Heme oxygenase type 2 plays a role in formalin-induced nociception

Although much attention has been focused in recent years on nitric oxide synthase (NOS) as an enzyme intimately involved in many types of nociceptive signaling, the enzyme heme oxygenase (HO) has received little attention. Yet, HO produces gaseous second messenger molecule CO which, like NO, has proven to be an important neurotransmitter in the CNS. In these studies we provide detailed evidence that HO activity is critical to formalin-induced licking behavior in mice. The HO inhibitor tin protoporphyrin (Sn-P) dose-dependently reduced formalin-stimulated licking behavior in both phases of the formalin assay. This apparent analgesic effect was unlikely due to the non-specific effects of this agent as Sn-P did not alter rotarod performance, and the blood-brain barrier impermeant HO inhibitor zinc protoporphyrin (Zn-P) had little effect on licking times. We also hypothesized that heme oxygenase type 2 (HO-2) was the specific isoform of HO involved in nociception. Mice with a targeted disruption of the HO-2 gene were found to have greatly reduced licking times. Furthermore, Sn-P did not further reduce licking times when administered to HO-2 knockout animals. Taken together our evidence indicates that HO plays an important role in nociceptive signaling related to inflammatory-type pain, and that HO-2 is the isozyme mediating this nociception.