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

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 and Ru-Rong Ji ()
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Gang Chen: Duke University Medical Center
Rou-Gang Xie: Duke University Medical Center
Yong-Jing Gao: Pain Research Laboratory, Institute of Nautical Medicine, Co-Innovation Center of Neuroregeneration, Nantong University
Zhen-Zhong Xu: Duke University Medical Center
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
Chul-Kyu Park: Duke University Medical Center
Mark Lay: Duke University Medical Center
Wei Chen: Duke University Medical Center
Ru-Rong Ji: Duke University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12531

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