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

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 CB₁ 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.