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

Anthony Park; Olivia Uddin; Ying Li; Radi Masri; Asaf Keller

doi:10.1016/j.jpain.2018.02.002

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

J Pain. 2018 Jul;19(7):727.e1-727.e15. doi: 10.1016/j.jpain.2018.02.002. Epub 2018 Mar 2.

Authors

Anthony Park¹, Olivia Uddin¹, Ying Li¹, Radi Masri², Asaf Keller³

Affiliations

¹ Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland.
² 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.
³ Program in Neuroscience and Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland. Electronic address: asafkeller@fastmail.us.

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 (GABA_B) 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 GABA_B 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 GABA_B 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.

Keywords: Synaptic regulation; gamma-aminobutyric acid; glutamate; higher-order thalamus; sensory processing.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Female
Male
Mice
Neural Inhibition / physiology*
Neuralgia / physiopathology*
Posterior Thalamic Nuclei / physiopathology*
Receptors, GABA-B / metabolism
Spinal Cord Injuries / complications
Spinal Cord Injuries / physiopathology*

Substances

Receptors, GABA-B

Abstract

Publication types

MeSH terms

Substances

Grants and funding