Abstract
Dysfunctions of genes transcription and translation in the nociceptive pathways play the critical role in development and maintenance of chronic pain. Circular RNAs (circRNAs) are emerging as new players in regulation of gene expression, but whether and how circRNAs are involved in chronic pain remains elusive. We showed here that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly increased circRNA-Filip1l (filamin A interacting protein 1-like) expression in spinal neurons of mice. Blockage of this increase attenuated CFA-induced nociceptive behaviors, and overexpression of spinal circRNA-Filip1l in naïve mice mimicked the nociceptive behaviors as evidenced by decreased thermal and mechanical nociceptive threshold. Furthermore, we found that mature circRNA-Filip1l expression was negatively regulated by miRNA-1224 via binding and splicing of precursor of circRNA-Filip1l (pre-circRNA-Filip1l) in the Argonaute-2 (Ago2)-dependent manner. Increase of spinal circRNA-Filip1l expression resulted from the decrease of miRNA-1224 expression under chronic inflammation pain state. MiRNA-1224 knockdown or Ago2 overexpression induced nociceptive behaviors in naïve mice, which was prevented by the knockdown of spinal circRNA-Filip1l. Finally, we demonstrated that an ubiquitin protein ligase E3 component n-recognin 5 (Ubr5), validated as a target of circRNA-Filip1l, plays a pivotal role in regulation of nociception by spinal circRNA-Filip1l. These data suggest that miRNA-1224-mediated and Ago2-dependent modulation of spinal circRNA-Filip1l expression regulates nociception via targeting Ubr5, revealing a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.
SIGNIFICANCE STATEMENT
CircRNAs are emerging as new players in regulation of gene expression. Here, we found that the increase of circRNA-Filip1l mediated by miRNA-1224 in Ago2-dependent way in the spinal cord is involved in regulation of nociception via targeting Ubr5. Our study reveals a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.
Footnotes
The authors declare no competing financial interests.
The study was supported by grants from the National Natural Science Foundation of China (81671096, 81271231 to Z. Pan, 31771161, 81720108013 to J.-L. Cao, 31500855 to L.-J. Zhu); Key project of the Natural Science Foundation of Jiangsu Education Department (15KJA320004 to Z. Pan); and the Project Funded by the Qing Lan Project, by the Six Talent Summit Project, by the 333 High-level Personnel Training Project.
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