Attenuation of mu-opioid tolerance and cross-tolerance by the competitive N-methyl-D-aspartate receptor antagonist LY235959 is related to tolerance and cross-tolerance magnitude

Although NMDA receptor antagonists attenuate the development of morphine to lerance, it is not clear whether NMDA receptor antagonists also prevent tol erance and cross-tolerance to other mu -opioid agonists and, if so, whether prevention is related to the efficacy of the agonist used to examine toler ance. A rat tail-withdrawal procedure was used to test the antinociceptive effects of the mu -opioids etorphine, morphine, and dezocine before and aft er twice-daily subcutaneous injections with either 0.003 mg/kg etorphine, 1 0 mg/kg morphine, or 3.0 mg/kg dezocine, each administered alone or in comb ination with 3.0 mg/kg of the competitive NMDA antagonist LY235959. After c hronic etorphine, the etorphine, morphine, and dezocine curves were shifted rightward 1.0-, 2.2-, and 3.4- fold, respectively. LY235959 prevented cros s-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 toleran ce and cross-tolerance to etorphine and reduced the magnitude of cross-tole rance to dezocine. After chronic dezocine, the etorphine, morphine, and dez ocine 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 c urve after administration of 1.0 mg/kg of the irreversible antagonist cloci nnamox: etorphine. morphine. dezocine. These data show that differences in tolerance magnitude are related to opioid efficacy and that attenuation of mu -opioid tolerance and cross-tolerance by LY235959 depends upon the magni tude of opioid tolerance.