Biomol Ther.  2019 Jul;27(4):414-422. 10.4062/biomolther.2018.073.

Inhibition of MicroRNA-15a/16 Expression Alleviates Neuropathic Pain Development through Upregulation of G Protein-Coupled Receptor Kinase 2

• Li T
• Wan Y
• Sun L
• Tao S
• Chen P
• Liu C
• Wang K
• Zhou C
• Zhao G

• KMID: 2455097
• DOI: http://doi.org/10.4062/biomolther.2018.073

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-1β and tumor-necrosis factor-α 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-κB 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.

Keyword

GRK2; miR-15a/16; Neuropathic pain; p38 MAPK

MeSH Terms

Animals
Computational Biology
Constriction
Down-Regulation
Hyperalgesia
Inflammation
Injections, Spinal
Mice
MicroRNAs
Neuralgia*
p38 Mitogen-Activated Protein Kinases
Phosphotransferases*
Protein Kinases
Rats
Sciatic Nerve
Spinal Cord
Up-Regulation*
MicroRNAs
Phosphotransferases
Protein Kinases
p38 Mitogen-Activated Protein Kinases