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Attenuation of morphine antinociceptive tolerance by an NMDA receptor antagonist and a cannabinoid receptor agonist: interactive effects
Author(s) -
Fischer Bradford D,
Henry Fredrick E,
Miller Laurence L,
Ward Sara J,
Dykstra Linda A
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a412-c
Subject(s) - morphine , pharmacology , agonist , cannabinoid , potency , chemistry , antagonist , nmda receptor , nociception , receptor , medicine , biochemistry , in vitro
The present study used dose‐addition analysis to evaluate the inhibition of morphine antinociceptive tolerance by an NMDA antagonist, a cannabinoid agonist, and their combinations. Chronic morphine administration (100 mg/kg, twice daily for 5 days) resulted in a 3.1‐fold rightward shift in the morphine dose‐effect curve. Co‐administration of either the NMDA antagonist LY235959 (LY; 1.0–3.2 mg/kg) or the cannabinoid agonist CP55940 (CP; 0.32–1.0 mg/kg) dose‐dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (2‐fold shift), resulting in equieffective doses of 1.8 mg/kg and 0.55 mg/kg for LY and CP, respectively. Subsequent experiments assessed LY/CP interactions using a fixed‐proportion design. Co‐administration of LY/CP mixtures (1:1, 3.2:1, or 10:1 LY/CP) dose‐dependently attenuated morphine tolerance. Dose‐addition analysis was used to compare the experimentally determined potency for each mixture (Zmix) with the predicted additive potency (Zadd). Mixtures of 1:1 and 3.2:1 LY/CP produced additive effects (Zmix = Zadd), while the mixture of 10:1 LY/CP produced a synergistic attenuation of morphine tolerance (Zmix < Zadd). These results suggest that LY235959 and CP55940 attenuate morphine antinociceptive tolerance in either an additive or synergistic manner, depending on their relative concentrations. Supported by grants R01‐DA02749 and T32‐DA07244.