Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.
Department of Pediatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
J Pain. 2023 Mar;24(3):463-477. doi: 10.1016/j.jpain.2022.10.007. Epub 2022 Oct 15.
Dysregulation of circular RNAs (circRNAs) has been reported to be functionally associated with chronic pain, but it is unknown whether and how circRNAs participate in visceral hypersensitivity. The expression of circKcnk9 was increased in spinal neurons of irritable bowel syndrome (IBS)-like rats. ShcircKcnk9 attenuated visceral hypersensitivity and inhibited c-Fos expression in IBS-like rats, whereas overexpression of spinal circKcnk9 induced visceral hypersensitivity and increased c-Fos expression in control rats. Furthermore, circKcnk9 was found to act as a miR-124-3p sponge. MiR-124-3p antagomir restored pain responses downregulated by shcircKcnk9 in IBS-like rats. Finally, the signal transducer and activator of transcription 3 (STAT3), validated as a target of miR-124-3p, could play a critical role in visceral hypersensitivity by regulating NSF/GluR2. PERSPECTIVE: Spinal circKcnk9 functions as a miR-124-3p sponge to promote visceral hypersensitivity by regulating the STAT3/NSF/GluR2 pathway. This pathway might provide a novel epigenetic mechanism of visceral hypersensitivity and a potential circRNA therapeutic target for IBS.
环状 RNA（circRNAs）的失调已被报道与慢性疼痛在功能上相关，但尚不清楚 circRNAs 是否以及如何参与内脏敏感性。肠易激综合征（IBS）样大鼠的脊髓神经元中circKcnk9 的表达增加。ShcircKcnk9 减轻了 IBS 样大鼠的内脏敏感性并抑制了 c-Fos 的表达，而脊髓 circKcnk9 的过表达则在对照大鼠中引起了内脏敏感性并增加了 c-Fos 的表达。此外，circKcnk9 被发现可作为 miR-124-3p 的海绵。miR-124-3p 拮抗剂恢复了 IBS 样大鼠中 shcircKcnk9 下调的疼痛反应。最后，信号转导子和转录激活子 3（STAT3）被验证为 miR-124-3p 的靶标，通过调节 NSF/GluR2 在内脏敏感性中发挥关键作用。观点：脊髓 circKcnk9 作为 miR-124-3p 的海绵通过调节 STAT3/NSF/GluR2 通路促进内脏敏感性。该通路可能为内脏敏感性提供了一种新的表观遗传机制，并为 IBS 提供了一种潜在的 circRNA 治疗靶标。
