Vesicular glutamate transporter 2 (VGLUT2)-which uptakes glutamate into presynaptic vesicles-is a fundamental component of the glutamate neurotransmitter system. Although several lines of evidence from genetically modified mice suggest a possible association of VGLUT2 with neuropathic pain, the specific role of VGLUT2 in the spinal cord during neuropathic pain, and its regulatory mechanism remain elusive. In this study, we report that spared nerve injury induced an upregulation of VGLUT2 in the spinal cord, and intrathecal administration of small hairpin RNAs (shRNA) against VGLUT2 before or after surgery attenuated mechanical allodynia, and pathologically-enhanced glutamate release. Meanwhile, nerve injury activated the Wnt1/β-catenin signaling pathway in a quick-onset and sustained manner, and blocking the Wnt1 signaling with a Wnt1 targeting antibody attenuated neuropathic pain. In naïve mice, administration of a Wnt agonist or Wnt1 increased spinal VGLUT2 protein levels. Moreover, intrathecal administration of the Wnt/β-catenin inhibitor, XAV939 attenuated mechanical allodynia, and this effect was concurrent with that of VGLUT2 downregulation. Pretreatment with VGLUT2 shRNAs abolished the allodynia induced by the Wnt agonist or Wnt1. These findings reveal a novel mechanism wherein there is Wnt1/β-catenin-dependent VGLUT2 upregulation in neuropathic pain, thus potentiating the development of new therapeutic strategies in pain management.

中文翻译：

---

Wnt1 /β-catenin信号传导可上调脊髓VGLUT2的表达，从而控制小鼠的神经性疼痛。

将谷氨酸吸收到突触前囊泡中的囊泡谷氨酸转运蛋白2（VGLUT2）是谷氨酸神经递质系统的基本组成部分。尽管来自转基因小鼠的几条证据表明VGLUT2与神经性疼痛可能存在关联，但在神经性疼痛期间VGLUT2在脊髓中的特定作用及其调节机制仍然难以捉摸。在这项研究中，我们报告说，幸免的神经损伤导致脊髓中的VGLUT2上调，并且在手术前后对VGLUT2鞘内注射小发夹RNA（shRNA）可以减轻机械性异常性疼痛，并在病理上增强谷氨酸的释放。同时，神经损伤以快速发作和持续的方式激活了Wnt1 /β-catenin信号通路，并用靶向Wnt1的抗体阻断Wnt1信号传导可减轻神经性疼痛。在幼稚的小鼠中，给予Wnt激动剂或Wnt1可增加脊髓VGLUT2蛋白水平。此外，鞘内注射Wnt /β-catenin抑制剂XAV939可减轻机械性异常性疼痛，该作用与VGLUT2下调同时发生。VGLUT2 shRNA预处理消除了Wnt激动剂或Wnt1诱导的异常性疼痛。这些发现揭示了一种新的机制，其中在神经性疼痛中存在Wnt1 /β-连环蛋白依赖性VGLUT2上调，从而加强了疼痛治疗中新治疗策略的开发。XAV939减弱了机械性异常性疼痛，这种作用与VGLUT2下调同时发生。用VGLUT2 shRNA预处理消除了Wnt激动剂或Wnt1诱导的异常性疼痛。这些发现揭示了一种新的机制，其中在神经性疼痛中存在Wnt1 /β-连环蛋白依赖性VGLUT2上调，从而加强了疼痛治疗中新治疗策略的开发。XAV939减弱了机械性异常性疼痛，该作用与VGLUT2下调同时发生。用VGLUT2 shRNA预处理消除了Wnt激动剂或Wnt1诱导的异常性疼痛。这些发现揭示了一种新的机制，其中在神经性疼痛中存在Wnt1 /β-连环蛋白依赖性VGLUT2上调，从而加强了疼痛治疗中新治疗策略的开发。