title: Involvement of Wnt/β-catenin signaling in the development of neuropathic pain.
abstract: Despite tremendous research effort in the field, our current understanding of the molecular mechanisms underlying neuropathic pain is still incomplete. In the present study, our objective was to elucidate the involvement of the Wnt/β-catenin signaling pathway in the development of neuropathic pain. We showed that Wnt/β-catenin signaling is activated in the spinal cord dorsal horn after partial sciatic nerve ligation (PSL). Expression of Wnt3a, a prototypic Wnt ligand that activates the Wnt/β-catenin pathway, was also upregulated in the dorsal horn. We then tested the effect of intrathecal administration of XAV939, a Wnt/β-catenin signaling inhibitor, and found that this treatment effectively attenuated the induction of neuropathic pain. Conversely, intrathecal administration of Wnt3a to the lumbar spinal cord of naïve animals triggered the development of allodynia. These results suggest a critical involvement of the Wnt/β-catenin pathway in the development of neuropathic pain. Moreover, we also found that PSL-induced microglial activation was significantly suppressed by intrathecal administration of XAV939 treatment. Because it was revealed that Wnt3a treatment triggered brain-derived neurotrophic factor (BDNF) release from microglial cells in vitro, it is possible that Wnt3a upregulation in the dorsal horn leads to the activation of microglial cells, then triggers BDNF secretion that is responsible for the establishment of neuropathic pain. Further studies will be needed for the comprehensive understanding of the roles of Wnt/β-catenin signaling in the development of neuropathic pain.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Itokazu
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Hayano
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: yamashita@molneu.med.osaka-u.ac.jp.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060508:Wnt3 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C495267:CTNNB1 protein, mouse; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; D051176:beta Catenin
keywords: Brain-derived neurotrophic factor; Microglia; Neuropathic pain; Wnt signaling