Abstract
“Mammalian tissues express at least two cannabinoid receptor types, CB1 and CB2, both G protein coupled. CB1 receptors are found predominantly at nerve terminals where they mediate inhibition of transmitter release. CB2 receptors occur mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous agonists for cannabinoid receptors also exist, and are all eicosanoids. The first-discovered of these ‘endocannabinoids’ was arachidonoylethanolamide and there is convincing evidence that this ligand and some of its metabolites can activate vanilloid VRI (TRPV1) receptors. Certain cannabinoids also appear to have TRPV1-like and/or non-CB1, non-CB2, non-TRPV1 targets. Several CB1- and CB2-selective agonists and antagonists have been developed. Antagonists include the CB1-selective SR141716A, AM251, AM281 and LY320135, and the CB2-selective SR144528 and AM630. These all behave as inverse agonists, one indication that CB1 and CB2 receptors can exist in a constitutively active state. ‘Neutral’ cannabinoid receptor antagonists have also been developed. CB1 and/or CB2 receptor activation appears to ameliorate inflammatory and neuropathic pain and certain multiple sclerosis symptoms. This might be exploited clinically by using CB1, CB2 or CB1/CB2 agonists, or inhibitors of the membrane transport or catabolism of endocannabinoids that are released in increased amounts, at least in animal models of pain and multiple sclerosis. We have recently discovered the presence of an allosteric site on the CB1 receptor. Consequently, it may also prove possible to enhance ‘autoprotective’ effects of released endocannabinoids with CB1 allosteric enhancers or, indeed, to reduce proposed ‘autoimpairing’ effects of released endocannabinoids such as excessive food intake with CB1 allosteric antagonists.”