Carbon monoxide as a novel mediator of the febrile response in the central nervous system.

Heme oxygenase catalyzes the metabolism of heme to biliverdin, free iron, and carbon monoxide (CO), which has been shown to be an important neuromodulatory agent. Recently, it has been demonstrated that lipopolysaccharide (LPS) can induce the enzyme heme oxygenase in glial cells. Therefore, the present study was designed to test the hypothesis that central CO plays a role in LPS-induced fever. Colonic body temperature (Tb) was measured in awake, unrestrained rats (basal Tb= 36.8 ± 0.2°C). Intracerebroventricular injection of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG; 75 nmol), a heme oxygenase inhibitor, caused no significant change in Tb, indicating that the central heme oxygenase pathway plays no tonic role in Tb under the experimental conditions used. Intraperitoneal injections of LPS (50-100 μg/kg) evoked dose-dependent increases in Tb. Intracerebroventricular injection of ZnDPBG in febrile rats attenuated LPS-induced fever (thermal index with ZnDPBG = 1.1 ± 0.2°C, thermal index with vehicle = 2.3 ± 0.4°C), suggesting that the central heme oxygenase pathway plays a role in fever generation. The antipyretic effect of ZnDPBG could be reversed by intracerebroventricular administration of heme-lysinate or CO-saturated saline. Collectively, our data indicate that CO arising from heme oxygenase may play an important role in fever generation by acting on the central nervous system.