Liu Changliang, Gao Rui, Tang Yidan, Chen Hai, Zhang Xueying, Sun Yalan, Zhao Qi, Lv Peilin, Wang Haiyang, Ye-Lehmann Shixin, Liu Jin, Chen Chan
Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China.
Front Neurosci. 2022 Aug 18;16:925300. doi: 10.3389/fnins.2022.925300. eCollection 2022.
Chronic neuropathic pain is commonly accompanied by cognitive impairment. However, the underlying mechanism in the occurrence of cognitive deficits under constant nociceptive irritation remains elusive. Herein, we established a chronic neuropathic pain model by chronic constriction injury (CCI) of the unilateral sciatic nerve in rats. Behavioral tests indicated that CCI rats with long-term nociceptive threshold decline developed significant dysfunction of working memory and recognitive memory starting at 14 days and lasting for at least 21 days. Afterward, circRNA expression profiles in the hippocampus of CCI and sham rats were analyzed high-throughput sequencing to explore the potential key factors associated with cognitive impairment induced by ongoing nociception, which showed 76 differentially expressed circRNAs, 39 upregulated and 37 downregulated, in the CCI group. These differentially expressed circRNA host genes were validated to be primarily associated with inflammation and apoptotic signaling pathways according to GO/KEGG analysis and the circRNA-miRNA-mRNA network, which was also confirmed through the analysis of neuroinflammation and neuronal apoptosis. Consequently, we assumed that enhanced neuroinflammation and neuronal apoptosis might act as potential regulators of cognitive impairment induced by chronic neuropathic pain. The identification of the regulatory mechanism would provide promising clinical biomarkers or therapeutic targets in the diagnostic prediction and intervention treatment of memory deficits under neuropathic pain conditions.
慢性神经性疼痛常伴有认知障碍。然而，在持续的伤害性刺激下，认知缺陷发生的潜在机制仍不清楚。在此，我们通过对大鼠单侧坐骨神经进行慢性压迫损伤（CCI）建立了慢性神经性疼痛模型。行为测试表明，长期伤害性阈值下降的CCI大鼠从第14天开始出现明显的工作记忆和认知记忆功能障碍，并持续至少21天。之后，通过高通量测序分析CCI大鼠和假手术大鼠海马中的环状RNA表达谱，以探索与持续性伤害感受诱导的认知障碍相关的潜在关键因素，结果显示CCI组有76种差异表达的环状RNA，其中39种上调，37种下调。根据基因本体论/京都基因与基因组百科全书（GO/KEGG）分析和环状RNA-微小RNA-信使RNA网络，这些差异表达的环状RNA宿主基因被证实主要与炎症和凋亡信号通路相关，通过神经炎症和神经元凋亡分析也得到了证实。因此，我们推测神经炎症和神经元凋亡增强可能是慢性神经性疼痛诱导认知障碍的潜在调节因素。对这种调节机制的鉴定将为神经性疼痛条件下记忆缺陷的诊断预测和干预治疗提供有前景的临床生物标志物或治疗靶点。
