Allopregnanolone (AP) induces opioid inhibition of hypothalamo-pituitary-adrenal (HPA) axis responses to interleukin-1β (IL-1β) in pregnancy

In late pregnancy HPA axis responses to cytokine challenge with systemic IL-1β are suppressed. Endogenous opioids [1] and AP [2] (a progesterone metabolite and GABA_A receptor enhancer) are involved. Here, we measured plasma ACTH via chronic jugular cannulae, to test whether opioid and AP actions on HPA responsiveness are linked. Pregnant (d21) rats were pretreated with finasteride (5α-reductase inhibitor, 25mg/kg sc) to block AP production (20h and 2h before IL-1β) and/or naloxone (opioid antagonist; 5mg/kg iv) 30min pre-IL-1β. Virgin rats were treated with AP (3mg/kg and 1mg/kg sc, -20h and -2h) and/or naloxone. Controls received vehicle. In the controls, IL-1β (500ng/kg iv) increased ACTH secretion in virgin, but not pregnant rats. Finasteride pre-treatment partially restored an ACTH response to IL-1β in pregnant rats, as did naloxone; with no additive effect of finasteride and naloxone, suggesting the actions of AP and opioid are not independent. AP treatment reduced ACTH responses to IL-1β in virgin rats, while naloxone alone had no effect. However, naloxone restored an ACTH response to IL-1β in AP-treated virgin rats, indicating that AP induces opioid tone. In pregnancy, proenkephalin-A (pENK-A) mRNA expression is up-regulated in the nucleus tractus solitarius (NTS)¹, where IL-1β actions are transduced. Here, AP-treatment increased pENK-A mRNA (measured by in situ hybridisation) expression in the NTS of virgin rats. Thus, in pregnancy AP induces opioid inhibition of HPA responses to IL-1β, possibly through up-regulated pENK-A expression in the NTS. [Support: BBSRC, British Council UK/KBN, Poland].

[1] Brunton et al J Neurosci (2005) 25: 5117–5126

[2] Brunton et al BES abstracts (2004):OC1