神经病理性疼痛是临床常见顽固性疾病，其机制尚不完全清楚是导致临床有效防治措施缺乏的主要原因。近年研究显示组蛋白去乙酰化修饰与疼痛关系密切。课题组以往研究发现，干预组蛋白去乙酰化酶HDAC5能有效减轻疼痛，但机制仍不明确。本项目预实验显示，pSNL神经病理性疼痛小鼠：1)脊髓背角神经元胞核中HDAC5增加；2)GABA能神经元相关谷氨酸脱羧酶GAD65/67表达下降；3)乙酰化的组蛋白H3K9（Acetyl-H3K9）可与GAD65/67共标于脊髓神经元，且表达水平降低；4)与GAD65/67基因启动子结合的Acetyl-H3K9数目降低。在前期研究基础上，本项目拟以核内蓄积的HDAC5抑制GABA能神经元活性为新视角，从整体、细胞及分子水平阐明HDAC5通过GAD65/67调控GABA能神经元活性介导疼痛的表观遗传学机制，以期为神经病理性疼痛提供有效治疗靶点，为镇痛药物研发提供依据。

Neuropathic pain is a common refractory disease. The understanding of its mechanism is incomplete, which results in the lack of effective treatment for the patients with neuropathic pain. Recent studies have shown that histone deacetylation modification is closely related to pain. According to our previous studies, intervention of histone deacetylase 5(HDAC5) can effectively alleviate neuropathic pain, but the mechanism is still unclear. The preliminary results showed that under neuropathic pain condition: 1) HDAC5 accumulated in spinal neuronal nuclei; 2)Spinal glutamic acid decarboxylases (GAD65/67) were decreased; 3) Acetylated Histone3 at site 9 serine (Acetyl-H3K9) co-expressed with GAD65/67 in spinal neurons were decreased；4) The number of acetyl-H3K9 binding to GAD65/67 gene promoter regions was decreased. Base on our previous research, this project purposes to further investigate the molecular mechanism of spinal nuclear accumulation of HDAC5 inhibiting GABAergic neuronal activity by targeting GAD65/67 in a pSNL-induced neuropathic pain animal model. This study is very likely to provide the rational basis for seeking effective therapeutic target for neuropathic pain.