Cross‐tolerance between delta‐9‐tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212‐2 and anandamide

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Abstract
1 Mice pretreated intraperitoneally for 2 days with delta-9-tetrahydrocannabinol (delta-9-THC) at a dose of 20 mg kg−1 day−1 and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta-9-THC. This pretreatment also induced tolerance to the hypothermic effects of the cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212-2 (4.9 fold), but not to the hypothermic effect of the putative endogenous cannabinoid, anandamide. 2 Vasa deferentia removed from mice pretreated intraperitoneally 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 contractions than vasa deferentia obtained from control animals. The cannabinoid pretreatment induced a 30 fold parallel rightward shift in the 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 fold). 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 produce tolerance not only to its own inhibitory effect on the vas deferens but also to that of three other cannabimimetic agents, suggests that this tissue would be suitable as an experimental model for investigating the mechanisms responsible for cannabinoid tolerance. 4 Further experiments are required to establish why tolerance to anandamide-induced hypothermia was not produced by a pretreatment with delta-9-THC that did induce tolerance to the hypothermic effects of delta-9-THC, CP 55,940 and WIN 55,212-2 and to the inhibitory effects of delta-9-THC, CP 55,940, WIN 55,212-2 and anandamide on the twitch response of the vas deferens.