Wnt1/β-catenin signaling upregulates spinal VGLUT2 expression to control neuropathic pain in mice
| Autor: | Rui-Bin Su, Xiao-Nan Liang, Yu-lei Li, Jing Peng, Ze-Hui Gong, Huanbai Wang, Gang Yu, Zhi-Ling Zhang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Agonist medicine.drug_class Glutamic Acid Pharmacology Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Downregulation and upregulation Animals Medicine RNA Small Interfering Wnt Signaling Pathway Injections Spinal beta Catenin business.industry Glutamate receptor Wnt signaling pathway Nerve injury Spinal cord Immunohistochemistry Up-Regulation Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Allodynia Spinal Cord Hyperalgesia Neuropathic pain Vesicular Glutamate Transport Protein 2 Neuralgia medicine.symptom business 030217 neurology & neurosurgery Synaptosomes |
| Zdroj: | Neuropharmacology. 164:107869 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2019.107869 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect