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Better therapeutic options are needed for pain. Baclofen, buspirone, and morphine are characterized as having analgesic properties. However, little is known about potential interactions between analgesic effects of these drugs when combined. Furthermore, it is not known if the magnitude of these potential interactions will be similar for all drug effects. Thus, we tested the effects of these drugs alone and in combination for their capacity to produce thermal antinociception and to decrease food-maintained responding. Four male and four female Sprague-Dawley rats responded for food under a fixed-ratio 10 schedule; afterward they were immediately placed on a 52°C hot plate. Morphine, baclofen, and buspirone were examined alone and in 1:1 combinations, based upon ED 50 values. Morphine and baclofen effects were evaluated with the opioid antagonist naltrexone and the GABA B antagonist (3-Aminopropyl)(diethoxymethyl)phosphinic acid (CGP35348), respectively. Morphine, baclofen, and buspirone dose dependently decreased operant responding, with the calculated ED 50 values being 7.09, 3.42, and 0.57 mg/kg, respectively. The respective antinociception ED 50 values were 16.15, 8.75, and 2.20 mg/kg. Analysis of 1:1 combinations showed the effects of morphine plus baclofen to decrease schedule-controlled responding and to produce thermal antinociception were synergistic. Effects of morphine plus buspirone and baclofen plus buspirone to decrease schedule-controlled responding were additive. Effects of the two combinations to produce thermal antinociception were synergistic. Naltrexone and CGP35348 antagonized the effects of morphine and baclofen, respectively. Synergistic antinociceptive effects, in conjunction with additive effects on food-maintained responding, highlight the therapeutic utility of opioid and non-opioid drug combinations.