METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers.
RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice.
CONCLUSIONS: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.
方法:我们通过评估单侧坐骨神经部分结扎后小鼠背侧脊髓中该交换体的表达/活性变化来检查系统xc-的含义。在这种神经性疼痛的手术模型中,我们还研究了系统xc-基因抑制(使用缺乏系统xc-特异性亚基xCT的小鼠)或其药理学操作(使用药理学抑制剂柳氮磺吡啶)对疼痛相关行为反应的影响.最后,我们通过测量GFAP的mRNA和蛋白水平以及选择M1和M2小胶质细胞标志物来评估脊髓中的胶质细胞活化和炎症反应.
结果:发现坐骨神经损伤在脊髓水平上调系统xc-。xCT的基因缺失减弱了神经外科术后疼痛致敏的幅度和持续时间,对机械和热刺激的反应减少证明了这一点,这伴随着神经胶质激活的减少。始终如一,系统xc-的药理学抑制在病变小鼠中具有镇痛作用。
结论:一起,这些观察结果为系统xc-在中枢致敏的生化过程中的作用提供了证据.我们建议,在缺乏xCT的转基因小鼠或柳氮磺胺吡啶治疗的小鼠中观察到的超敏反应降低是由腰脊髓神经胶质增生减少和/或小胶质细胞M1/M2极化向抗炎表型的转变介导的系统xc-。这些发现表明,靶向系统xc-的药物可能有助于预防或减轻神经性疼痛。