Microglial Cannabinoid CB2 Receptors in Pain Modulation

Abstract

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 Gi/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.

Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality

“…In this case, cannabinoids can act on spinal CB1rs to inhibit capsaicin-sensitive fibers in the dorsal horn and reduce the firing of wide dynamic range (WDR) neurons in response to noxious stimuli [ 222 , 224 ]. Additionally, activation of the spinal CB1r can decrease NMDA receptor activation by potentially inhibiting glutamate release into the spinal cord [ 225 ], and activation of CB2r suppresses activity in spinal nociceptive neurons, particularly under conditions of sensitization, and regulates the immune response, favoring the neuroprotective actions of neuroglia [ 226 , 227 ].…”

“…These effects emphasize the importance of developing cannabinoid medications with targeted selectivity for CB2 receptors. By focusing on CB2 activation, researchers might achieve better pain relief with fewer side effects than medications that activate CB1 and CB2 receptors [ 18 , 22 , 227 ].…”

Cannabinoid CB2 receptor orthologues; in vitro function and perspectives for preclinical to clinical translation

“…Based on preclinical studies, the CB 2 receptor has been proposed to be a promising drug target for specific types of acute and chronic pain, in particular those involving inflammation and also pain without a major inflammatory component such as neuropathic and acute post‐surgical pain (Whiteside et al, 2007; Xu et al, 2023). It is well established that CB 2 receptor‐mediated anti‐nociception can occur indirectly via modification of pathological processes such as inflammation, with some evidence also supporting more direct influence on pain transmission via peripheral terminals of sensory neurons and/or neurons or microglia in the spinal cord (Carey et al, 2023; Whiteside et al, 2007; Xu et al, 2023). CB 2 receptor‐selective agonism is an attractive treatment approach due to low risk of CNS adverse effects that have been associated with some other analgesic therapies, such as opioids or CB 1 receptor agonists, as well as having potential to act synergistically (Grenald et al, 2017; Whiteside et al, 2007).…”