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β-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain

Author

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  • Gang Chen

    (Duke University Medical Center
    Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University)

  • Rou-Gang Xie

    (Duke University Medical Center
    Xijing Hospital, Fourth Military Medical University)

  • Yong-Jing Gao

    (Pain Research Laboratory, Institute of Nautical Medicine, Co-Innovation Center of Neuroregeneration, Nantong University)

  • Zhen-Zhong Xu

    (Duke University Medical Center
    Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine)

  • Lin-Xia Zhao

    (Pain Research Laboratory, Institute of Nautical Medicine, Co-Innovation Center of Neuroregeneration, Nantong University)

  • Sangsu Bang

    (Duke University Medical Center)

  • Temugin Berta

    (Duke University Medical Center
    Pain Research Center, University of Cincinnati Medical Center)

  • Chul-Kyu Park

    (Duke University Medical Center
    College of Medicine, Gachon University)

  • Mark Lay

    (Duke University Medical Center)

  • Wei Chen

    (Duke University Medical Center)

  • Ru-Rong Ji

    (Duke University Medical Center
    Duke University Medical Center)

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-Ala2, NMe-Phe4, Gly-ol5]-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.

Suggested Citation

  • Gang Chen & Rou-Gang Xie & Yong-Jing Gao & Zhen-Zhong Xu & Lin-Xia Zhao & Sangsu Bang & Temugin Berta & Chul-Kyu Park & Mark Lay & Wei Chen & Ru-Rong Ji, 2016. "β-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12531
    DOI: 10.1038/ncomms12531
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