Tolerance development of 8α,9α- and 8β,9β- epoxyhexahydrocannabinols in the mouse

Seven daily administrations of 8α,9α- and 8β,9β-epoxyhexahydrocannabinols (EHHCs) (10 mg/kg, i.v. and 5 mq/kg, i.v., respectively, once a day) developed tolerance to their pharmacological effects such as hypothermia, catalepsy and pentobarbital-induced sleep prolongation in the mouse. Comparing with the effect obtained on the 1st day, the significant reduction was observed on the 3rd to 4th day of EHHCs treatments. Tolerant mice received EHHCs for 3 consecutive days showed cross-tolerance to Δ⁸-tetrahydrocannabinol (THC) in all the pharmacological indices. Furthermore, EHHCs-tolerant mice were also cross-tolerant to hypothermic effect of chlorpromazine. On the other hand, 8β,9β-EHHC-tolerant, but not 8α,9α-EHHC-tolerant mice showed cross-tolerance to hypothermia induced with morphine. These results suggest that both epoxides may contribute to the tolerance development to Δ⁸-THC as active metabolites at least in part.