Antihyperalgesic Effects of Indomethacin, Ketorolac, and Metamizole in Rats: Effects of Metformin.

Preclinical Research Metformin-dependent mechanisms have been implicated in the antinociceptive effect of some non-steroidal anti-inflammatory drugs (NSAIDs). In this study, the effect of local peripheral or systemic administration of metformin on the local peripheral or systemic antinociception induced by indomethacin, ketorolac and metamizole was assessed in the rat carrageenan-induced thermal hyperalgesia model. Rats were injected with carrageenan (1%, 50 µl) into the right hindpaw which reduced paw withdrawal latency, a measure of thermal hyperalgesia. Local peripheral or systemic administration of indomethacin, ketorolac or metamizole dose-dependently reduced carrageenan-induced thermal hyperalgesia. Local peripheral pre-treatment with metformin (800 µg/paw) partially inhibited the anti-hyperalgesic effect of indomethacin (200 µg/paw) and metamizole (200 µg/paw), but not that of ketorolac (200 µg/paw). In contrast, systemic pre-treatment with metformin (200 mg/kg) attenuated the antihyperalgesic effect of metamizole (10 mg/kg), but not that observed with either indomethacin (10 mg/kg) or ketorolac (10 mg/kg). These findings suggest that some but not all NSAIDs have effects mediated by metformin-dependent mechanisms. Drug Dev Res 78 : 98-104, 2017. ©2017 Wiley Periodicals, Inc.