregnancy. Suppressed responsiveness of parvocellular paraventricular nucleus (pPVN) corticotropin-releasing hormone neurons, and hence the HPA axis, following IL-1β in late pregnancy is evidently explained by presynaptic inhibition of noradrenaline release in the pPVN, owing to increased endogenous opioid peptide enkephalin production in brainstem nucleus tractus solitarii neurons. Allopregnanolone, a neurosteroid metabolite of progesterone, signals the pregnancy status of the animal to the brain and stimulates opioid production in the brainstem. In this review, we discuss the supporting evidence for these mechanisms.