title: Attenuation of morphine antinociceptive tolerance by a CB(1) receptor agonist and an NMDA receptor antagonist: Interactive effects.
abstract: CB(1) cannabinoid (CB(1)) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB(1)/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB(1) receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (z(mix)) with predicted additive potency (z(add)). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (z(add) = z(mix)), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (z(add) > z(mix)). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations.
authors.affiliation: Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. bradford_fischer@hms.harvard.edu
authors.forename: Bradford D
authors.initials: BD
authors.lastname: Fischer
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Ward
authors.forename: Fredrick E
authors.initials: FE
authors.lastname: Henry
authors.forename: Linda A
authors.initials: LA
authors.lastname: Dykstra
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006358:Hot Temperature; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D003511:Cyclohexanols; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D043884:Receptor, Cannabinoid, CB1; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C088643:LY 235959
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