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Here we demonstrate an active role of \u03b2-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<jats:sup>2<\/jats:sup>, NMe-Phe<jats:sup>4<\/jats:sup>, Gly-ol<jats:sup>5<\/jats:sup>]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in <jats:italic>Arrb2<\/jats:italic> knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in <jats:italic>Arrb2<\/jats:italic>-KO mice and conditional KO mice lacking <jats:italic>Arrb2<\/jats:italic> in presynaptic terminals expressing Nav1.8. Loss of <jats:italic>Arrb2<\/jats:italic> 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 <jats:italic>Arrb2<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/ncomms12531","type":"journal-article","created":{"date-parts":[[2016,8,19]],"date-time":"2016-08-19T11:17:54Z","timestamp":1471605474000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["\u03b2-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain"],"prefix":"10.1038","volume":"7","author":[{"given":"Gang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rou-Gang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Jing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Zhong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-Xia","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangsu","family":"Bang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Temugin","family":"Berta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul-Kyu","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Lay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Rong","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,19]]},"reference":[{"key":"BFncomms12531_CR1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.cell.2009.09.028","volume":"139","author":"AI Basbaum","year":"2009","unstructured":"Basbaum, A. 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