CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity

There are two well characterized cannabinoid receptors (CBRs), CB1-Rs and CB2-Rs, with other candidates, such as GPR55, PPARs and vanilloid TRPV1 (VR1) receptors, which are either activated by cannabinoids and/or endocannabinoids (eCBs). The neuronal and functional expression of CB2-Rs in the brain has been much less well characterized in comparison with the expression of the ubiquitous CB1-Rs. CB2-Rs were previously thought to be predominantly expressed in immune cells in the periphery and were traditionally referred to as peripheral CB2-Rs. We and others have now demonstrated the expression of CB2-Rs in neuronal, glial and endothelial cells in the brain, and this warrants a re-evaluation of the CNS effects of CB2-Rs. In the present review we summarize our current understanding of CNR2 genomic structure, its polymorphic nature, subtype specificity, from mice to human subjects, and its variants that confer vulnerabilities to neuropsychiatric disorders beyond neuro-immuno-cannabinoid activity.