Carbon monoxide (CO) are produced by heme oxygenase (HO), and HO was detected in hypothalamus. However, the roles of CO produced in hypothalamus was not fully elucidated. So, we tested the effects of CO on body temperature because preoptic-anterior hypothalamus was known as the presumptive primary fever-producing site. CO-saturated aCSF (4 microl, i.c.v.) and hemin (10 microg, i.c.v.) elicited marked febrile response. Pretreatment with indomethacin completely inhibited CO- and hemin-induced fever. Zinc protoporphyrin-IX (10 microg, i.c.v.) or ODQ (50 microg, i.c.v.) partially reduced hemin-induced febrile response. Dibutyryl-cGMP (100 microg, i.c.v.) produced profound febrile response and this febrile response was attenuated by indomethacin. These results indicate that endogenous CO may have a role as a pyrogenic mediator in CNS and CO-mediated pyresis is dependent on prostaglandin production and partially on activation of soluble guanylate cyclase.