Pharmacological Actions of Cannabinoids 39expressed in cultured cells but also when expressed naturally. The existence of such
constitutive activity is reflected in the pharmacological properties of established
cannabinoid receptor antagonists, all of which appear to be inverse agonists rather
than neutral antagonists. Ligands that behave as neutral cannabinoid receptor
antagonists are beginning to be described in the literature. These now need to be
characterized more fully, as such antagonists would serve as important additional
pharmacological tools and might also possess advantages over inverse agonists in
the clinic. Evidence for the presence of non-CB 1 , non-CB 2 pharmacological targets
for at least some cannabinoid receptor agonists is emerging, prompting a need
to establish the extent to which these proposed additional targets contribute to
the pharmacology of these agonists. For some of these targets, ligands that do
not also interact with CB 1 or CB 2 receptors have already been identified, and it
will now be important to characterize the actions of these ligands more fully and
to investigate the possibility of developing potent and selective non-CB 1 ,non-
CB 2 agonists for all the proposed new targets. This in turn will greatly facilitate
a fuller understanding of these targets as well as the discovery of any additional
targets. The extent to which cross-talk can occur between identical (e.g. CB 1 -
CB 1 ) or different pharmacological targets for cannabinoids (e.g. between CB 2 and
abnormal cannabidiol receptors), or between cannabinoid and non-cannabinoid
targets (e.g. between CB 1 and dopamine D 2 receptors), and the nature of the
mechanisms that underlie such cross-talk also merit further investigation.
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