Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: Interactive effects

NEUROPHARMACOLOGY

卷:58

Article

Fischer, Bradford D.^1,2  Ward, Sara J.⁴  Henry, Fredrick E.²  Dykstra, Linda A.^2,3 

[1] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA

[2] Univ N Carolina, Dept Psychol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

[4] Temple Univ, Dept Pharmaceut Sci, Philadelphia, PA 19140 USA

关键词: CB1;    Cannabinoid;    NMDA;    Morphine;    Antinociception;    Tolerance;    Dose-addition;   

DOI  :  10.1016/j.neuropharm.2009.08.005

来源: Elsevier

【 摘 要 】

CB1 cannabinoid (CB1) 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 CB1/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, 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. (C) 2009 Elsevier Ltd. All rights reserved.

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