title: Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors.
abstract: Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major nonpsychoactive component of marijuana, and its modified derivatives significantly suppress chronic inflammatory and neuropathic pain without causing apparent analgesic tolerance in rodents. The cannabinoids significantly potentiate glycine currents in dorsal horn neurons in rat spinal cord slices. The analgesic potency of 11 structurally similar cannabinoids is positively correlated with cannabinoid potentiation of the α3 GlyRs. In contrast, the cannabinoid analgesia is neither correlated with their binding affinity for CB1 and CB2 receptors nor with their psychoactive side effects. NMR analysis reveals a direct interaction between CBD and S296 in the third transmembrane domain of purified α3 GlyR. The cannabinoid-induced analgesic effect is absent in mice lacking the α3 GlyRs. Our findings suggest that the α3 GlyRs mediate glycinergic cannabinoid-induced suppression of chronic pain. These cannabinoids may represent a novel class of therapeutic agents for the treatment of chronic pain and other diseases involving GlyR dysfunction.
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Tanxing
authors.initials: T
authors.lastname: Cui
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Willenbring
authors.forename: Yun
authors.initials: Y
authors.lastname: Guan
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D059350:Chronic Pain / Q000188:drug therapy; D015232:Dinoprostone / Q000009:adverse effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009437:Neuralgia / Q000188:drug therapy*; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018009:Receptors, Glycine; C113965:glycine receptor alpha3 subunit; D002185:Cannabidiol; D015232:Dinoprostone