Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat

Interleukin (IL)-1 is a potent endogenous pyrogen which causes fever when injected into a number of brain sites. However, the brain sites at which endogenous IL-1 acts to influence body temperature remain equivocal. The aim of this study was to determine the effect of local administration of the interleukin-1 receptor antagonist (IL-1ra) into specific sites in the hypothalamus, and other brain regions known to contain receptors for IL-1, on the febrile response of rats to peripheral injection of lipopolysaccharide (LPS) into a subcutaneous air pouch (intrapouch, i.p.o.) that does not lead to LPS appearance in the circulation. Injection of LPS (100 μg kg −1 , i.p.o.) induced a rise in body temperature which commenced 1·5 h after injection and was maximal at 3 h (38·9 ± 0·2 °C, compared with 37·0 ± 0·1 °C at 0 h, n = 6, P < 0·001). Intracerebroventricular (i.c.v.) IL-1ra (500 μg in 5 μl) significantly attenuated LPS fever (IL-1ra, 37·7 ± 0·2 °C; saline, 38·9 ± 0·2 °C; n = 6, P < 0·001). Unilateral microinjection of IL-1ra (50 μg in 0·5 μl at 0 + 1 h) into the anterior hypothalamus (AH), paraventricular hypothalamic nucleus (PVH), peri-subfornical organ, subfornical organ (SFO) or hippocampus (dentate gyrus and CA3 region) also significantly reduced the fever induced by LPS. The same dose of IL-1ra had no effect on fever when administered into the ventromedial hypothalamus (VMH), organum vasculosum lamina terminalis (OVLT), CA1 field of the hippocampus, striatum or cortex. These data indicate that the action of endogenous IL-1 in the brain during fever is site specific, acting at the AH, PVH, SFO and hippocampus, but not the VMH, OVLT and striatum or cortex.