Morphine in Combination with Metabotropic Glutamate Receptor Antagonists on Schedule‐Controlled Responding and Thermal Nociception

Abstract

The present study examined the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists on schedule‐controlled responding and thermal nociception. Drug interaction data were examined with isobolographic and dose‐addition analysis. Morphine, the mGlu1 receptor antagonist JNJ16259685, the mGlu5 receptor antagonist MPEP, and the mGlu2/3 receptor antagonist LY341495 all decreased rates of schedule‐controlled responding. JNJ16259685/morphine, MPEP/morphine, and LY341495/morphine mixtures produced additive effects on this endpoint. Morphine also produced dose‐dependent antinociception in the assay of thermal nociception, whereas JNJ16259685, MPEP, and LY341495 failed to produce an effect. In this assay, JNJ16259685/morphine and LY341495/morphine mixtures produced supra‐additive effects, whereas MPEP/morphine mixtures produced additive effects. These results suggest that an mGlu1 and an mGlu2/3 receptor antagonist, but not an mGlu5 receptor antagonist, selectively enhances the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study. Supported by grants R01‐DA02749 and T32‐DA07244.