Intrathecal administration of endothelin-1 (ET-1) produced a dose-dependent increase in tail-pinch latency, i.e., antinociception, in both diabetic and non-diabetic mice. The dose ranges which produced a significant antinociception in diabetic mice (0.0001 to 0.0003 nmol) were lower than those in non-diabetic mice (0.001 to 0.003 nmol). Furthermore, the antinociceptive effect of ET-1 in diabetic mice was decreased when the doses of ET-1 were increased. Indeed, when ET-1 in a dose of 0.003 nmol, which produced significant antinociception in non-diabetic mice, it had no antinociceptive effect in diabetic mice. These results suggest that the mechanism which underlies the antinociceptive effects of ET-1 is up-regulated in diabetic mice, as compared with that in non-diabetic mice.