title: Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats.
abstract: Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.
authors.affiliation: Department of Pain Management, Cleveland Clinic, Cleveland, OH, USA.|Department of Immunology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China.|Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pain Management, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Mian
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bihua
authors.initials: B
authors.lastname: Bie
authors.affiliation: Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Foss
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Pain Management, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Rosenquist
authors.affiliation: Department of General Anesthesiology, Cleveland Clinic, Cleveland, OH, USA.|Anesthesiology Institute, Cleveland Clinic, 9500 Euclid Ave. - NE6-306, Cleveland, OH, 44195, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Naguib
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage; D000073883:CX3C Chemokine Receptor 1; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications / Q000503:physiopathology* / Q000517:prevention & control; D004817:Epidermis / Q000294:innervation; D006930:Hyperalgesia / Q000150:complications / Q000503:physiopathology* / Q000517:prevention & control; D007511:Ischemia / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000517:prevention & control; D010880:Piperidines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D012019:Reflex Sympathetic Dystrophy / Q000150:complications / Q000503:physiopathology*; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000502:physiology
chemical_list: C534147:1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl)piperidine; D001572:Benzofurans; D000073883:CX3C Chemokine Receptor 1; C516305:CX3CR1 protein, rat; C469526:Cnr2 protein, rat; D010880:Piperidines; D043885:Receptor, Cannabinoid, CB2; D019707:Receptors, Chemokine
keywords: CB2; CX3CR1; chemokine; ischemia; neuroinflammation