Crosby Nathan D, Zaucke Frank, Kras Jeffrey V, Dong Ling, Luo Z David, Winkelstein Beth A
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, United States.
Center for Biochemistry, Medical Faculty, University of Cologne, D-50931 Cologne, Germany.
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.
小关节损伤会引发持续性疼痛，这种疼痛可能由脊髓中的结构可塑性维持。星形胶质细胞衍生的血小板反应蛋白，尤其是血小板反应蛋白-4（TSP4），已被证明与神经性疼痛中的突触形成和脊髓敏化有关，但在疼痛性关节损伤中，TSP4的反应及其与脊髓突触变化的关系尚未得到研究。本研究调查了TSP4在大鼠损伤性小关节牵张后持续性疼痛的发生和维持中的作用，并检验了兴奋性突触形成导致这种疼痛的假设。疼痛性小关节负荷诱导背角兴奋性突触形成，同时DRG中TSP4减少，脊髓中TSP4的星形胶质细胞释放增加，所有这些都与持续性触觉异常性疼痛的时间进程平行。用反义寡核苷酸阻断损伤诱导的脊髓TSP4表达，或用加巴喷丁治疗降低脊髓中其神经元受体处的TSP4活性，均可减轻疼痛性小关节负荷后出现的异常性疼痛和背角突触形成。即使在小关节进行非疼痛性生理负荷后，脊髓TSP4的增加也会促进异常性疼痛和脊髓兴奋性过高的发展。这些结果表明，脊髓TSP4通过诱导兴奋性突触形成并促进小关节机械负荷的转导，导致脊髓兴奋性过高，在持续性关节介导性疼痛的发生和维持中起重要作用。
