CENTRAL EFFECTS OF GLUCOCORTICOID RECEPTOR ANTAGONIST RU-38486 ON LIPOPOLYSACCHARIDE AND STRESS-INDUCED FEVER

Intracerebroveritricular administration of the glucocorticoid type II receptor antagonist RU-38486 leads to an increased fever after injecti on of lipopolysaccharide (LS) in awake unrestrained rats, indicating t hat endogenous glucocorticoids act centrally to lower temperature afte r the intraperitoneal injection of LPS. The current study examined whe re in the brain glucocorticoids exert these effects on fever and if th ese effects involve plasma interleukin-6 and corticosterone: RU-38486 injected intracerebroventricularly (10 ng/animal) led to a significant ly greater rid in biotelemetered body temperature (BT) 120-240 min pos t-LPS (50 mg/kg ip) compared with controls (0.89 +/- 0.14 vs. 0.44 +/- 0.22 degrees C, P = 0.0482), confirming our earlier study; and also l ed to a significantly greater rise in BT after exposure to an open fie ld when the RU-38486 was infused intracerebroventricularly (10 ng/ml, 1 mu l/h) for 20 h before the exposure (1.48 +/- 0.18 vs. 1.06 +/- 0.1 1 degrees C, P = 0.023). When rats were injected with RU-38486 into th e anterior hypothalamus (1 ng/animal), there was an increased rise in BT after injection of LPS (1.74 +/- 0.27 vs. 0.82 +/- 0.22 degrees C, P = 0.0075) but not after exposure to an open field (1 ng intrahypotha lamically, 1 h preexposure). There were nb differences in plasma inter leukin (IL)g-like activity or plasma corticosterone after intracerebro ventricular injection of RU-38486 and intraperitoneal injection of LPS . We conclude that endogenous glucocorticoids are working centrally to modulate fever after LPS and exposure to open field, and that LPS-ind uced fever is modulated by glucocorticoids in the anterior hypothalamu s. The precise location of glucocorticoid negative feedback on psychol ogical stress-induced fever is not known.