Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat.

We have shown in past isobolographic studies that a small amount of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) can enhance morphine antinociception in mice. However, previous studies of the Delta(9)-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 Delta(9)-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 Delta(9)-THC and from 0.1 to 5 mg/kg morphine. The combination ED(50) value for the fixed ratios (total dose) in relation to the ED(50) value of the drugs alone was determined. The isobolographic analysis indicated a synergistic interaction between Delta(9)-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 Delta(9)-THC and morphine in combination. As with acute preclinical pain models in which the Delta(9)-THC/morphine combination results in less tolerance development, the implication of the study for chronic pain conditions is discussed.