CROSS-TOLERANCE BETWEEN DELTA-9-TETRAHYDROCANNABINOL AND THE CANNABIMIMETIC AGENTS, CP-55,940, WIN-55,212-2 AND ANANDAMIDE

1 Mice pretreated intraperitoneally for 2 days with delta-9-tetrahydro cannabinol (delta-9-THC) at a dose of 20 mg kg-1 day-1 and then challe nged intravenously with this drug, 24h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta-9-THC. Th is pretreatment also induced tolerance to the hypothermic effects of t he cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212-2 (4.9 f old), but not to the hypothermic effect of the putative endogenous can nabinoid, anandamide. 2 Vasa deferentia removed from mice pretreated i ntraperitoneally with delta-9-THC twice at a dose of 20 mg kg-1 day-1 were less sensitive to its inhibitory effect on electrically-evoked co ntractions than vasa deferentia obtained from control animals. The can nabinoid pretreatment induced a 30 fold parallel rightward shift in th e lower part of the concentration-response curve of delta-9-THC and a marked reduction in the maximal inhibitory effect of the drug. It also induced tolerance to the inhibitory effects on the twitch response of CP 55,940 (8.7 fold), WIN 55,212-2 (9.6 fold) and anandamide (12.3 fo ld). 3 The results confirm that cannabinoid tolerance can be rapid in onset and support the hypothesis that it is mainly pharmacodynamic in nature. The finding that in vivo pretreatment with delta-9-THC can pro duce tolerance not only to its own inhibitory effect on the vas defere ns but also to that of three other cannabimimetic agents, suggests tha t this tissue would be suitable as an experimental model for investiga ting the mechanisms responsible for cannabinoid tolerance. 4 Further e xperiments are required to establish why tolerance to anandamide-induc ed hypothermia was not produced by a pretreatment with delta-9-THC tha t did induce tolerance to the hypothermic effects of delta-9-THC, CP 5 5,940 and WIN 55,212-2 and to the inhibitory effects of delta-9-THC, C P 55,940, WIN 55,212-2 and anandamide on the twitch response of the va s deferens.