Caffeine, an adenosine A₁, A_2A, and A_2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with nonsteroidal anti-inflammatory drugs or opioids. In this study, we have examined the effects of novel specific adenosine receptor antagonists in an acute animal model of nociception. Several A_2B-selective compounds showed antinociceptive effects in the hot-plate test. In contrast, A₁- and A_2A-selective compounds did not alter pain thresholds, and an A₃ adenosine receptor antagonist produced thermal hyperalgesia. Evaluation of psychostimulant effects of these compounds in the open field showed only small effects of some antagonists at high doses. Coadministration of low, subeffective doses of A_2B-selective antagonists with a low dose of morphine enhanced the efficacy of morphine. Our results indicate that analgesic effects of caffeine are mediated, at least in part, by A_2B adenosine receptors.