Interactions between Delta and Mu Opioid Agonists in Assays of Pain‐Depressed Operant Responding and Schedule‐Controlled Rate Suppression

Abstract

Interactions between delta and mu opioid agonists in rodents vary as a function of behavioral endpoint. Previous literature includes assessment of interactions across therapeutic (eg: antinociceptive) and side effect (eg: sedation, respiratory depression) endpoints. The present study is the first to characterize these receptor interactions using a mult‐cycle operant assay of pain‐depressed behavior as the antinociceptive measure. The selective delta agonist SNC80 (ED50 = 4.11mg/kg) and the selective mu agonist methadone (ED50 = 0.35mg/kg) both produced dose‐dependent restoration of lactic acid pain‐depressed operant responding. SNC80 (ED50 = 56.0mg/kg) and methadone (ED50 = 1.55mg/kg) also produced a dose‐dependent suppression of response rates in the operant assay in the absence of the pain‐like stimulus. Based on relative potencies in the nociceptive assay, fixed‐ratio mixtures of SNC80 and methadone (35.1:1, 11.7:1, 3.9:1) are currently being characterized in both assays. Preliminary data indicate that the 11.7:1 mixture produced additive effects in the antinociceptive assay and sub‐additive effects in the rate suppression assay, thus yielding a higher therapeutic index (TI or dose ratio) for the mixture relative to the TI of either drug alone. These results provide further evidence that delta/mu interactions depend on experimental endpoint and that assessment of these interactions utilizing an assay of pain‐depressed behavior is possible.Support or Funding InformationAR0554975‐02A1 (NIAMS) to G.W.S.