D1 Dopamine/Mu Opioid Receptor Interactions in Operant Conditioning Assays of Pain‐Depressed Responding and Drug‐Induced Rate Suppression: Assessment of Therapeutic Index in Rats

Abstract

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.