SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats\
SIRT1 attenuates neuropathic pain by epigenetic regulation of mGluR1/5 expressions in type 2 diabetic rats\
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DOI：
10.1097/j.pain.0000000000000739
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发表时间：
2017-01-01
期刊：
影响因子：
7.4
通讯作者：
Yin, Xiao-Xing
中科院分区：
文献类型：
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作者：
Zhou, Cheng-Hua;Zhang, Ming-Xing;Yin, Xiao-Xing
越来越多的证据表明，表观遗传修饰介导的疼痛相关基因表达的变化在神经病理性疼痛的发生和维持中起着重要作用。Sirtuin 1（SIRT 1）是一种依赖于NAD（+）的脱乙酰酶，参与慢性疼痛的发生。此外，SIRT 1可能是预防2型糖尿病（T2 DM）的一个新的治疗靶点。但是SIRT 1在T2 DM诱导的神经病理性疼痛中的作用仍然未知。在这项研究中，我们发现，脊髓SIRT 1的表达和活性在高脂肪喂养/低剂量链脲佐菌素诱导的神经病理性疼痛大鼠显着下调。SIRT 1定位于脊髓神经元，而不是在星形胶质细胞或小胶质细胞。此外，代谢型谷氨酸受体（mGluR 1）和mGluR 5的表达，这在中枢敏化和神经病理性疼痛中起关键作用，并在Grm 1/5（编码mGluR 1/5）启动子区域的H3乙酰化水平在糖尿病神经病理性疼痛大鼠中增加。SIRT 1激活剂SRT 1720逆转糖尿病神经病理性疼痛大鼠的热痛觉过敏和机械异常性疼痛以及脊髓神经元激活。同时，增加的表达mGluR 1/5和H3乙酰化水平在Grm 1/5启动子区域被逆转SIRT 1激活。此外，Ad-SIRT 1-shRNA敲低SIRT 1基因可诱导正常大鼠痛行为和脊髓神经元激活，并伴有Grm 1/5启动子区mGluR 1/5和H3乙酰化水平的表达增加。因此，我们得出结论，SIRT 1介导的mGluR 1/5表达的表观遗传调控参与了2型糖尿病大鼠神经病理性疼痛的发展。
Accumulating evidence has demonstrated that epigenetic modification-mediated changes in pain-related gene expressions play an important role in the development and maintenance of neuropathic pain. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, is involved in the development of chronic pain. Moreover, SIRT1 may be a novel therapeutic target for the prevention of type 2 diabetes mellitus (T2DM). But the role of SIRT1 in T2DM-induced neuropathic pain remains unknown. In this study, we found that spinal SIRT1 expression and activity were downregulated significantly in high-fat-fed/low-dose streptozotocin-induced neuropathic pain rats. SIRT1 localized in spinal neurons but not in astrocytes or microglia. Furthermore, the expressions of metabotropic glutamate receptor (mGluR1) and mGluR5, which play a key role in central sensitization and neuropathic pain, and H3 acetylation levels at Grm1/5 (encoding mGluR1/5) promoter regions were increased in diabetic neuropathic pain rats. SIRT1 activator SRT1720 reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal activation in diabetic neuropathic pain rats. Concurrently, increased expressions of mGluR1/5 and H3 acetylation levels at Grm1/5 promoter regions were reversed by SIRT1 activation. In addition, knockdown of SIRT1 by Ad-SIRT1-shRNA induced pain behaviors and spinal neuronal activation in normal rats, which was accompanied by the increased expressions of mGluR1/5 and H3 acetylation levels at Grm1/5 promoter regions. Therefore, we concluded that SIRT1-mediated epigenetic regulation of mGluR1/5 expressions was involved in the development of neuropathic pain in type 2 diabetic rats.