We examined the effects of various nitric oxide synthase (NOS) inhibitors on carrageenan-induced thermal hyperalgesia. 2. First, we determined the time point at which a subcutaneous plantar injection of carrageenan into the rat hindpaw produced maximum thermal hyperalgesia. Subsequently, we demonstrated that intrathecal administration of the non-selective NOS inhibitor L-N(G)-nitro-arginine methyl ester (L-NAME) produces a dose-dependent reduction of carrageenan-induced thermal hyperalgesia. 3. Four relatively selective NOS inhibitors were then tested for their efficacy at reducing carrageenan-induced thermal hyperalgesia. Initially, the effects of prolonged treatment with inhibitors of neuronal [7-nitroindazole (7-NI) and 3-bromo-7-nitroindazole (3-Br)] and inducible [aminoguanidine (AG) and 2-amino-5,6-dihydro-methylthiazine (AMT)] NOS were examined. All agents were injected three times intrathecally during the course of inflammation caused by the plantar injection of carrageenan, and thermal hyperalgesia was measured at 6 h post-carrageenan using a plantar apparatus. 4. All inhibitors, except for 7-NI, were effective at attenuating the carrageenan-induced thermal hyperalgesia when compared with vehicle treatment. 5. Finally, the effects of early versus late administration of neuronal and inducible NOS inhibitors on carrageenan-induced thermal hyperalgesia were examined. We found that neither 3-Br nor AG significantly affected thermal hyperalgesia when administered during the early phase of carrageenan inflammation, while only AG was able to reduce thermal hyperalgesia when administered during the late phase of the injury. 6. Our results suggest that inducible NOS contributes to thermal hyperalgesia in only the late stages of the carrageenan-induced inflammatory response, while neuronal NOS likely plays a role throughout the entire time course of the injury.
