Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Inhibition of MicroRNA-15a/16 Expression Alleviates Neuropathic Pain Development through Upregulation of G Protein-Coupled Receptor Kinase 2

  • Li, Tao (Department of Anesthesiology, China-Japan Union Hospital, Jilin University) ;
  • Wan, Yingchun (Department of Endocrinology, China-Japan Union Hospital, Jilin University) ;
  • Sun, Lijuan (Department of Endocrinology, China-Japan Union Hospital, Jilin University) ;
  • Tao, Shoujun (Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine) ;
  • Chen, Peng (Department of Anesthesiology, China-Japan Union Hospital, Jilin University) ;
  • Liu, Caihua (Department of Anaesthesiology, The Central Hospital of Wuhan Affiliated with Tongji Medical College of Huazhong University of Science and Technology) ;
  • Wang, Ke (Department of Gynaecology and Obstetrics, China-Japan Union Hospital, Jilin University) ;
  • Zhou, Changyu (Department of Gastroenterology, China-Japan Union Hospital, Jilin University) ;
  • Zhao, Guoqing (Department of Anesthesiology, China-Japan Union Hospital, Jilin University)
  • Received : 2018.04.30
  • Accepted : 2018.08.14
  • Published : 2019.07.01
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Abstract

There is accumulating evidence that microRNAs are emerging as pivotal regulators in the development and progression of neuropathic pain. MicroRNA-15a/16 (miR-15a/16) have been reported to play an important role in various diseases and inflammation response processes. However, whether miR-15a/16 participates in the regulation of neuroinflammation and neuropathic pain development remains unknown. In this study, we established a mouse model of neuropathic pain by chronic constriction injury (CCI) of the sciatic nerves. Our results showed that both miR-15a and miR-16 expression was significantly upregulated in the spinal cord of CCI rats. Downregulation of the expression of miR-15a and miR-16 by intrathecal injection of a specific inhibitor significantly attenuated the mechanical allodynia and thermal hyperalgesia of CCI rats. Furthermore, inhibition of miR-15a and miR-16 downregulated the expression of interleukin-$1{\beta}$ and tumor-necrosis factor-${\alpha}$ in the spinal cord of CCI rats. Bioinformatic analysis predicted that G protein-coupled receptor kinase 2 (GRK2), an important regulator in neuropathic pain and inflammation, was a potential target gene of miR-15a and miR-16. Inhibition of miR-15a and miR-16 markedly increased the expression of GRK2 while downregulating the activation of p38 mitogen-activated protein kinase and $NF-{\kappa}B$ in CCI rats. Notably, the silencing of GRK2 significantly reversed the inhibitory effects of miR-15a/16 inhibition in neuropathic pain. In conclusion, our results suggest that inhibition of miR-15a/16 expression alleviates neuropathic pain development by targeting GRK2. These findings provide novel insights into the molecular pathogenesis of neuropathic pain and suggest potential therapeutic targets for preventing neuropathic pain development.

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References

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