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Upregulation of GLT-1 by treatment with ceftriaxone alleviates radicular pain by reducing spinal astrocyte activation and neuronal hyperexcitability

Authors

  • K.J. Nicholson,

    1. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania
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  • T.M. Gilliland,

    1. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania
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  • B.A. Winkelstein

    Corresponding author
    1. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania
    2. Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania
    • Correspondence to: Beth A. Winkelstein, PhD, Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd Street, Philadelphia, PA 19104-6321. E-mail: winkelst@seas.upenn.edu

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Abstract

Cervical nerve root injury commonly leads to radicular pain. Normal sensation relies on regulation of extracellular glutamate in the spinal cord by glutamate transporters. The goal of this study was to define the temporal response of spinal glutamate transporters (glial glutamate transporter 1 [GLT-1], glutamate-aspartate transporter [GLAST], and excitatory amino acid carrier 1) following nerve root compressions that do or do not produce sensitivity in the rat and to evaluate the role of glutamate uptake in radicular pain by using ceftriaxone to upregulate GLT-1. Compression was applied to the C7 nerve root. Spinal glutamate transporter expression was evaluated at days 1 and 7. In a separate study, rats underwent a painful root compression and were treated with ceftriaxone or the vehicle saline. Glial glutamate transporter expression, astrocytic activation (glial fibrillary acidic protein [GFAP]), and neuronal excitability were assessed at day 7. Both studies measured behavioral sensitivity for 7 days after injury. Spinal GLT-1 significantly decreased (P < 0.04) and spinal GLAST significantly increased (P = 0.036) at day 7 after a root injury that also produced sensitivity to both mechanical and thermal stimuli. Within 1 day after ceftriaxone treatment (day 2), mechanical allodynia began to decrease; both mechanical allodynia and thermal hyperalgesia were attenuated (P < 0.006) by day 7. Ceftriaxone also reduced (P < 0.024) spinal GFAP and GLAST expression, and neuronal hyperexcitability in the spinal dorsal horn, restoring the proportion of spinal neurons classified as wide dynamic range to that of normal. These findings suggest that nerve root-mediated pain is maintained jointly by spinal astrocytic reactivity and neuronal hyperexcitability and that these spinal modifications are associated with reduced glutamate uptake by GLT-1. © 2013 Wiley Periodicals, Inc.

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