The effect of lithium chloride on WIN 55,212-2-induced tolerance in isolated guinea pig ileum

Abstract

Tolerance to most of the cannabinoid effects has been reported, either in humans or in other species. Pharmacodynamic properties of these agents are perceived to be responsible for this phenomenon. The effect of lithium was examined on tolerance to WIN 55,212-2, a synthetic cannabinoid, in guinea pig ileum, a functional model to examine the mode of action of cannabinoids. Ileum strips were mounted in bath containing 37 degrees C Tyrode, under 0.5 g resting tension. The pulses were delivered, via platinum electrode, to the tissue and subsequent twitches were recorded using PowerLab system. WIN 55,212-2 could inhibit electrically stimulated twitches of guinea pig ileum in a dose dependent manner (pD(2)=8.56+/-0.41). Tolerance to this effect could be induced by incubating isolated ileum for 4h with WIN 55,212-2 (3 x IC(50)) (pD(2)=6.36+/-0.26, degree of tolerance: 159.32) (P<0.01). Lithium (1mM) could interfere with the development of this cannabinoid-induced tolerance and restores the sensitivity of ileum to inhibitory action of WIN 55,212-2 either when strips were exposed to lithium chloride during 4h incubation period (pD(2)=7.26+/-0.39) (P>0.05 versus non-tolerant group) (degree of tolerance: 20.28), or when lithium was added immediately before examining the inhibitory action of WIN 55,212-2 (pD(2)=8.09+/-0.33) (P<0.05 versus corresponding tolerant group) (degree of tolerance: 2.96). Upon these results, it appears reasonable to consider an interventional role for lithium which may be able to break the chain of development and/or expression of tolerance to WIN 55,212-2 in this experimental model.