奥沙利铂诱导化疗大鼠的周围神经病理性疼痛的分子机制  

The molecular mechanism of oxaliplatin‐induced peripheral neuropathic pain

作　　者：杨少敏 吴松斌 吴佳蔓 黄佳彬 黄铭杰 熊东林 郝悦 孙武平 肖礼祖 Yang Shaomin;Wu Songbin;Wu Jiaman;Huang Jiabin;Huang Mingjie;Xiong Donglin;Hao Yue;Sun Wuping;Xiao Lizu(Department of Pain Medicine,Huazhong University of Science and Technology Union Shenzhen Hospital(Nanshan Hospital),Shenzhen Municipal Key Laboratory for Pain Medicine,Shenzhen 518052,China;School of Pharmaceutical Sciences,Health Science Center,Shenzhen University,Shenzhen 518060,China)

机构地区：[1]华中科技大学协和深圳医院疼痛科,深圳市疼痛学重点实验室,深圳518052 [2]深圳大学医学部药学院,深圳518060

出　　处：《中华医学杂志》2021年第43期3581-3587,共7页National Medical Journal of China

基　　金：深圳市科技创新委员会项目(JCYJ201604291814515);深圳市南山区卫生科技计划项目(2019012)。

摘　　要：目的探讨奥沙利铂诱导化疗引起的周围神经病理性疼痛(CIPNP)的分子机制。方法SPF级SD雄性大鼠16只采用随机数字表法分为两组:奥沙利铂实验组(5.0%葡萄糖溶液中溶解2.4 mg/kg奥沙利铂,n=8)和对照组(等体积5%的葡萄糖溶液,n=8)。通过奥沙利铂连续给药建立大鼠CIPNP模型,测定并比较两组大鼠机械性痛觉、热痛觉过敏、冷痛觉过敏等疼痛行为学指标。采用RNA测序技术对大鼠背根神经节(DRG)基因转录组水平进行定量,分析奥沙利铂诱导CIPNP的分子机制。结果实验组大鼠在第7天开始出现机械痛觉异常和冷热痛觉过敏,在第14天达到最强。通过转录组测序,共定量到20152个基因,以组间差异倍数绝对值≥2和P<0.05的标准筛选到379个差异表达基因(DEG);其中Npy、Car3、Cdkn1a、Nts、Prc1、Ms4a7和Ecel17个基因为外周神经损伤疼痛相关基因。通过基因本体论功能分析,奥沙利铂诱导的差异表达基因主要参与氧运输、细胞分裂、中间体、着丝粒、氧转运蛋白活性、氧结合等功能。通过京都基因与基因组百科全书信号通路(KEGG)分析,奥沙利铂诱导的差异表达基因主要参与疟疾、非洲锥虫病、原发性免疫缺陷、过氧化物酶体增殖物激活受体信号通路(PPAR)等。结论奥沙利铂可能通过诱导疼痛相关基因以及相关信号通路引起外周神经性疼痛。Objective To investigate the molecular mechanism of oxaliplatin-induced chemotherapy-induced peripheral neuropathic pain(CIPNP).Methods A total of 16 male Sprague-Dawley rats of specific pathogen-free grade were randomly divided into two groups:oxaliplatin experimental group(2.4 mg/kg oxaliplatin dissolved in 5.0%glucose solution,n=8)and control group(equal volume 5%glucose solution,n=8).The rat model of CIPNP was established by continuous administration with oxaliplatin.In addition,mechanical allodynia,thermal hyperalgesia and cold hyperalgesia were measured and compared between the two groups.To explore the molecular mechanism of oxaliplatin-induced CIPNP,the gene expression of dorsal root ganglia(DRG)from the rat model of CIPNP was analyzed using RNA sequencing(RNA-Seq).Results Mechanical and thermal hypersensitivity was exhibited on day 7 and a stronger hypersensitivity was observed on day 14.A total of 20152 genes were quantified by RNA-Seq,and 379 differentially expressed genes(DEGs)were obtained with absolute fold change cut-offs≥2 and P value<0.05.There were 7 genes(Npy,Car3,Cdkn1a,Nts,Prc1,Ms4a7 and Ecel1)that were involved in peripheral nerve injury-related neuropathic pain.Gene ontology(GO)functional enrichment analyses indicated that the DEGs induced by oxaliplatin were involved in oxygen transport,cell division,intermediate,centromere,oxygen transporter activity,oxygen binding.Moreover,the result of Kyoto Encyclopedia of genes and genomes(KEGG)analyses highlighted that the DEGs induced by oxaliplatin were involved in malaria,African trypanosomiasis,primary immunodeficiency,peroxisome proliferator activated receptor(PPAR)signaling pathway.Conclusion Oxaliplatin induces CIPNP via pain-related genes and signaling pathways.

关 键 词：奥沙利铂 周围神经病理性疼痛 转录组测序 

分 类 号：R730.53[医药卫生—肿瘤] R741.02[医药卫生—临床医学]