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TrkB.T1 contributes to neuropathic pain after spinal cord injury through regulation of cell cycle pathways.

Abstract
Spinal cord injury (SCI) frequently causes severe, persistent central neuropathic pain that responds poorly to conventional pain treatments. Brain-derived neurotrophic factor (BDNF) signaling appears to contribute to central sensitization and nocifensive behaviors in certain animal models of chronic pain through effects mediated in part by the alternatively spliced truncated isoform of the BDNF receptor tropomyosin-related kinase B.T1 (trkB.T1). Mechanisms linking trkB.T1 to SCI-induced chronic central pain are unknown. Here, we examined the role of trkB.T1 in central neuropathic pain after spinal cord contusion. Genetic deletion of trkB.T1 in mice significantly reduced post-SCI mechanical hyperesthesia, locomotor dysfunction, lesion volumes, and white matter loss. Whole genome analysis, confirmed at the protein level, revealed that cell cycle genes were upregulated in trkB.T1(+/+) but not trkB.T1(-/-) spinal cord after SCI. TGFβ-induced reactive astrocytes from WT mice showed increased cell cycle protein expression that was significantly reduced in astrocytes from trkB.T1(-/-) mice that express neither full-length trkB nor trkB.T1. Administration of CR8, which selectively inhibits cyclin-dependent kinases, reduced hyperesthesia, locomotor deficits, and dorsal horn (SDH) glial changes after SCI, similar to trkB.T1 deletion, without altering trkB.T1 protein expression. In trkB.T1(-/-) mice, CR8 had no effect. These data indicate that trkB.T1 contributes to the pathobiology of SCI and SCI pain through modulation of cell cycle pathways and suggest new therapeutic targets.
AuthorsJunfang Wu, Cynthia L Renn, Alan I Faden, Susan G Dorsey
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 33 Issue 30 Pg. 12447-63 (Jul 24 2013) ISSN: 1529-2401 [Electronic] United States
PMID23884949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Brain-Derived Neurotrophic Factor
  • Receptor, trkB
Topics
  • Animals
  • Astrocytes (cytology, physiology)
  • Brain-Derived Neurotrophic Factor (metabolism)
  • Cell Cycle (physiology)
  • Hyperesthesia (genetics, pathology, physiopathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuralgia (genetics, pathology, physiopathology)
  • Posterior Horn Cells (physiology)
  • Primary Cell Culture
  • Receptor, trkB (genetics, metabolism)
  • Recovery of Function (physiology)
  • Signal Transduction (physiology)
  • Spinal Cord Injuries (genetics, pathology, physiopathology)
  • Up-Regulation (physiology)

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