title: Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain.
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.
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lingyong
authors.initials: L
authors.lastname: Li
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Jing-Dun
authors.initials: JD
authors.lastname: Xie
authors.affiliation: Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: huilinpan@mdanderson.org.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013127:Spinal Nerves / Q000378:metabolism / Q000473:pathology; D027981:Symporters / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014161:Transduction, Genetic; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D016194:Receptors, N-Methyl-D-Aspartate; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters
keywords: cation-chloride cotransporters; gene therapy; neuropathic pain; synaptic plasticity; synaptic transmission