胰高血糖素样肽1受体在大鼠慢性炎性痛发生机制中的作用
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篇名: 胰高血糖素样肽1受体在大鼠慢性炎性痛发生机制中的作用
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摘要: 目的:研究胰高血糖素样肽1受体(GLP-1R)在大鼠慢性炎性痛发生机制中的作用。方法:取大鼠随机分为正常对照组、生理盐水1组和完全弗氏佐剂(CFA)1组,另取大鼠随机分为生理盐水2组、CFA2组和(GLP-1R激动药)GLP-1组(5 μg/kg),采用左后足趾侧注射CFA复制大鼠慢性炎性痛模型,后3组大鼠建模后第7天腹腔注射相应药物,连续给药1周。采用Hargreaves热痛仪测定前3组大鼠建模前1 d(-1 d)、建模当天(0 d)和建模后1、3、7、14 d的舔足潜伏期,后3组大鼠建模后8、10、12、14 d的舔足潜伏期,每个时间点6只大鼠。建模后第7天,采用免疫荧光组织化学染色观察模型组大鼠GLP-1R分子的分布情况。采用Western blot法检测前3组大鼠建模后1、3、7、14 d背根神经节(DRG)中GLP-1R蛋白的表达水平,后3组大鼠建模后14 d DRG中GLP-1R、肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)及IL-1β蛋白的表达水平,每个时间点3只大鼠。结果:与正常对照组和生理盐水1组比较,CFA1组大鼠建模后1、3、7、14 d的舔足潜伏期明显缩短(P<0.01),DRG中GLP-1R蛋白表达水平明显降低(P<0.01),-1、0 d的舔足潜伏期差异无统计学意义(P>0.05)。GLP-1R分子与NeuN双重标记明显,且与降钙素基因相关肽(CGRP)阳性神经元双重标记明显,与植物凝集素B4 (IB4)阳性神经元未见明显双重标记。与生理盐水2组比较,CFA2组大鼠建模后8、10、12、14 d的舔足潜伏期明显缩短(P<0.01),建模后14 d DRG中GLP-1R蛋白表达水平明显降低(P<0.01),TNF-α、IL-6及IL-1β蛋白表达水平明显升高(P<0.01)。与CFA2组比较,GLP-1组大鼠建模后8、10、12、14 d的舔足潜伏期明显延长(P<0.05或P<0.01),建模后14 d DRG中GLP-1R蛋白表达水平明显升高(P<0.01),TNF-α、IL-6及IL-1β蛋白表达水平明显降低(P<0.05或P<0.01)。结论:GLP-1R分子主要表达于DRG中的CGRP阳性神经元,其表达水平随慢性疼痛的发生与发展而逐渐降低,且升高GLP-1R表达能够有效缓解慢性炎性痛,其可能与降低DRG中炎症因子的表达有关。
ABSTRACT: OBJECTIVE: To study the role of glucagon-like peptide 1 receptor (GLP-1R) on chronic inflammatory pain mechanism in rats. METHODS: The rats were randomly divided into normal control group, normal saline group 1 and complete Freund’s adjuvant (CFA) group 1. Other rats were randomly divided into normal saline group 2, CFA 2 group and (GLP-1R agonist) GLP-1 group (5 μg/kg). Chronic inflammatory pain model was induced by left hind toe side injection of CFA. The latter 3 groups were given relevant medicine intraperitoneally on the 7th day after modeling, for consecutive a week. The licking incubation of the former 3 groups were determined by Hargreaves thermal pain instrument 1 d before modeling (-1 d), on modeling day (0 d), 1, 3, 7, 14 d after modeling; the licking incubation of the latter 3 groups were determined 8, 10, 12, 14 d after modeling; those of each 6 rats were determined at each time point. 7 d after modeling, distribution of receptor GLP-1R molecule in model group was observed by immunofluorescence double labeling. Western blot method was used to detect the expression of GLP-1R protein in dorsal root ganglia (DRG) of rats in former 3 groups 1, 3, 7 and 14 d after modeling. The expression of GLP-1R, TNF-α, IL-6 and IL-1β protein in DRG of rats were also determined in latter 3 groups 14 d after modeling; those of each 3 rats were determined at each time point. RESULTS: Compared with normal control group and normal saline group 1, licking incubation of CFA group 1 was shortened significantly 1, 3, 7, 14 d after modeling (P<0.01), and the protein expression of GLP-1R in DRG was decreased significantly (P<0.01); there was no statistical significance in licking incubation -1 and 0 d (P>0.05). GLP-1R molecules were double labeled with NeuN and calcitonin gene-related peptide (CGRP)-positive neurons no significant double marker was found between GLP-1R molecules and phytohemagglutinin B4 positive neurons. Compared with normal saline group 2, licking incubation of CFA group 2 was shortened significantly 8, 10, 12, 14 d after modeling (P<0.01); the protein expression of GLP-1R in RG was decreased significantly 14 d after modeling (P<0.01); the protein expression of TNF-α, IL-6 and IL-1β were increased significantly (P<0.01). Compared with CFA group 2, licking incubation of GLP-1 group was prolonged significantly 8, 10, 12, 14 d after modeling (P<0.05 or P<0.01); the protein expression of GLP-1R in DRG was increased significantly 14 d after modeling (P<0.01), and the protein expression of TNF-α, IL-6 and IL-1β were decreased significantly (P<0.05 or P<0.01). CONCLUSIONS: GLP-1R molecule is mainly expressed in CGRP-positive neurons of DRG. The expression level of GLP-1 receptor gradually decreases with the occurrence and development of chronic pain. The increase of GLP-1R expression can effectively relieve chronic inflammatory pain, which is related with reducing reduce the expression of inflammatory factors in DRG.
期刊: 2018年第29卷第19期
作者: 王健,牛云圃,崔佳,王磊,樊婷婷,张维
AUTHORS: WANG Jian,NIU Yunpu,CUI Jia,WANG Lei,FAN Tingting,ZHANG Wei
关键字: 胰高血糖素样肽1受体;完全弗式佐剂;慢性炎性痛;炎症因子;大鼠
KEYWORDS: Glucagon-like peptide 1 receptor; Complete Freund’s adjuvant; Chronic inflammatory pain; Inflammatory factor; Rat
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