We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150 mg/kg; −1 h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150 mg/kg; p.o., −1 h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300 μg) and nociceptive pain induced by exposure to noxious heat (50 °C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10 mg/kg, −30 min) attenuated or abolished the antinociceptive activity of nicorandil (100 mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity.