Effect of intrathecal NIS-lncRNA antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes mellitus.
Effect of intrathecal NIS-lncRNA antisense oligonucleotides on neuropathic pain caused by nerve trauma, chemotherapy, or diabetes mellitus.
复制标题
DOI：
10.1016/j.bja.2022.09.027
复制
发表时间：
2022-11
影响因子：
9.8
通讯作者：
C. Wen;Tolga Berkman;Xiang Li;Shibin Du;Gokulapriya Govindarajalu;Hai-jun Zhang;A. Bekker;Steve Davidson;Y. Tao
中科院分区：
文献类型：
--
作者：
C. Wen;Tolga Berkman;Xiang Li;Shibin Du;Gokulapriya Govindarajalu;Hai-jun Zhang;A. Bekker;Steve Davidson;Y. Tao
通过背根神经节（DRG）显微注射小发夹干扰RNA（siRNA）或产生NIS-lncRNA敲低小鼠，阻断损伤后DRG中神经损伤特异性长链非编码RNA（NIS-lncRNA）的表达增加，可减轻神经病理性疼痛。然而，这些策略在临床上是不切实际的。本研究采用食品和药物管理局（FDA）批准的反义寡核苷酸策略来检测NIS-lncRNAASOs对神经性疼痛的作用。方法在坐骨神经慢性压迫性损伤（CCI）、第四腰（L4）脊神经结扎、观察紫杉醇或链脲佐菌素腹腔注射对DRGNIS-lncRNA和C-C趋化因子配体2（CCL 2，一种NIS-lncRNA下游靶点）表达的影响及伤害性超敏反应。我们还评估了whicheNIS-lncRNAantisense oligonucleotides produced cellular toxicity.ResultsIntrathecalNIS-lncRNAantisense oligonucleotides衰减CCI诱导的机械异常性疼痛，热痛觉过敏，冷痛觉过敏，和正在进行的伤害性反应，而不改变基础或急性伤害性反应和运动功能。鞘内注射NIS-lncRNA反义寡核苷酸还阻断了CCI诱导的同侧L3和L4 DRG中NIS-lncRNA和CCL 2的增加以及同侧L3和L4脊髓背角中神经元和星形胶质细胞的过度活动。在脊神经结扎或腹腔注射紫杉醇或链脲佐菌素后，在反义寡核苷酸治疗的小鼠中发现了类似的结果。正常的形态结构和无细胞丢失观察在DRG和脊髓的反义寡核苷酸treated mice. Conclusion这些发现进一步验证了作用ofNIS-lncRNAin创伤，化疗，或糖尿病引起的神经病理性疼痛和展示潜在的临床应用ofNIS-lncRNAantisense寡核苷酸神经病理性疼痛管理。
BackgroundBlocking increased expression of nerve injury-specific long non-coding RNA (NIS-lncRNA) in injured dorsal root ganglia (DRG) through DRG microinjection ofNIS-lncRNAsmall hairpin interfering RNA or generation ofNIS-lncRNAknockdown mice mitigates neuropathic pain. However, these strategies are impractical in the clinic. This study employed a Food and Drug Administration (FDA)-approved antisense oligonucleotides strategy to examine the effect ofNIS-lncRNAASOs on neuropathic pain.MethodsEffects of intrathecal injection ofNIS-lncRNAantisense oligonucleotides on day 7 or 14 after chronic constriction injury (CCI) of the sciatic nerve, fourth lumbar (L4) spinal nerve ligation, or intraperitoneal injection of paclitaxel or streptozotocin on the expression of DRGNIS-lncRNAand C–C chemokine ligand 2 (CCL2, anNIS-lncRNAdownstream target) and nociceptive hypersensitivity were examined. We also assessed whetherNIS-lncRNAantisense oligonucleotides produced cellular toxicity.ResultsIntrathecalNIS-lncRNAantisense oligonucleotides attenuated CCI-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and ongoing nociceptive responses, without changing basal or acute nociceptive responses and locomotor function. IntrathecalNIS-lncRNAantisense oligonucleotides also blocked CCI-induced increases inNIS-lncRNAand CCL2 in the ipsilateral L3 and L4 DRG and hyperactivities of neurones and astrocytes in the ipsilateral L3 and L4 spinal cord dorsal horn. Similar results were found in antisense oligonucleotides-treated mice after spinal nerve ligation or intraperitoneal injection of paclitaxel or streptozotocin. Normal morphologic structure and no cell loss were observed in the DRG and spinal cord of antisense oligonucleotides-treated mice.ConclusionThese findings further validate the role ofNIS-lncRNAin trauma-, chemotherapy-, or diabetes-induced neuropathic pain and demonstrate potential clinical application ofNIS-lncRNAantisense oligonucleotides for neuropathic pain management.