Microglial Cannabinoid CB₂ Receptors in Pain Modulation

Pain, especially chronic pain, can strongly affect patients' quality of life. Cannabinoids ponhave been reported to produce potent analgesic effects in different preclinical pain models, where they primarily function as agonists of G_i/o protein-coupled cannabinoid CB₁ and CB₂ receptors. The CB₁ receptors are abundantly expressed in both the peripheral and central nervous systems. The central activation of CB₁ receptors is strongly associated with psychotropic adverse effects, thus largely limiting its therapeutic potential. However, the CB₂ receptors are promising targets for pain treatment without psychotropic adverse effects, as they are primarily expressed in immune cells. Additionally, as the resident immune cells in the central nervous system, microglia are increasingly recognized as critical players in chronic pain. Accumulating evidence has demonstrated that the expression of CB₂ receptors is significantly increased in activated microglia in the spinal cord, which exerts protective consequences within the surrounding neural circuitry by regulating the activity and function of microglia. In this review, we focused on recent advances in understanding the role of microglial CB₂ receptors in spinal nociceptive circuitry, highlighting the mechanism of CB₂ receptors in modulating microglia function and its implications for CB₂ receptor- selective agonist-mediated analgesia.