TY - JOUR T1 - MicroRNA-1224 splicing circularRNA-Filip1l in an Ago2- dependent manner regulates chronic inflammatory pain via targeting Ubr5 JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.1631-18.2018 SP - 1631-18 AU - Zhiqiang Pan AU - Guo-Fang Li AU - Meng-Lan Sun AU - Ling Xie AU - Di Liu AU - Qi Zhang AU - Xiao-Xiao Yang AU - Sunhui Xia AU - Liu Xiaodan AU - Huimin Zhou AU - Zhou-Ya Xue AU - Ming Zhang AU - Ling-Yun Hao AU - Li-Jiao Zhu AU - Jun-Li Cao Y1 - 2019/01/16 UR - http://www.jneurosci.org/content/early/2019/01/15/JNEUROSCI.1631-18.2018.abstract N2 - 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 STATEMENTCircRNAs 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. ER -