DEVELOPMENT OF CROSS-TOLERANCE BETWEEN DELTA(9)-TETRAHYDROCANNABINOL,CP-55,940 AND WIN-55,212

In previous studies it was shown that the structurally dissimilar comp ounds Delta(9)-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacolo gical assays, suggesting that a single mechanism may not account for a ll of their actions. To further explore possible differences among the se cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of Delta(9)-THC, CP 55,940 and WIN 55,212 to produce hypo activity, hypothermia, antinociception and catalepsy was assessed in m ice that had been chronically treated with either Delta(9)-THC or CP 5 5,940. The results indicated the Delta(9)-THC-treated mice were tolera nt to Delta(9)-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectivel y. Mice chronically treated with Delta(9)-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 acid WIN 55,212. The t olerance induced by repetitive administration of CP 55,940 was substan tial. The ED(50) for CP 55,940 was shifted 102 fold for spontaneous ac tivity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tol erance to Delta(9)-THC and WIN 55,212 was observed in CP 55,940 chroni cally treated mice. These findings indicate that cross-tolerance devel ops between Delta(9)-THC, CP 55,940 and WIN 55,212 and that these agen ts have some actions in common. However, quantitative differences in t heir development of cross-tolerance suggests that all of their actions may not be identical.