PT  - JOURNAL ARTICLE
AU  - Richard M. Allen
AU  - Linda A. Dykstra
TI  - Attenuation of μ-Opioid Tolerance and Cross-Tolerance by the Competitive <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Antagonist LY235959 Is Related to Tolerance and Cross-Tolerance Magnitude
DP  - 2000 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1012--1021
VI  - 295
IP  - 3
4099  - http://jpet.aspetjournals.org/content/295/3/1012.short
4100  - http://jpet.aspetjournals.org/content/295/3/1012.full
SO  - J Pharmacol Exp Ther2000 Dec 01; 295
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics