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.