Downregulation of ciRNA-Kat6b in dorsal spinal horn is required for neuropathic pain by regulating Kcnk1 in miRNA-26a-dependent manner.
Downregulation of ciRNA-Kat6b in dorsal spinal horn is required for neuropathic pain by regulating Kcnk1 in miRNA-26a-dependent manner.
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DOI：
10.1111/cns.14235
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发表时间：
2023-10
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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神经损伤诱导的脊髓神经元基因表达的适应不良变化对于神经病理性疼痛的发生至关重要。环状RNA（ciRNA）正在成为基因表达的关键调节因子。在这里，我们鉴定了一种在人类和小鼠中具有保守性的神经系统组织特异性ciRNA-Kat 6。我们的目的是研究脊髓背角ciRNA-Kat 6 b是否以及如何参与神经病理性疼痛。采用单侧坐骨神经慢性缩窄性损伤（CCI）术制备神经病理性疼痛模型。通过RNA测序获得差异表达的ciRNA。通过定量RT-PCR进行ciRNA-Kat 6 b的神经系统组织特异性鉴定以及ciRNA-Kat 6 b和microRNA-26 a（miRNA-26 a）表达水平的测量。通过生物信息学分析预测靶向miRNA-26 a的ciRNA-Kat 6 b和靶向Kcnk 1的miRNA-26 a，并通过体外荧光素酶报告测试和体内实验（包括Western blot、免疫荧光和RNA-RNA免疫沉淀）进行验证。通过对热和机械刺激的超敏反应来检查神经性疼痛与ciRNA-Kat 6 b、miRNA-26 a或Kcnk 1之间的相关性。外周神经损伤下调雄性小鼠脊髓背角中的ciRNA-Kat 6 b。挽救这种下调阻断了神经损伤诱导的miRNA-26 a增加，逆转了miRNA-26 a触发的钾通道Kcnk 1（背角中的关键神经性疼痛参与者）减少，并消除了CCI诱导的疼痛超敏反应。相反，模拟这种下调增加了脊髓中的miRNA-26 a水平并降低了Kcnk 1，导致幼稚小鼠的神经性疼痛样综合征。从机制上讲，下调ciRNA-Kat 6 b减少了miRNA-26 a与ciRNA-Kat 6 b的结合，提高了miRNA-26 a与Kcnk 1 mRNA 3′非翻译区的结合，并使Kcnk 1 mRNA变性，从而引发神经病理性疼痛小鼠背角中KCNK 1蛋白的减少。背角神经元中的ciRNA-Kat 6 b/miRNA-26 a/Kcnk 1通路调节神经性疼痛的发生和维持，ciRNA-Kat 6 b可能是镇痛和治疗策略的潜在新靶点。背角神经元中的ciRNA-Kat 6 b/miRNA-26 a/Kcnk 1通路调节神经病理性疼痛的发展和维持，这可能是潜在的治疗靶点。
Nerve injury‐induced maladaptive changes in gene expression in the spinal neurons are essential for neuropathic pain genesis. Circular RNAs (ciRNA) are emerging as key regulators of gene expression. Here, we identified a nervous‐system‐tissues‐specific ciRNA‐Kat6 with conservation in humans and mice. We aimed to investigate whether and how spinal dorsal horn ciRNA‐Kat6b participates in neuropathic pain. Unilateral sciatic nerve chronic constrictive injury (CCI) surgery was used to prepare the neuropathic pain model. The differentially expressed ciRNAs were obtained by RNA‐Sequencing. The identification of nervous‐system‐tissues specificity of ciRNA‐Kat6b and the measurement of ciRNA‐Kat6b and microRNA‐26a (miRNA‐26a) expression level were carried out by quantitative RT‐PCR. The ciRNA‐Kat6b that targets miRNA‐26a and miRNA‐26a that targets Kcnk1 were predicted by bioinformatics analysis and verified by in vitro luciferase reports test and in vivo experiments including Western‐blot, immunofluorescence, and RNA–RNA immunoprecipitation. The correlation between neuropathic pain and ciRNA‐Kat6b, miRNA‐26a, or Kcnk1 was examined by the hypersensitivity response to heat and mechanical stimulus. Peripheral nerve injury downregulated ciRNA‐Kat6b in the dorsal spinal horn of male mice. Rescuing this downregulation blocked nerve injury‐induced increase of miRNA‐26a, reversed the miRNA‐26a‐triggered decrease of potassium channel Kcnk1, a key neuropathic pain player, in the dorsal horn, and alleviates CCI‐induced pain hypersensitivities. On the contrary, mimicking this downregulation increased the miRNA‐26a level and decreased Kcnk1 in the spinal cord, resulting in neuropathic pain‐like syndrome in naïve mice. Mechanistically, the downregulation of ciRNA‐Kat6b reduced the accounts of miRNA‐26a binding to ciRNA‐Kat6b, and elevated the binding accounts of miRNA‐26a to the 3′ untranslated region of Kcnk1 mRNA and degeneration of Kcnk1 mRNA, triggering in the reduction of KCNK1 protein in the dorsal horn of neuropathic pain mice. The ciRNA‐Kat6b/miRNA‐26a/Kcnk1 pathway in dorsal horn neurons regulates the development and maintenance of neuropathic pain, ciRNA‐Kat6b may be a potential new target for analgesic and treatment strategies. The ciRNA‐Kat6b/miRNA‐26a/Kcnk1 pathway in dorsal horn neurons regulates the development and maintenance of neuropathic pain which may be a potential therapeutic target.
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DOI：
10.1016/j.mcn.2013.08.002
发表时间：
2013-11
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
Pollema-Mays SL;Centeno MV;Ashford CJ;Apkarian AV;Martina M
通讯作者：
Martina M
影响因子：
5.4
作者：
Li, He;Wan, Hong-Quan;Zhang, Chun-Guo
通讯作者：
Zhang, Chun-Guo
影响因子：
5.3
作者：
Pan, Zhiqiang;Li, Guo-Fang;Cao, Jun-Li
通讯作者：
Cao, Jun-Li
影响因子：
8.9
作者：
Gilron, Ian;Baron, Ralf;Jensen, Troels
通讯作者：
Jensen, Troels
脊髓 miR-219 表达的表观遗传修饰通过靶向 CaMKII gamma 调节慢性炎症疼痛
影响因子：
5.3
作者：
Pan, Zhiqiang;Zhu, Li-Jiao;Cao, Jun-Li
通讯作者：
Cao, Jun-Li