Basal and PAF-, interleukin 1-, ether stress-induced hypothalamic pituitary adrenal secretion of conscious rat: modulation by PAF antagonists.

We have previously shown that exogenous (1 to 5 nmol i.c.v.) PAF induces a rapid increase in plasma ACTH and beta endorphin followed by an increase in plasma corticosterone in conscious rats. The stimulatory action of PAF on the secretion of hypothalamic-pituitary-adrenal (HPA) axis products is mediated at least partly by stimulating hypothalamic CRF release. In addition rat hypothalamic membranes have two populations of specific PAF binding sites. In order to clarify the mode of PAF action on the stress-related hormones, we have now investigated the effect of two PAF antagonists, BN 50739 and RP 52770, on basal and PAF-induced ACTH and corticosterone secretion by conscious rats and on PAF specific binding to rat hypothalamic membranes. The role of PAF as a mediator of neuroendocrine secretion in response to acute stress was examined by determining the effect of PAF antagonists on ether-stress inducing HPA activity. We have also investigated their effect on IL 1-induced HPA activity. The ability of BN 50739 and RP 52770 to displace 3H PAF from its hypothalamic binding sites was correlated with their ability to alter basal hormone secretion and to counteract the PAF-stimulated secretion of HPA axis hormones in vivo (P less than 0.05 by ANOVA). Pretreatment with BN 50739. (50 nmol i.c.v.) did not alter ACTH response to a 1 min ether exposure or to IL1 beta injection (2 nmol i.c.v.). In contrast, RP 52770 (55 nmol i.c.v.) significantly inhibited the ether stress-induced ACTH and corticosterone production by 50% (P less than 0.05). In parallel, pretreatment with RP 52770 (55 nmol i.c.v.) caused a significant inhibition of IL1 beta-induced ACTH secretion. These results suggest that PAF acts, in vivo, on ACTH and corticosterone secretion, through a centrally mediated CRF dependent mechanism involving PAF receptor sites. Additionally, the data also indicate that PAF could have a central role in mediating basal and stress-induced ACTH secretion and that IL 1-induced HPA secretion may be mediated at least in part through the production of PAF.