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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 2, 2007; DOI: 10.1124/jpet.107.131417

0022-3565/08/3242-732-739$20.00
JPET 324:732-739, 2008
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BEHAVIORAL PHARMACOLOGY

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

Bradford D. Fischer, Eric I. Zimmerman, Mitchell J. Picker, and Linda A. Dykstra

Departments of Psychology (B.D.F., M.J.P., L.A.D.) and Pharmacology (E.I.Z., L.A.D.), University of North Carolina, Chapel Hill, North Carolina

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 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone], the mGlu5 receptor antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] 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 and LY341495 potentiated the antinociceptive effects of morphine, 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 enhance the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study.

Received September 9, 2007; accepted November 1, 2007.

Address correspondence to: Bradford D. Fischer, Department of Psychology, CB# 3270, Davie Hall, University of North Carolina, Chapel Hill, NC 27599-3270. E-mail: bfischer{at}email.unc.edu






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