生长分化因子15对福尔马林诱导双相疼痛的镇痛作用及其机制的探究
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1.上海交通大学药学院;2.上海交通大学附属第六人民医院药剂科

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国家自然科学基金资助项目(No.81603082);2019年上海市“医苑新星”青年医学人才培养资助计划(临床药师项目)[沪卫人事〔2020〕87 号];上海市临床药学重点专科建设项目(AB83110002016007) 因子15对福尔马林诱导双相疼痛的镇痛作用及其机制的探究


Antinociceptive effect and its mechanism of growth differentiation factor 15 on formalin–induced pain in mice
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School of Pharmacy,Shanghai Jiao Tong University

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    摘要:

    目的:探讨生长分化因子15(GDF-15)对福尔马林诱导的双相疼痛的镇痛作用以及其可能的机制。方法:首先采用中枢给药鞘内注射GDF-15(50 ng)进行了福尔马林双相痛实验,并设置不同剂量组系统性腹腔注射GDF-15(10 μg/kg、30 μg/kg以及100 μg/kg)进行福尔马林双相痛实验,记录比较福尔马林双相疼痛阈值;采用蛋白免疫印迹和组织免疫荧光实验检验GDF-15的特异性受体GFRAL的表达情况;并采用实时荧光PCR法检测中枢给予GDF-15(50 ng)对福尔马林小鼠脊髓IL-6、IL-1β、TNF-α、PDYN以及PENK的mRNA表达的影响。结果:中枢给予GDF-15对福尔马林II相炎性疼痛有显著镇痛作用,而对急性疼痛未见有显著作用(P<0.05);系统性给予GDF-15对福尔马林II相炎性疼痛有显著镇痛作用(P<0.05),且呈剂量依赖性;GDF-15的特异性受体GFRAL在大脑、小脑和脊髓中表达,其中在脊髓背角中仅在神经元细胞表达;中枢给予GDF-15可以降低福尔马林小鼠脊髓中促炎因子IL-6(P<0.05)和TNF-α(P<0.005)的表达。结论:GDF-15对福尔马林诱导的II相炎性疼痛存在镇痛作用,且可能是通过降低促炎因子IL-6和TNF-α的表达发挥作用。

    Abstract:

    Objective:This study aimed to investigate the antinociceptive effect of growth differentiation factor 15(GDF-15)and its possible mechanism. Methods:Intrathecal injection of GDF-15 (50 ng) was given for formalin–induced pain model test and different dose groups were set up with intraperitoneal injection of GDF-15 (10 μg/kg, 30 μg/kg and 100 μg/kg) to perform a formalin–induced pain model test. The formalin pain threshold was compared with vehicle control group to measure the analgesic effect. Western blot and immunofluorescence experiments were used to test the expression of GDF-15’s specific receptor GFRAL. Real-time PCR was used to measure the mRNA expression of IL-6, IL-1β, TNF-α, PDYN and PENK in the spinal cord of formalin mice (50 ng). Results:The results showed that both intrathecal and intraperitoneal administration demonstrated that GDF-15 had a antinociceptive effect on inflammatory pain and the antinociceptive effect of intraperitoneal administration was dose-dependent, while there was no significant effect on acute pain. The specific receptor of GDF-15, GFRAL, was expressed in the brain, cerebellum and spinal cord, and it only expressed in neurons in the spinal cord dorsal horn. Also, we found that intrathecal injection of GDF-15 can inhibit the expression of pro-inflammatory factors IL-6 and TNF-α in the spinal cord of formalin mice. Conclusion: GDF-15 has a antinociceptive effect on formalin-induced inflammatory pain and its possible mechanism is by reducing the expression of pro-inflammatory factors IL-6 and TNF-α.

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  • 收稿日期:2022-05-06
  • 最后修改日期:2022-06-08
  • 录用日期:2022-08-11
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