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Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain.
- Source :
-
Cell reports [Cell Rep] 2016 May 17; Vol. 15 (7), pp. 1376-1383. Date of Electronic Publication: 2016 May 05. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Ganglia, Spinal metabolism
Ganglia, Spinal pathology
Injections, Spinal
Male
Neuralgia pathology
Posterior Horn Cells metabolism
Posterior Horn Cells pathology
Rats, Sprague-Dawley
Spinal Nerves metabolism
Spinal Nerves pathology
Symporters metabolism
Synapses metabolism
Transduction, Genetic
gamma-Aminobutyric Acid metabolism
K Cl- Cotransporters
Chlorides metabolism
Homeostasis
Neuralgia metabolism
Receptors, N-Methyl-D-Aspartate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 15
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 27160909
- Full Text :
- https://doi.org/10.1016/j.celrep.2016.04.039