SFKs/p38 Pathway is Involved in Radicular Pain by Promoting Spinal Expression of Pro-Inflammatory Cytokines in a Rat Model of Lumbar Disc Herniation
SFKs/p38 Pathway is Involved in Radicular Pain by Promoting Spinal Expression of Pro-Inflammatory Cytokines in a Rat Model of Lumbar Disc Herniation
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SFKs/p38 通路通过促进腰椎间盘突出大鼠模型中促炎细胞因子的脊柱表达参与神经性疼痛
DOI：
10.1097/brs.0000000000003076
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发表时间：
2019
期刊：
影响因子：
3
通讯作者：
Yi Zhong（钟祎）
中科院分区：
文献类型：
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作者：
Yi Zhong（钟祎）
研究设计.一项对照、随机、动物研究。Objective.本研究的目的是探讨src家族激酶/p38通路在大鼠腰椎间盘突出症（LDH）模型中的作用。背景数据总结。LDH常引起神经根性疼痛，其机制尚不清楚。我们已经报道脊髓src家族激酶（SFKs）可能参与了这一过程，但其下游机制有待进一步研究。方法.将自体髓核植入大鼠腰4/5脊神经根诱导LDH。分别采用Von Frey细丝法和辐射热法测定机械痛阈和热痛阈。采用Basso、Beattie和Bresnahan（BBB）量表检测运动功能。Western blotting法检测脊髓组织中p-SFKs、t-SFKs、p-p38、t-p38蛋白的表达。免疫组化染色确定p-p38的细胞定位。采用酶联免疫吸附法（ELISA）检测脊髓肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1b和IL-6水平。结果NP组大鼠出现持续性机械痛敏和热痛敏，表现为缩足阈和缩足潜伏期明显降低。BBB评分显示NP植入大鼠后爪运动功能保持完整。Western blotting和免疫组化染色显示，NP大鼠同侧脊髓背角磷酸化SFKs（p-SFKs）和磷酸化p38 MAPK（p-p38）表达依次上调，而对侧脊髓背角无明显变化。鞘内注射SFKs抑制剂降低脊髓p-p38表达。SFKs和p38抑制剂均以剂量反应方式减轻疼痛行为，而不干扰运动功能，并降低NP大鼠脊髓TNF-α、IL-1b和IL-6的表达。结论脊髓SFKs通过激活p38 MAPK和增加NP植入大鼠的促炎细胞因子表达而促进神经根性疼痛。靶向SFKs/p38通路可能有助于缓解神经根性疼痛。
Study Design. A controlled, randomized, animal study. Objective. The aim of this study was to investigate the role of src-family kinases/p38 pathway in a rat model of lumbar disc herniation (LDH). Summary of Background Data. LDH always generates radicular pain, and the mechanism remains unclear. We have.reported that spinal src-family kinases (SFKs) may be involved in the process, but the downstream mechanism needs further investigation. Methods. LDH was induced by implantation of autologous nucleus pulposus (NP), harvest from the tail, in lumbar 4/5 spinal nerve roots of rat. Von Frey filaments and radiant heat tests were performed to determine mechanical and thermal pain threshold respectively. Basso, Beattie, and Bresnahan (BBB) scale.was assessed to test the locomotor function. The protein level of p-SFKs, t-SFKs, p-p38, t-p38 in spinal cord was examined by western blotting analysis. Cellular location of p-p38 was determined by immunochemistry staining. Spinal tumor necrosis factor-alpha (TNF-a), interleukin (IL)-1b, and IL-6 levels were.detected by enzyme-linked immunosorbent assay (ELISA). Results. Rats with NP implantation showed persistent ipsilateral mechanical allodynia and thermal hyperalgesia, which manifested as obvious decrease of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). BBB scale indicated the locomotor function of hindpaws in rats with NP implantation kept intact. Western blotting and immunohistochemistry staining revealed that phosphorylated SFKs (p-SFKs) and phosphorylated p38 MAPK (p-p38) were sequentially upregulated in ipsilateral spinal dorsal horn, but not in contralateral side of rats with NP. Intrathecal delivery of SFKs inhibitor reduced spinal p-p38 expression. Both SFKs and p38 inhibitors alleviated pain behaviors in a dose-responsive manner without disturbing locomotor function and reduced spinal expression of TNF-a, IL-1b, and IL-6 in rats with NP. Conclusion. Spinal SFKs contribute to radicular pain by activation of p38 MAPK and increasing pro-inflammatory cytokines expression in rats with NP implantation. Targeting SFKs/p38 pathway may be helpful for alleviating radicular pain.