Thrombospondin-4 and excitatory synaptogenesis promote spinal sensitization after painful mechanical joint injury

Exp Neurol. 2015 Feb:264:111-20. doi: 10.1016/j.expneurol.2014.11.015. Epub 2014 Dec 5.


Facet joint injury induces persistent pain that may be maintained by structural plasticity in the spinal cord. Astrocyte-derived thrombospondins, especially thrombospondin-4 (TSP4), have been implicated in synaptogenesis and spinal sensitization in neuropathic pain, but the TSP4 response and its relationship to synaptic changes in the spinal cord have not been investigated for painful joint injury. This study investigates the role of TSP4 in the development and maintenance of persistent pain following injurious facet joint distraction in rats and tests the hypothesis that excitatory synaptogenesis contributes to such pain. Painful facet joint loading induces dorsal horn excitatory synaptogenesis along with decreased TSP4 in the DRG and increased astrocytic release of TSP4 in the spinal cord, all of which parallel the time course of sustained tactile allodynia. Blocking injury-induced spinal TSP4 expression with antisense oligonucleotides or reducing TSP4 activity at its neuronal receptor in the spinal cord with gabapentin treatment both attenuate the allodynia and dorsal horn synaptogenesis that develop after painful facet joint loading. Increased spinal TSP4 also facilitates the development of allodynia and spinal hyperexcitability, even after non-painful physiological loading of the facet joint. These results suggest that spinal TSP4 plays an important role in the development and maintenance of persistent joint-mediated pain by inducing excitatory synaptogenesis and facilitating the transduction of mechanical loading of the facet joint that leads to spinal hyperexcitability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Amines / therapeutic use
  • Analgesics / therapeutic use
  • Animals
  • Arthralgia / drug therapy
  • Arthralgia / pathology*
  • Cyclohexanecarboxylic Acids / therapeutic use
  • Excitatory Postsynaptic Potentials / drug effects
  • Gabapentin
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Hyperalgesia / drug therapy
  • Joint Capsule / pathology
  • Male
  • Neurons / drug effects
  • Neurons / physiology
  • Pain Measurement
  • Rats
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / pathology*
  • Thrombospondins / genetics
  • Thrombospondins / metabolism*
  • Time Factors
  • Tubulin / metabolism
  • Zygapophyseal Joint* / drug effects
  • gamma-Aminobutyric Acid / therapeutic use


  • Amines
  • Analgesics
  • Cyclohexanecarboxylic Acids
  • Glial Fibrillary Acidic Protein
  • Thrombospondins
  • Tubulin
  • thrombospondin 4
  • gamma-Aminobutyric Acid
  • Gabapentin