Cannabinoid CB₂ receptor-mediated analgesia: mechanism-based insights and therapeutic potential

Agonists of the cannabinoid 2 (CB₂) receptor have shown promise for the treatment of pain in a variety of animal models. However, despite current preclinical evidence supporting the use of CB₂ agonists for pain, successful translation of findings from preclinical models to human patients is lacking. This gap may reflect an incomplete understanding of the types of pain that best respond to CB₂ receptor activation, as well as limited knowledge of mechanisms underlying CB₂-mediated attenuation of pain behaviours. Additionally, how ligand-specific biased signalling impacts CB₂-mediated analgesia in various types of pain has not been well characterized. Here, we review the preclinical literature that has examined the potential therapeutic efficacy of CB₂ agonists in rodent pain models associated with inflammation, traumatic nerve injury, toxic neuropathy (e.g. due to chemotherapy and anti-retroviral treatment), post-surgical pain, visceral pain and disease-associated (e.g. due to cancer, arthritis and diabetes) pain states. We also discuss what is currently known about the mechanisms underlying these effects with an emphasis on insights derived from recently developed CB₂ reporter mice and conditional knockout (cKO) mouse models. These tools compensate for limitations of functional (rather than complete) global knockout (KO) mouse lines and lack of specificity of available CB₂ receptor antibodies to provide a more comprehensive understanding of CB₂-mediated analgesic mechanisms.