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Author Notes:

Corresponding Author: Yung-Jen Huang, Department of Neuroscience, 301 Old Main Dr ILSB 3149, Texas A&M University, College Station, TX 77843, redkie@gmail.com

The authors wish to thank Misty Malamakal, Joel Turtle, Josh Reynolds, Melissa Brumley, Julia Forsberg and Jason Lu for comments on an earlier version of this article.

Conflict of Interest: The authors declare no competing financial interests

Subjects:

Research Funding:

This research was supported by National Institutes of Health Grant HD058412.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • GABA
  • GABA(A) receptor
  • KCC2
  • Central sensitization
  • Allodynia
  • Pain
  • SCI
  • NEUROPATHIC PAIN MODEL
  • DORSAL-HORN
  • GABAERGIC INHIBITION
  • DIABETIC-RATS
  • MECHANICAL ALLODYNIA
  • RECEPTOR ACTIVATION
  • COTRANSPORTER KCC2
  • DESCENDING CONTROL
  • DOWN-REGULATION
  • NERVE LIGATION

Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization

Tools:

Journal Title:

Experimental Neurology

Volume:

Volume 285, Number Pt A

Publisher:

, Pages 82-95

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABA A receptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl − transporter, KCC2, leading to a reduction in intracellular Cl − that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl − levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury.

Copyright information:

© 2016 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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