Rationale and objectives <p>In vivo receptor interactions vary as a function of behavioral endpoint, with key differences between reflexive and non-reflexive measures that assess the motivational aspects of pain and pain relief. There have been no assessments of D₁ dopamine agonist / mu opioid receptor (MOR) agonist interactions in non-reflexive behavioral measures of pain. We examined the hypothesis that D₁/MOR mixtures show enhanced effectiveness in blocking pain depressed behaviors while showing decreased side effects such as sedation and drug reward.</p> Methods <p>SKF82958 and methadone were used as selective/high efficacy D₁ and mu agonists, respectively. An FR10 operant schedule was utilized in the presence and absence of a lactic acid inflammatory pain-like manipulation, to measure antinociceptive and operant-rate-suppressing effects, respectively. Rewarding properties of the drug combinations were determined using a conditioned place preference procedure.</p> Results <p>Methadone alone, but not SKF82958 alone, produced dose-dependent restoration of pain-depressed responding. Both SKF82958 and methadone produced dose-dependent response rate suppression. Three fixed proportion mixtures, based on the relative potencies of the drugs in the rate suppression assay, produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that the 0.17:1 mixture produced supra-additive antinociception and additive sedation. The 0.055:1 mixture produced additive antinociception with sub-additive sedation, and the 0.018:1 mixture had the highest therapeutic index (TI) relative to other mixtures and drugs alone. The antinociceptive doses and component doses for the 0.018:1 mixture did not produce conditioned place preference.</p> Conclusions <p>These results suggest that D₁-selective dopamine agonists may have utility as candidate opioid-sparing analgesics.</p>