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Dopamine neurons in the ventrolateral periaqueductal gray (PAG) have been reported to contribute to antinociception. The objective of this study was to determine how this dopamine-mediated antinociception differs from what is known about morphine-induced antinociception. Microinjection of the dopamine receptor agonist apomorphine into the PAG produced a dose-dependent increase in hot plate latency and a decrease in open field activity that was greater in male than in female rats. The peak antinociceptive effect occurred 5 min after apomorphine administration. Surprisingly, the antinociceptive potency of apomorphine was enhanced following systemic administration of the opioid receptor antagonist naloxone in male, but not in female rats. The antinociceptive potency of microinjecting apomorphine into the ventrolateral PAG in male and female rats was also enhanced following twice-daily injections for 2 days. The characteristics of apomorphine-induced antinociception differ from previous reports of morphine antinociception following PAG microinjections in that morphine antinociception peaks at 15 min, is blocked by naloxone, and is susceptible to tolerance with repeated administration. These results indicate that apomorphine-induced antinociception is distinct from opioid-induced antinociception, and that dopamine receptor agonists may provide a novel approach to pain modulation.