Spinal CircKcnk9 Regulates Chronic Visceral Hypersensitivity of Irritable Bowel Syndrome

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 hypersensitiv-ity. 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 hypersensitiv-ity 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.(c) 2022 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

The dysregulation of circRNAs is functionally associated with chronic pain, and this study found that circKcnk9 expression is increased in IBS-like rats. The study also revealed that circKcnk9 regulates c-Fos expression and visceral hypersensitivity through binding with miR-124-3p. This study provides a potential therapeutic target for IBS through targeting circKcnk9.