title: Reactive oxygen species (ROS) modulate AMPA receptor phosphorylation and cell-surface localization in concert with pain-related behavior.
abstract: Sensitization of dorsal horn neurons (DHNs) in the spinal cord is dependent on pain-related synaptic plasticity and causes persistent pain. The DHN sensitization is mediated by a signal transduction pathway initiated by the activation of N-methyl-d-aspartate receptors (NMDA-Rs). Recent studies have shown that elevated levels of reactive oxygen species (ROS) and phosphorylation-dependent trafficking of GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) are a part of the signaling pathway for DHN sensitization. However, the relationship between ROS and AMPA-R phosphorylation and trafficking is not known. Thus, this study investigated the effects of ROS scavengers on the phosphorylation and cell-surface localization of GluA1 and GluA2. Intrathecal NMDA- and intradermal capsaicin-induced hyperalgesic mice were used for this study since both pain models share the NMDA-R activation-dependent DHN sensitization in the spinal cord. Our behavioral, biochemical, and immunohistochemical analyses demonstrated that: 1) NMDA-R activation in vivo increased the phosphorylation of AMPA-Rs at GluA1 (S818, S831, and S845) and GluA2 (S880) subunits; 2) NMDA-R activation in vivo increased cell-surface localization of GluA1 but decreased that of GluA2; and 3) reduction of ROS levels by ROS scavengers PBN (N-tert-butyl-α-phenylnitrone) or TEMPOL (4-hydroxy-2, 2, 6, 6-tetramethylpiperidin-1-oxyl) reversed these changes in AMPA-Rs, as well as pain-related behavior. Given that AMPA-R trafficking to the cell surface and synapse is regulated by NMDA-R activation-dependent phosphorylation of GluA1 and GluA2, our study suggests that the ROS-dependent changes in the phosphorylation and cell-surface localization of AMPA-Rs are necessary for DHN sensitization and thus, pain-related behavior. We further suggest that ROS reduction will ameliorate these molecular changes and pain.
authors: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Daniel Z
authors: DZ
authors: Lee
authors: Jin M
authors: JM
authors: Chung
authors: Kyungsoon
authors: K
authors: Chung
authors: Myoung-Goo
authors: MG
authors: Kang
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects / Q000502:physiology*; D059350:Chronic Pain / Q000378:metabolism*; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013113:Spin Labels
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; C104722:glutamate receptor ionotropic, AMPA 2; C001803:tempol