Papers of the Week

In vivo receptor interactions vary as a function of behavioral endpoint. Our laboratory has begun investigating the effects of D1 dopamine receptor agonists and D1 dopamine/mu opioid receptor interactions. This decision is based on studies that have shown (1) dopamine D1 receptors produce pain relief in rodent models of acute pain, (2) a mixed literature indicating D1 agonists either do or do not possess abuse liability, perhaps due in part to behavioral endpoint selection, and (3) co-localization of D1 and mu receptors in brain. This is the first report of D1/mu receptor interactions using an assay of pain depressed behavior. A multiple-cycle FR10 operant schedule and a simple FR10 schedule were utilized in the presence of (antinociception) and in the absence of (rate suppression / sedation) a lactic acid inflammatory pain-like manipulation, with antinociception defined as the therapeutic effect, and sedation defined as a side effect. SKF82958 and methadone were used as selective/high efficacy D1 dopamine and mu opioid agonists, respectively. Both SKF82958 and methadone alone produced dose-dependent restoration of pain-depressed responding and response rate suppression in the mult-cycle schedule, but SKF82958 was ineffective in restoring pain-depressed responding in the simple FR10 schedule. Equal potency 1:1 SKF82958/methadone mixtures and 1:3 and 3:1 mixtures are currently being tested in both operant schedules to determine the nature of the interaction (additive, superadditive, subadditive). Results will indicate if therapeutic index varies as a function of operant schedule, and the degree to which the addition of SKF82958 produces opioid-sparing effects.