title: β-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain.
abstract: Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of β-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in Arrb2-KO mice and conditional KO mice lacking Arrb2 in presynaptic terminals expressing Nav1.8. Loss of Arrb2 also results in prolongation of inflammatory pain and neuropathic pain and enhancement of GluN2B-mediated NMDA currents in spinal lamina IIo not lamina I neurons. Finally, spinal over-expression of Arrb2 reverses chronic neuropathic pain after nerve injury. Thus, spinal Arrb2 may serve as an intracellular gate for acute to chronic pain transition via desensitization of NMDAR.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Anesthesiology and Pain Management, Xijing Hospital, Department of Neuroscience, Fourth Military Medical University, Xian, Shanxi 710032, China.
authors.forename: Rou-Gang
authors.initials: RG
authors.lastname: Xie
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 3100058, China.
authors.forename: Zhen-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Lin-Xia
authors.initials: LX
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Sangsu
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA.
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Physiology, College of Medicine, Gachon University, Incheon 21999, South Korea.
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lay
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D059350:Chronic Pain / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D009437:Neuralgia / Q000209:etiology / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000209:etiology / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D066148:Spinal Cord Dorsal Horn / Q000166:cytology / Q000378:metabolism; D013376:Substantia Gelatinosa / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016202:N-Methylaspartate