title: 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.
abstract: 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 mu-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 mu-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 mu-opioid tolerance and cross-tolerance by LY235959 depends upon the magnitude of opioid tolerance.
authors.affiliation: Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3270, USA. rmallen@email.unc.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Allen
authors.forename: L A
authors.initials: LA
authors.lastname: Dykstra
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003516:Cycloparaffins / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005048:Etorphine / Q000493:pharmacokinetics / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013764:Tetrahydronaphthalenes
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003516:Cycloparaffins; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D013764:Tetrahydronaphthalenes; D005048:Etorphine; D009020:Morphine; C088643:LY 235959; C010827:dezocine