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Research ArticleNeuropharmacology

Nerve Injury Increases GluA2-Lacking AMPA Receptor Prevalence in Spinal Cords: Functional Significance and Signaling Mechanisms

Shao-Rui Chen, Hong-Yi Zhou, Hee Sun Byun and Hui-Lin Pan
Journal of Pharmacology and Experimental Therapeutics December 2013, 347 (3) 765-772; DOI: https://doi.org/10.1124/jpet.113.208363
Shao-Rui Chen
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (S.-R.C., H.-Y.Z., H.S.B., H.-L.P.); Graduate Program in Neuroscience, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas (H.-L.P.)
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Hong-Yi Zhou
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (S.-R.C., H.-Y.Z., H.S.B., H.-L.P.); Graduate Program in Neuroscience, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas (H.-L.P.)
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Hee Sun Byun
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (S.-R.C., H.-Y.Z., H.S.B., H.-L.P.); Graduate Program in Neuroscience, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas (H.-L.P.)
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Hui-Lin Pan
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas (S.-R.C., H.-Y.Z., H.S.B., H.-L.P.); Graduate Program in Neuroscience, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas (H.-L.P.)
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Abstract

The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critically involved in the excitatory synaptic transmission, and blocking AMPARs at the spinal level reverses neuropathic pain. However, little is known about changes in the composition of synaptic AMPARs in the spinal dorsal horn after peripheral nerve injury. AMPARs lacking the GluA2 subunit are permeable to Ca2+, and their currents show unique inward rectification. We found that AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs) of spinal dorsal horn neurons exhibited a linear current-voltage relationship in control rats, whereas AMPAR-EPSCs of dorsal horn neurons displayed inward rectification in rats with spinal nerve injury. In nerve-injured rats, compared with control rats, the GluA2 protein level was significantly less in the plasma membrane but was greater in the cytosolic vesicle fraction in the dorsal spinal cord. However, the GluA1 protein levels in these fractions did not differ significantly between nerve-injured and control rats. Blocking N-methyl-d-aspartate receptors (NMDARs) abolished inward rectification of AMPAR-EPSCs of dorsal horn neurons in nerve-injured rats. Furthermore, inhibition of calpain or calcineurin, but not protein kinase C, completely blocked nerve injury–induced inward rectification of AMPAR-EPSCs of dorsal horn neurons. In addition, blocking GluA2-lacking AMPARs at the spinal cord level reduced nerve injury–induced pain hypersensitivity. Our study suggests that nerve injury increases GluA2 internalization and the prevalence of GluA2-lacking AMPARs in the spinal dorsal horn to maintain chronic neuropathic pain. Increased prevalence of spinal GluA2-lacking AMPARs in neuropathic pain is mediated by NMDARs and subsequent stimulation of calpain and calcineurin signaling.

Footnotes

    • Received July 25, 2013.
    • Accepted September 11, 2013.
  • S.-R.C. and H.-Y.Z. contributed equally to this work.

  • This work was supported the National Institutes of Health (Grants DE022015 and NS073935) and by the N.G. and Helen T. Hawkins endowment (to H.-L.P.).

  • dx.doi.org/10.1124/jpet.113.208363.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 3
1 Dec 2013
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Research ArticleNeuropharmacology

AMPA Receptor Plasticity in Neuropathic Pain

Shao-Rui Chen, Hong-Yi Zhou, Hee Sun Byun and Hui-Lin Pan
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 765-772; DOI: https://doi.org/10.1124/jpet.113.208363

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Research ArticleNeuropharmacology

AMPA Receptor Plasticity in Neuropathic Pain

Shao-Rui Chen, Hong-Yi Zhou, Hee Sun Byun and Hui-Lin Pan
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 765-772; DOI: https://doi.org/10.1124/jpet.113.208363
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