College of Veterinary Medicine, Huazhong Agricultural University, No.1, Shizishan Street, Hongshan District, Wuhan, 430070, Hubei, People's Republic of China.
J Mol Neurosci. 2020 Aug;70(8):1198-1207. doi: 10.1007/s12031-020-01527-6. Epub 2020 Apr 2.
Electroacupuncture (EA) treatment has proved to significantly decrease nociception in inflammatory nociception model by suppressing the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). However, repeated EA treatment results in gradual attenuation of its analgesic effects, which was defined as "EA tolerance." Recent studies have shown that let-7b-5p microRNA (miRNA) contributes to the EA tolerance. The present study aimed to explore the function of let-7b-5p in p38MAPK pathway and the development of EA tolerance in the inflammatory nociception. Dual luciferase reporter gene experiments were used in cortical neurons to determine the target gene locus of let-7b-5p. The threshold of nociception was assessed by tail flick latency (TFL) and paw withdrawal threshold (PWT). Western blots were used to measure the expression of mitogen-activated protein kinase phosphatase 1 (MKP-1) and phosphorylation level of p38MAPK after intracerebroventricular (ICV) injections of let-7b-5p agomir, antagomir, and controls. In vitro dual luciferase experiments demonstrated that the MKP-1-3' untranslated region (UTR) is a target of let-7b-5p. In vivo experiment, rat with repeated EA treatment exhibits gradual decrease in TFL and PWT, which showed formation of EA tolerance. This trend was delayed after IVC injection of let-7b-5p antagomir and facilitated after IVC injection of let-7b-5p agomir. The protein levels of MKP-1 in the EA+let-7b-5p antagomir group were significantly higher than in the EA + let-7b-5p agomir group. However, P-p38MAPK in the EA+let-7b-5p antagomir group was significantly lower than in the EA+let-7b-5p agomir group. By upregulating the p38MAPK pathway through the inactivation of the MKP-1 gene, let-7b-5p contributes to EA tolerance in complete Freund's adjuvant (CFA)-induced inflammatory nociception rats. Our work revealed the mechanism of EA tolerance and indicated that let-7b-5p could be targeted to improve the long-term effects of EA.
电针（EA）治疗已被证明通过抑制 p38 丝裂原活化蛋白激酶（p38MAPK）的磷酸化，可显著降低炎症性伤害感受模型中的伤害感受。然而，重复的 EA 治疗会导致其镇痛效果逐渐减弱，这被定义为“EA 耐受”。最近的研究表明，let-7b-5p 微 RNA（miRNA）有助于 EA 耐受。本研究旨在探讨 let-7b-5p 在 p38MAPK 通路中的作用及其在炎症性伤害感受中 EA 耐受的发展。皮质神经元中的双荧光素酶报告基因实验用于确定 let-7b-5p 的靶基因座。通过尾巴拍打潜伏期（TFL）和足底退缩阈值（PWT）评估伤害感受阈值。Western blot 用于测量鞘内（ICV）注射 let-7b-5p agomir、antagomir 和对照后促分裂原活化蛋白激酶磷酸酶 1（MKP-1）和 p38MAPK 磷酸化水平。体外双荧光素酶实验表明，MKP-1-3'非翻译区（UTR）是 let-7b-5p 的靶标。在体内实验中，重复 EA 治疗的大鼠表现出 TFL 和 PWT 的逐渐下降，这表明形成了 EA 耐受。这种趋势在 ICV 注射 let-7b-5p antagomir 后延迟，在 ICV 注射 let-7b-5p agomir 后促进。EA+let-7b-5p antagomir 组的 MKP-1 蛋白水平明显高于 EA+let-7b-5p agomir 组。然而，EA+let-7b-5p antagomir 组的 P-p38MAPK 明显低于 EA+let-7b-5p agomir 组。通过使 MKP-1 基因失活上调 p38MAPK 通路，let-7b-5p 有助于完全弗氏佐剂（CFA）诱导的炎症性伤害感受大鼠的 EA 耐受。我们的工作揭示了 EA 耐受的机制，并表明 let-7b-5p 可以作为靶点来改善 EA 的长期效果。
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