Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat

We have shown in past isobolographic studies that a small amount of Δ9-tetrahydrocannabinol (Δ9-THC) can enhance morphine antinociception in mice. However, previous studies of the Δ9-THC/morphine interaction were performed using normal mice or rats and evaluated acute thermal antinociception. Less is known about cannabinoid and opioid interactions involved in mechanical nociception and in chronic inflammatory pain models, such as Freund's complete adjuvant-induced arthritic model. One fixed-ratio combination was chosen for testing the interaction between Δ9-THC and morphine in the Freund's adjuvant-induced arthritic model. This combination represented a 1:1 ratio of the drugs and thus consisted of equieffective doses ranging from 0.1 to 5 mg/kg Δ9-THC and from 0.1 to 5 mg/kg morphine. The combination ED50 value for the fixed ratios (total dose) in relation to the ED50 value of the drugs alone was determined. The isobolographic analysis indicated a synergistic interaction between Δ9-THC and morphine in both the non-arthritic and the arthritic rats. Since Freund's adjuvant-induced alteration in endogenous opioid tone has been previously shown, our data indicate that such changes did not preclude the use of Δ9-THC and morphine in combination. As with acute preclinical pain models in which the Δ9-THC/morphine combination results in less tolerance development, the implication of the study for chronic pain conditions is discussed.