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Pain After Spinal Cord Injury Is Associated With Abnormal Presynaptic Inhibition in the Posterior Nucleus of the Thalamus

  • Anthony Park
    Affiliations
    Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland
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  • Olivia Uddin
    Affiliations
    Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland
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  • Ying Li
    Affiliations
    Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland
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  • Radi Masri
    Affiliations
    Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland

    Department of Endodontics, Periodontics and Prosthodontics, University of Maryland Baltimore, School of Dentistry, Baltimore, Maryland
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  • Asaf Keller
    Correspondence
    Address reprint requests to Asaf Keller, PhD, Department of Anatomy and Neurobiology, University of Maryland, School of Medicine, 20 Penn St, Baltimore, MD 21201.
    Affiliations
    Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland
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Published:February 23, 2018DOI:https://doi.org/10.1016/j.jpain.2018.02.002

      Highlights

      • Electrolytic model of spinal cord injury (SCI) produces features of pain after SCI (SCI-Pain).
      • SCI-Pain abolishes tonic activation of presynaptic GABAB autoreceptors in posterior thalamus.
      • SCI-Pain abolishes GABAB receptor mediated presynaptic regulation of glutamatergic terminals.

      Abstract

      Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae of spinal cord injury, characterized as relentless, excruciating pain that is largely refractory to treatments. Although it is generally agreed that SCI-Pain results from maladaptive plasticity in the pain processing pathway that includes the spinothalamic tract and somatosensory thalamus, the specific mechanisms underlying the development and maintenance of such pain are yet unclear. However, accumulating evidence suggests that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved in somatosensory and pain processing. We previously described several presynaptic mechanisms by which activity in PO is regulated, including the regulation of GABAergic as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid (GABAB) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic GABAB receptors on GABAergic projections to PO—characteristic of normal animals—was absent in mice with SCI-Pain. Also absent in mice with SCI-Pain was the normal presynaptic regulation of glutamatergic projections to the PO by GABAB receptors. The loss of these regulatory presynaptic mechanisms in SCI-Pain may be an element of maladaptive plasticity leading to PO hyperexcitability and behavioral pain, and may suggest targets for development of novel treatments.

      Perspective

      This report presents synaptic mechanisms that may underlie the development and maintenance of SCI-Pain. Because of the difficulty in treating SCI-Pain, a better understanding of the underlying neurobiological mechanisms is critical, and may allow development of better treatment modalities.

      Key words

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