“Although cannabinoids have been used for millennia for treating pain and other symptoms, their mechanisms of action remain obscure.
With the heralded identification of multiple G-protein-coupled receptors (GPCRs) mediating cannabinoid effects nearly two decades ago, the mystery of cannabinoid pharmacology was thought to be solved…
Despite the wealth of information on cannabinoid-induced peripheral antihyperalgesic and antinociceptive effects in many pain models, the molecular mechanism(s) for these actions remains unknown.
Although metabotropic cannabinoid receptors have important roles in many pharmacological actions of cannabinoids, recent studies have led to the recognition of a family of at least five ionotropic cannabinoid receptors (ICRs). The known ICRs are members of the family of transient receptor potential (TRP) channels and include TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1.
Cannabinoid activation of ICRs can result in desensitization of the TRPA1 and TRPV1 channel activities, inhibition of nociceptors and antihyperalgesia and antinociception in certain pain models.
Thus, cannabinoids activate both metabotropic and ionotropic mechanisms to produce peripheral analgesic effects.”