Central effects of glucocorticoid receptor antagonist RU-38486 on lipopolysaccharide and stress-induced fever.
Intracerebroventricular administration of the glucocorticoid type II receptor antagonist RU-38486 leads to an increased fever after injection of lipopolysaccharide (LPS) in awake unrestrained rats, indicating that endogenous glucocorticoids act centrally to lower temperature after the intraperitoneal injection of LPS. The current study examined where in the brain glucocorticoids exert these effects on fever and if these effects involve plasma interleukin-6 and corticosterone. RU-38486 injected intracerebroventricularly (10 ng/animal) led to a significantly greater rise in biotelemetered body temperature (BT) 120-240 min post-LPS (50 mg/kg ip) compared with controls (0.89 +/- 0.14 vs. 0.44 +/- 0.22 degree C, P = 0.0482), confirming our earlier study, and also led to a significantly greater rise in BT after exposure to an open field when the RU-38486 was infused intracerebroventricularly (10 ng/ml, 1 microliter/h) for 20 h before the exposure (1.48 +/- 0.18 vs. 1.06 +/- 0.11 degree C, P = 0.023). When rats were injected with RU-38486 into the 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 degree C, P = 0.0075) but not after exposure to an open field (1 ng intrahypothalamically, 1 h preexposure). There were no differences in plasma interleukin (IL)-6-like activity or plasma corticosterone after intracerebroventricular 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-induced fever is modulated by glucocorticoids in the anterior hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)
McClellan
J L
JL
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109.
Klir
J J
JJ
Morrow
L E
LE
Kluger
M J
MJ
D000818:Animals; D007025:Anterior Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D005334:Fever / Q000139:chemically induced* / Q000209:etiology*; D007276:Injections, Intraventricular; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological / Q000150:complications*
D015850:Interleukin-6; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003345:Corticosterone