The endogenous opioid system has been found to be involved in fever caused by pyrogens. In the present study, we have investigated the role of the μ-opioid receptor in the brain in fever induced by lipopolysaccharide. Rats were microinjected with 1 μg of the μ-opioid receptor-selective antagonist, cyclic d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), into the preoptic anterior hypothalamus. Thirty minutes later, lipopolysaccharide (50 μg/kg) was injected intraperitoneally (i.p.). CTAP reduced by 1 o C the fever induced by lipopolysaccharide. However, it did not affect lipopolysaccharide fever when it was given 3 h after lipopolysaccharide injection. These data indicate that μ-opioid receptors within the preoptic anterior hypothalamus mediate the initiation of lipopolysaccharide fever and suggest that the opioid system is involved in the pathogenesis of fever in rats.