Carbon monoxide as a novel mediator of the febrile response in the centralnervous system

Heme oxygenase catalyzes the metabolism of heme to biliverdin,free iron, an d carbon monoxide (CO), which has been shown to be an important neuromodula tory agent. Recently, it has been demonstrated that lipopolysaccharide (LPS ) can induce the enzyme heme oxygenase in glial cells. Therefore, the prese nt study was designed to test the hypothesis that central CO plays a role i n LPS-induced fever. Colonic body temperature (T-b) was measured in awake, unrestrained rats (basal T-b = 36.8 +/- 0.2 degrees C). Intracerebroventric ular injection of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG; 75 nmol), a heme oxygenase inhibitor, caused no significant change in T-b, indicating that the central heme oxygenase pathway plays no tonic role in T-b under th e experimental conditions used. Intraperitoneal injections of LPS (50-100 m u g/kg) evoked dose-dependent increases in T-b. Intracerebroventricular inj ection of ZnDPBG in febrile rats attenuated LPS-induced fever (thermal inde x with ZnDPBG = 1.1 +/-. 0.2 degrees C, thermal index with vehicle = 2.3 +/ - 0.4 degrees C), suggesting that the central heme oxygenase pathway plays a role in fever generation. The antipyretic effect of ZnDPBG could be rever sed by intracerebroventricular administration of hemelysinate or GO-saturat ed saline. Collectively, our data indicate that CO arising from heme oxygen ase may play an important role in fever generation by acting on the central nervous system.