Xia Li, Zhang Yunlong, Dong Tieli
Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, No. 2 Jingba Road, Jinshui District, Zhengzhou, 450014, People's Republic of China.
Department of Anesthesiology, Maternal and Child Health Hospital of Zhengzhou, Zhengzhou, 450000, China.
J Mol Neurosci. 2016 Jul;59(3):411-20. doi: 10.1007/s12031-016-0748-1. Epub 2016 Apr 8.
Neuropathic pain results in considerable trouble to people's physical and mental health. The pathophysiological mechanisms underlying its occurrence and development remain unclear. A large number of experiments show that microRNAs (miRNAs) play a major role in the pathogenesis of neuropathic pain and neuroinflammation resulting from nerve injury. Among various miRNAs, microRNA-221 (miR-221) overexpression has been reported in a chronic constrictive injury (CCI)-induced rat model of neuropathic pain. However, the role of miR-221 in the regulation of neuropathic pain is unknown. In this study, we investigated the potential role and underlying mechanism of miR-221 in regulating neuropathic pain. Our findings show that miR-221 is overexpressed in the spinal cord and the isolated microglia of CCI rats. Intrathecal injection of a miR-221 inhibitor attenuated CCI-induced mechanical allodynia and thermal hyperalgesia, and reduced proinflammatory cytokine expression, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in CCI rats. Using a dual-luciferase reporter assay, we show that suppressor of cytokine signaling 1 (SOCS1), an important regulator of inflammation, is a direct target of miR-221. Treatment with the miR-221 inhibitor significantly inhibited the expression of SOCS1. Furthermore, the miR-221 inhibitor markedly suppressed the activation of nuclear factor-kappa B (NF-κB) and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Knockdown of SOCS1 in CCI rats abrogated the inhibitory effect of the miR-221 inhibitor on CCI-induced neuropathic pain and the NF-κB and p38 MAPK signaling pathways. Together, these results suggest that inhibition of miR-221 alleviates neuropathic pain and neuroinflammation through increasing SOCS1 and by inhibiting the NF-κB and p38 MAPK signaling pathways, indicating that miR-221 may be a promising molecular target for the treatment of neuropathic pain.
神经病理性疼痛给人们的身心健康带来了相当大的困扰。其发生和发展的病理生理机制尚不清楚。大量实验表明，微小RNA（miRNA）在神经病理性疼痛和神经损伤所致神经炎症的发病机制中起主要作用。在各种miRNA中，据报道在慢性压迫性损伤（CCI）诱导的神经病理性疼痛大鼠模型中，微小RNA - 221（miR - 221）表达上调。然而，miR - 221在神经病理性疼痛调节中的作用尚不清楚。在本研究中，我们调查了miR - 221在调节神经病理性疼痛中的潜在作用及潜在机制。我们的研究结果表明，miR - 221在CCI大鼠的脊髓和分离的小胶质细胞中表达上调。鞘内注射miR - 221抑制剂可减轻CCI诱导的机械性异常性疼痛和热痛觉过敏，并降低CCI大鼠中促炎细胞因子的表达，包括肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和IL - 6。使用双荧光素酶报告基因检测，我们表明细胞因子信号转导抑制因子1（SOCS1），一种重要的炎症调节因子，是miR - 221的直接靶点。用miR - 221抑制剂处理可显著抑制SOCS1的表达。此外，miR - 221抑制剂显著抑制核因子κB（NF - κB）和p38丝裂原活化蛋白激酶（p38 MAPK）信号通路的激活。在CCI大鼠中敲低SOCS1可消除miR - 221抑制剂对CCI诱导的神经病理性疼痛以及NF - κB和p38 MAPK信号通路的抑制作用。总之，这些结果表明抑制miR - 221可通过增加SOCS1以及抑制NF - κB和p38 MAPK信号通路来减轻神经病理性疼痛和神经炎症，表明miR - 221可能是治疗神经病理性疼痛的一个有前景的分子靶点。
