Inverse agonism and neutral antagonism at cannabinoid CB 1 receptors

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There are at least two types of cannabinoid receptor, CB 1 and CB 2, both G protein coupled. CB 1 receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release whereas CB 2 receptors are found mainly on immune cells, one of their roles being to modulate cytokine release. Endogenous cannabinoid receptor agonists also exist and these “endocannabinoids” together with their receptors constitute the “endocannabinoid system”. These discoveries were followed by the development of a number of CB 1- and CB 2-selective antagonists that in some CB 1 or CB 2 receptor-containing systems also produce “inverse cannabimimetic effects”, effects opposite in direction from those produced by cannabinoid receptor agonists. This review focuses on the CB 1-selective antagonists, SR141716A, AM251, AM281 and LY320135, and discusses possible mechanisms by which these ligands produce their inverse effects: (1) competitive surmountable antagonism at CB 1 receptors of endogenously released endocannabinoids, (2) inverse agonism resulting from negative, possibly allosteric, modulation of the constitutive activity of CB 1 receptors in which CB 1 receptors are shifted from a constitutively active “on” state to one or more constitutively inactive “off” states and (3) CB 1 receptor-independent mechanisms, for example antagonism of endogenously released adenosine at A 1 receptors. Recently developed neutral competitive CB 1 receptor antagonists, which are expected to produce inverse effects through antagonism of endogenously released endocannabinoids but not by modulating CB 1 receptor constitutive activity, are also discussed. So too are possible clinical consequences of the production of inverse cannabimimetic effects, there being convincing evidence that released endocannabinoids can have “autoprotective” roles.