The relevance of cannabinoid receptor 2 in the central nervous system: an update over the last 3 years

The endocannabinoid system is a neuromodulatory network regulating synaptic plasticity, neuronal activity, and neuroinflammatory responses in both the central and peripheral nervous systems. The endocannabinoid system comprises endogenous ligands, termed endocannabinoids, and two principal receptors, cannabinoid receptor type 1 and type 2 (CB1R and CB2R). While CB1R is predominantly associated with the central nervous system and mediates the psychotropic effects of cannabis-derived compounds, CB2R was initially considered mainly peripheral. However, growing evidence over the last decades has highlighted a pivotal role for CB2R in central nervous system homeostasis and pathology. Importantly, the lack of psychotropic effects associated with CB2R signaling has positioned this receptor as a promising therapeutic target for several brain-related disorders, including neuroinflammatory, neurodegenerative, neuropsychiatric, and neurovascular conditions. Here, we provide a structured review of experimental studies published over the last 3 years investigating CB2R modulation in the central nervous system, with a particular focus on disease mechanisms and emerging therapeutic strategies.