Inverse agonism at cannabinoid receptors

There are at least two types of cannabinoid receptor, CB1 and CB2, both G protein coupled. CB1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release. CB2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous ligands for these receptors (endocannabinoids) also exist. These discoveries have prompted the development of CB1and CB2-selective agonists and antagonists. The latter include the CB1-selective SR141716A and LY320135 and the CB2-selective SR144528 and AM630, all of which appear to be inverse agonists. Indeed, antagonists without inverse agonist activity have yet to be developed. As most experiments directed at investigating inverse agonism at cannabinoid receptors have been performed with SR141716A, this review focusses on this agent. It presents evidence that the endocannabinoid system is tonically active and that this activity can stem both from ongoing release of endocannabinoids and from the presence of constitutively active CB1 receptors. Thus, SR141716A seems to induce some inverse cannabimimetic effects by opposing responses to endogenously released endocannabinoids and other such effects by decreasing tonic activity induced by constitutively active CB1 receptors. The interaction of SR141716A with constitutively active receptors is discussed in terms of ‘‘two-state’’ and ‘‘three-state’’ models. D 2003 Elsevier Science B.V. All rights reserved.