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选择性I型组蛋白去乙酰化酶抑制剂对蜜蜂毒诱致的大鼠自发痛和热痛敏的抑制作用

杨帆, 杨艳, 王燕, 杨菲, 李春丽, 王晓亮, 李震, 陈军

首都医科大学基础医学院疼痛生物医学研究所，北京 100069；第四军医大学唐都医院疼痛生物医学研究所暨功能性脑疾病研究所；西安 710038；中国人民解放军脑应激与行为重点实验室，西安 710038；北京脑疾病研究院，北京 100069

摘要

为了明确I型组蛋白去乙酰化酶(histone deacetylase, HDAC)抑制剂对外周炎性痛的减轻是否有效，本实验采用对大鼠足底皮下注射蜜蜂毒的方法研究了两种选择性I型HDAC抑制剂MS-275和MGCD0103的镇痛作用。蜜蜂毒模型能够呈现多种疼痛表现型，包括持续性自发痛相关行为，原发性热和机械痛敏，以及镜像热痛敏。鞘内提前给予剂量为60 nmol/20 μL的MS-275和MGCD0103能够显著抑制蜜蜂毒诱致的持续性自发痛和原发性热痛敏，而对原发性机械痛敏和镜像热痛敏无显著影响；而且，由皮下注射蜜蜂毒诱致的HDAC1和HDAC2的高表达通过鞘内提前给予MS-275得到了完全抑制。本研究为证明由HDAC1/2介导的组蛋白低乙酰化染色质结构的表观遗传学调控参与介导蜜蜂毒诱致的持续性自发痛和热痛敏提供了新的证据，并表明I型HDAC抑制剂对外周炎性痛的发生具有良好的预防效果。

关键词： 蜜蜂毒; 组蛋白去乙酰化酶; 持续性自发痛; 热痛敏; 机械痛敏

分类号：R441.1

Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain

Yang Fan, YANG Yan, WANG Yan, YANG Fei, LI Chun-Li, WANG Xiao-Liang, LI Zhen, CHEN Jun

Institute for Biomedical Sciences of Pain, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China； Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, the Fourth Military Medical University, Xi’an 710038, China； Key Laboratory of Brain Stress and Behavior, PLA, Xi’an 710038, China； Beijing Institute for Brain Disorders, Beijing 100069, China

Abstract

To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.

Key words: bee venom; histone deacetylase; persistent spontaneous nociception; thermal hypersensitivity; mechanical hypersensitivity

收稿日期：2015-04-24　　录用日期：2015-05-20

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引用本文：

杨帆, 杨艳, 王燕, 杨菲, 李春丽, 王晓亮, 李震, 陈军. 选择性I型组蛋白去乙酰化酶抑制剂对蜜蜂毒诱致的大鼠自发痛和热痛敏的抑制作用[J]. 生理学报 2015; 67 (5): 447-454.

Yang Fan, YANG Yan, WANG Yan, YANG Fei, LI Chun-Li, WANG Xiao-Liang, LI Zhen, CHEN Jun. Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain. Acta Physiol Sin 2015; 67 (5): 447-454 (in Chinese with English abstract).