Department of Anesthesiology, the First Hospital of Jilin University, Changchun, Jilin, 130021, P.R. China.
Department of Otolaryngology, Head and Neck Surgery, the First Hospital of Jilin University, Changchun, Jilin, 130021, P.R. China.
Exp Physiol. 2020 Sep;105(9):1588-1597. doi: 10.1113/EP088596. Epub 2020 Aug 6.
What is the central question of this study? Dexmedetomidine has a capacity for sedation, anti-anxiety and analgesia with minimal suppression of respiratory function; what is its role in neuropathic pain and what is the involvement of miRNAs? What is the main finding and its importance? Dexmedetomidine attenuates inflammation and apoptosis and the stimulation of TLR4-NF-κB signalling in rat spinal cord via miR-101 overexpression and E2F2 downregulation.
The significant analgesic effect of dexmedetomidine (Dex) has been underscored in neuropathic pain (NPP), but the underlying mechanism remains unclear. This study explored the functional effect of Dex on microRNA (miR)-101-regulated E2 promoter binding factor 2 (E2F2) with the engagement of Toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) signalling. Chronic constriction injury (CCI) was performed to generate an NPP rat model. The expression of miR-101, E2F2 and TLR4-NF-κB signalling-relevant proteins was assessed by RT-quantitative PCR, immunoblotting and immunohistochemistry. Inflammatory factors were detected by enzyme-linked immunosorbent assay. The results showed that Dex increased mechanical withdrawal threshold and thermal latency to withdraw. The expression of interleukin (IL)-6, IL-8 and tumour necrosis factor-α was increased in CCI rats, but these trends were reversed by Dex. In addition, Dex repressed caspase-9 expression and apoptotic cell numbers in spinal cord tissues in CCI rats. Moreover, the expression of E2F2 was significantly increased, while miR-101 was diminished in CCI rats, which was reversed by Dex. Furthermore, miR-101 inhibitor, E2F2 restoration or administration of a TLR4-specific agonist weakened the effect of Dex. Together, these results suggest that Dex has the capacity to ameliorate NPP by regulating the miR-101-E2F2-TLR4-NF-κB axis in rats subjected to CCI.
本研究的核心问题是什么？右美托咪定具有镇静、抗焦虑和镇痛作用，且对呼吸功能的抑制作用最小；它在神经病理性疼痛中的作用是什么，miRNA 有何参与？主要发现及其重要性是什么？右美托咪定通过 miR-101 过表达和 E2 启动子结合因子 2（E2F2）下调，减轻大鼠脊髓 TLR4-NF-κB 信号转导中的炎症和细胞凋亡刺激。
右美托咪定（Dex）在神经病理性疼痛（NPP）中具有显著的镇痛作用，但作用机制尚不清楚。本研究探讨了 Dex 对 microRNA（miR）-101 调节的 E2 启动子结合因子 2（E2F2）的功能影响，以及 Toll 样受体 4（TLR4）-核因子-κB（NF-κB）信号的参与。采用慢性缩窄性损伤（CCI）建立 NPP 大鼠模型。通过 RT-定量 PCR、免疫印迹和免疫组织化学评估 miR-101、E2F2 和 TLR4-NF-κB 信号相关蛋白的表达。通过酶联免疫吸附试验检测炎症因子。结果显示，Dex 增加机械缩足反射阈值和热缩足潜伏期。CCI 大鼠白细胞介素（IL）-6、IL-8 和肿瘤坏死因子-α表达增加，但 Dex 可逆转这些趋势。此外，Dex 抑制 CCI 大鼠脊髓组织中 caspase-9 表达和凋亡细胞数量。而且，CCI 大鼠 E2F2 表达明显增加，miR-101 减少，Dex 可逆转这一趋势。此外，miR-101 抑制剂、E2F2 恢复或 TLR4 特异性激动剂给药削弱了 Dex 的作用。综上所述，这些结果表明，Dex 通过调节 CCI 大鼠 miR-101-E2F2-TLR4-NF-κB 轴，具有改善 NPP 的能力。
