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      Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

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      Cell Reports

      Elsevier BV

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          Abstract

          Chronic neuropathic pain is a debilitating condition that remains difficult to treat. Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor (NMDAR) activity in the spinal dorsal horn are key mechanisms underlying neuropathic pain. However, the reciprocal relationship between synaptic inhibition and excitation in neuropathic pain is unclear. Here, we show that intrathecal delivery of K(+)-Cl(-) cotransporter-2 (KCC2) using lentiviral vectors produces a complete and long-lasting reversal of pain hypersensitivity induced by nerve injury. KCC2 gene transfer restores Cl(-) homeostasis disrupted by nerve injury in both spinal dorsal horn and primary sensory neurons. Remarkably, restoring Cl(-) homeostasis normalizes both presynaptic and postsynaptic NMDAR activity increased by nerve injury in the spinal dorsal horn. Our findings indicate that nerve injury recruits NMDAR-mediated signaling pathways through the disruption of Cl(-) homeostasis in spinal dorsal horn and primary sensory neurons. Lentiviral vector-mediated KCC2 expression is a promising gene therapy for the treatment of neuropathic pain.

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          Author and article information

          Journal
          Cell Reports
          Cell Reports
          Elsevier BV
          22111247
          May 2016
          May 2016
          : 15
          : 7
          : 1376-1383
          Article
          10.1016/j.celrep.2016.04.039
          4871741
          27160909
          © 2016

          https://www.elsevier.com/tdm/userlicense/1.0/

          http://creativecommons.org/licenses/by-nc-nd/4.0/

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