Tolerance to the antinociceptive effect of epibatidine after acute and chronic administration in mice

Epibatidine is a novel potent antinociceptive agent that acts through nicotinic receptors. In this study we investigated the development of tolerance to the antinociceptive effects of epibatidine enantiomers after acute and chronic administration in mice using the tail-flick test. Contrary to nicotine, mice treated with epibatidine enantiomers at different times and doses did not develop significant tolerance after s.c. acute nor after repeated injections. In mice that chronically received (+)-epibatidine, no significant tolerance was seen after acute challenge with (+)-epibatidine. However, a significant shift in (-)-epibatidine's dose-response curve was obtained in animals that received (-)-epibatidine. In nicotine-tolerant animals, no significant tolerance was seen after acute challenge with (+)-epibatidine. However, the animals were less sensitive to the acute (-)-epibatidine challenge. Our results show that development of tolerance to epibatidine antinociceptive effects has a different profile and characteristics than that found for nicotine.