title: WNT signaling underlies the pathogenesis of neuropathic pain in rodents.
abstract: Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain-inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/β-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-α and regulated the NR2B glutamate receptor and Ca2+-dependent signals through the β-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.
authors.affiliation: Department of Neurobiology, Parker University Research Institute, Dallas, Texas 75229, USA.
authors.forename: Yan-Kai
authors.initials: YK
authors.lastname: Zhang
authors.forename: Zhi-Jiang
authors.initials: ZJ
authors.lastname: Huang
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Yue-Peng
authors.initials: YP
authors.lastname: Liu
authors.forename: Angela A
authors.initials: AA
authors.lastname: Song
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Song
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009437:Neuralgia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D020382:Interleukin-18; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D002118:Calcium