糖尿病神经病理性疼痛（DNP）仍缺乏有效治疗手段。组蛋白乙酰化修饰介导的突触可塑性相关基因表达改变参与疼痛发生，而与突触可塑性和疼痛密切相关的代谢型谷氨酸受体（mGluR）1/5可被组蛋白乙酰化修饰。预实验提示，Sirt1作为重要的Ⅲ类组蛋白去乙酰化酶及2型糖尿病潜在治疗新靶点，可能参与DNP发生，且沉默Sirt1可上调脊髓Grm1/5启动子组蛋白H3乙酰化及突触相关蛋白PSD-95水平。据此，我们提出：Sirt1下调可促进Grm1/5启动子组蛋白乙酰化，进而增加mGluR1/5表达，引起脊髓神经元可塑性改变，导致DNP发生。本项目拟以2型糖尿病大鼠和db/db小鼠DNP模型、Sirt1条件性基因敲除小鼠及原代脊髓神经元细胞为研究对象，从整体、细胞及分子水平研究Sirt1通过调控mGluR1/5去乙酰化介导脊髓神经元可塑性改变，参与DNP发生的新机制，为寻找理想的防治DNP药物提供新靶点。

There are no effective treatments for diabetic neuropathic pain (DNP). Histone acetylation-mediated expression changes of synaptic plasticity-related genes have been reported to be involved in the development of chronic pain. Metabotropic glutamate receptors (mGluRs) 1 and 5, which are closely related to synaptic plasticity and chronic pain, can be modified by histone acetylation. The results of our preliminary experiments suggested that sirt1, an important class III histone deacetylase and a new target of type 2 diabetes mellitus, may be related to DNP. Moreover, sirt1 shRNA could increase histone H3 acetylation at Grm1 and 5 promoter, and up-regulate the expression of postsynaptic density-95 (PSD-95). Therefore, we hypothesize that the down-regulated sirt1 expression could promote histone H3 acetylation at Grm1/5 promoter, increase the expressions of mGluR1 and mGluR5, and cause the changes in spinal synaptic plasticity, leading to development of DNP. The current project is aimed to clarify the new mechanisms for sirt1-mediated deacetylation of mGluR1 and mGluR5 in spinal synaptic plasticity and DNP, using type 2 diabetic rats, db/db mice, sirt1 conditional knock-out mice and primary cultured spinal neurons. This project will provide a new potential target for the discovery of analgesic drugs used to relieve DNP.