Wnt1/β-catenin signaling upregulates spinal VGLUT2 expression to control neuropathic pain in mice.

Abstract

Vesicular glutamate transporter 2 (VGLUT2)-which uptakes glutamate into presynaptic vesicles-is a fundamental component of the glutamate neurotransmitter system. Although several lines of evidence from genetically modified mice suggest a possible association of VGLUT2 with neuropathic pain, the specific role of VGLUT2 in the spinal cord during neuropathic pain, and its regulatory mechanism remain elusive. In this study, we report that spared nerve injury induced an upregulation of VGLUT2 in the spinal cord, and intrathecal administration of small hairpin RNAs (shRNA) against VGLUT2 before or after surgery attenuated mechanical allodynia, and pathologically-enhanced glutamate release. Meanwhile, nerve injury activated the Wnt1/β-catenin signaling pathway in a quick-onset and sustained manner, and blocking the Wnt1 signaling with a Wnt1 targeting antibody attenuated neuropathic pain. In naïve mice, administration of a Wnt agonist or Wnt1 increased spinal VGLUT2 protein levels. Moreover, intrathecal administration of the Wnt/β-catenin inhibitor, XAV939 attenuated mechanical allodynia, and this effect was concurrent with that of VGLUT2 downregulation. Pretreatment with VGLUT2 shRNAs abolished the allodynia induced by the Wnt agonist or Wnt1. These findings reveal a novel mechanism wherein there is Wnt1/β-catenin-dependent VGLUT2 upregulation in neuropathic pain, thus potentiating the development of new therapeutic strategies in pain management.

• Authors: Zhi-Ling Zhang, Gang Yu, Jing Peng, Huan-Bai Wang, Yu-Lei Li, Xiao-Nan Liang, Rui-Bin Su, Ze-Hui Gong
• Journal: Neuropharmacology (Neuropharmacology) Vol. 164 Pg. 107869 (03 01 2020) ISSN: 1873-7064 [Electronic] England
• PMID: 31785260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• RNA, Small Interfering
• Slc17a6 protein, mouse
• Vesicular Glutamate Transport Protein 2
• beta Catenin
• Glutamic Acid

Topics

• Animals
• Glutamic Acid (metabolism)
• Hyperalgesia (drug therapy)
• Immunohistochemistry
• Injections, Spinal
• Male
• Mice
• Mice, Inbred C57BL
• Neuralgia (physiopathology)
• RNA, Small Interfering (administration & dosage, therapeutic use)
• Spinal Cord (drug effects, metabolism)
• Synaptosomes (drug effects, metabolism)
• Up-Regulation
• Vesicular Glutamate Transport Protein 2 (biosynthesis)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (metabolism)