Peripheral pain is enhanced by insulin-like growth factor 1 and its receptors in a mouse model of type 2 diabetes mellitus

Insulin-like growth factor 1 (IGF1) is a neurotrophic factor with many actions, including a possible hyperalgesic effect. This study investigated the effects of IGF1 on the overall behavior of diabetic mice and explored the possible mechanisms underlying IGF1-induced pain.Mice were divided into five groups (db/m, db/db, vehicle-treated db/db, IGF1-treated db/db, and IGF1 + JB1-treated db/db mice). Behavioral studies were conducted using the hot plate and Von Frey tests after intraplantar injection of recombinant (r) IGF1 (50 μg/kg) and the IGF1 receptor (IGF1R) antagonist JB1 (6 μg/mouse). Morphological changes in dorsal root ganglia (DRG) were evaluated using electron microscopy. Immunofluorescence was used to detect IGF1R expression and colocalisation with pain mediators in the DRG. Changes in the expression of IGF1R, extracellular signal-regulated kinase (ERK), and ras-associated factor-1 (c-raf) in the DRG were evaluated using western blotting.Intraplantar injection of rIGF1 resulted in a hyperalgesic effect after 2 hours. This IGF1-induced hypersensitivity was attenuated by prior intraplantar injection of the IGF1R antagonist. There was no significant change in neuronal structure in the db/m group, whereas neuronal structure was impaired in the other four groups. Moreover, IGF1R was colocalised with pain mediators in the DRG of mice. Intraplantar injection of rIGF1 resulted in increased IGF1R, phosphorylated (p-) ERK, and c-raf expression in the DRG; prior intraplantar injection of the IGF1R antagonist attenuated rIGF1-induced increases in p-ERK and c-raf.The results indicate that IGF1-induced acute hyperalgesia may be associated with the IGF1R/c-raf/ERK pathway. The IGF1-induced hypersensitivity was attenuated by an IGF1R antagonist.摘要: 背景 胰岛素样生长因子1(insulin like growth factor 1,IGF1)是一种包括痛觉过敏效应在内的多效能神经营养因子。本研究探索了IGF1对糖尿病小鼠整体行为学的影响, 并探讨了IGF1诱导疼痛可能涉及的机制。 方法 将小鼠分成5组:db/m组、db/db组、生理盐水处理的 db/db组、IGF1处理的 db/db组和IGF1 + JB1处理的db/db组。使用rIGF1(50 μg/kg)及其受体抑制剂JB1(6 μg/只)后比较各组小鼠疼痛行为学的相应指标。应用电镜观察小鼠背根神经节(dorsal root ganglia, DRG)形态学的改变;应用免疫荧光组织化学法检测DRG内IGF1R表达及与痛觉介质的共定位情况;应用western blotting方法检测DRG内IGF1R、细胞外信号调节蛋白激酶(extracellularsignal-regulated kinase,ERK)、ras相关因子-1(ras-associated factor-1,c-raf)的蛋白水平的改变。 结果 足底注射rIGF1后2小时具有致痛觉过敏效应, 预先足底注射IGF1R抑制剂则能阻断此效应。除db/m小鼠组的神经细胞结构未见明显变化外, 其他4组均有受损。糖尿病小鼠DRG中IGF1R与痛觉介质共定位。足底内注射rIGF1后可以导致小鼠DRG内IGF1R、p-ERK、c-raf蛋白的表达增高。预先足底注射IGF1R抑制剂后可以减弱此效应。 结论 IGF1诱导的急性痛觉过敏可能与IGF1R / c-raf / ERK信号通路有关。这种致痛作用可以被IGF1R拮抗剂减弱。.