Vol. 295, Issue 3, 1012-1021, December 2000

Attenuation of µ-Opioid Tolerance and Cross-Tolerance by the Competitive N-Methyl-D-aspartate Receptor Antagonist LY235959 Is Related to Tolerance and Cross-Tolerance Magnitude¹

Richard M. Allen and Linda A. Dykstra²

Curriculum in Neurobiology (R.M.A., L.A.D.), Departments of Psychology and Pharmacology (L.A.D.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Although NMDA receptor antagonists attenuate the development of morphine tolerance, it is not clear whether NMDA receptor antagonists also prevent tolerance and cross-tolerance to other µ-opioid agonists and, if so, whether prevention is related to the efficacy of the agonist used to examine tolerance. A rat tail-withdrawal procedure was used to test the antinociceptive effects of the µ-opioids etorphine, morphine, and dezocine before and after twice-daily subcutaneous injections with either 0.003 mg/kg etorphine, 10 mg/kg morphine, or 3.0 mg/kg dezocine, each administered alone or in combination with 3.0 mg/kg of the competitive NMDA antagonist LY235959. After chronic etorphine, the etorphine, morphine, and dezocine curves were shifted rightward 1.0-, 2.2-, and 3.4-fold, respectively. LY235959 prevented cross-tolerance to morphine and dezocine. After chronic morphine, the etorphine and morphine curves were shifted rightward 2.5- and 2.9-fold, respectively, and the dezocine curve was flattened. LY235959 prevented morphine tolerance and cross-tolerance to etorphine and reduced the magnitude of cross-tolerance to dezocine. After chronic dezocine, the etorphine, morphine, and dezocine curves were shifted rightward 4.1-, 3.5-, and 9.6-fold, respectively. LY235959 did not prevent but reduced the magnitude of tolerance and cross-tolerance. In a separate experiment, the following rank order of efficacy was determined from the magnitudes of rightward shift in each dose-effect curve after administration of 1.0 mg/kg of the irreversible antagonist clocinnamox: etorphine > morphine > dezocine. These data show that differences in tolerance magnitude are related to opioid efficacy and that attenuation of µ-opioid tolerance and cross-tolerance by LY235959 depends upon the magnitude of opioid tolerance.