The molecular mechanism of action of Δ9-tetrahydrocannabinol (THC), the psychotropic constituent of Cannabis, has been a puzzle during the three decades separating its characterization, in 1964, and the cloning, in the 1990s, of cannabinoid
CB1 and CB2 receptors. However, while these latter proteins do mediate most of the pharmacological actions of THC, they do not seem to
act as receptors for other plant cannabinoids (phytocannabinoids), nor are they the unique targets of the endogenous lipids
that were originally identified in animals as agonists of CB1 and CB2 receptors, and named endocannabinoids. Over the last decade, several potential alternative receptors for phytocannabinoids,
endocannabinoids, and even synthetic cannabimimetics, have been proposed, often based uniquely on pharmacological evidence
obtained in vitro. In particular, the endocannabinoid anandamide, and the other most abundant Cannabis constituent, cannabidiol, seem to be the most “promiscuous” of these compounds. In this article, we review the latest data
on the non-CB1, non-CB2 receptors suggested so far for endocannabinoids and plant or synthetic cannabinoids, and lay special emphasis on uncharacterized
or orphan G-protein-coupled receptors as well as on transient receptor potential channels.
Keywords cannabinoid - receptor - TRP - channel - G-protein - endocannabinoid - phytocannabinoid - GPR55 - GPR119