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The Journal of Neuroscience, March 11, 2009, 29(10):3206-3219; doi:10.1523/JNEUROSCI.4514-08.2009

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Neurobiology of Disease
Persistent Inflammation Induces GluR2 Internalization via NMDA Receptor-Triggered PKC Activation in Dorsal Horn Neurons

Jang-Su Park,^1 * Nana Voitenko,^2 * Ronald S. Petralia,³ Xiaowei Guan,¹ Ji-Tian Xu,¹ Jordan P. Steinberg,⁴ Kogo Takamiya,^4,5 Andrij Sotnik,² Olga Kopach,² Richard L. Huganir,^4,6 and Yuan-Xiang Tao¹

¹Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ²Department of General Physiology of Nervous System, Bogomoletz Institute of Physiology, Kiev 01024, Ukraine, ³Laboratory of Neurochemistry, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, and Departments of ⁴Neuroscience and ⁵Neurosurgery and ⁶Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Correspondence should be addressed to Dr. Yuan-Xiang Tao, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 367 Ross, 720 Rutland Avenue, Baltimore, MD 21205. Email: ytao1{at}jhmi.edu

Spinal cord GluR2-lacking AMPA receptors (AMPARs) contribute to nociceptive hypersensitivity in persistent pain, but the molecular mechanisms underlying this event are not completely understood. We report that complete Freund's adjuvant (CFA)-induced peripheral inflammation induces synaptic GluR2 internalization in dorsal horn neurons during the maintenance of CFA-evoked nociceptive hypersensitivity. This internalization is initiated by GluR2 phosphorylation at Ser⁸⁸⁰ and subsequent disruption of GluR2 binding to its synaptic anchoring protein (GRIP), resulting in a switch of GluR2-containing AMPARs to GluR2-lacking AMPARs and an increase of AMPAR Ca²⁺ permeability at the synapses in dorsal horn neurons. Spinal cord NMDA receptor-mediated triggering of protein kinase C (PKC) activation is required for the induction and maintenance of CFA-induced dorsal horn GluR2 internalization. Moreover, preventing CFA-induced spinal GluR2 internalization through targeted mutation of the GluR2 PKC phosphorylation site impairs CFA-evoked nociceptive hypersensitivity during the maintenance period. These results suggest that dorsal horn GluR2 internalization might participate in the maintenance of NMDA receptor/PKC-dependent nociceptive hypersensitivity in persistent inflammatory pain.

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Received Sept. 20, 2008; revised Feb. 4, 2009; accepted Feb. 9, 2009.

Correspondence should be addressed to Dr. Yuan-Xiang Tao, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 367 Ross, 720 Rutland Avenue, Baltimore, MD 21205. Email: ytao1{at}jhmi.edu

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