title: Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.
abstract: Treating neuropathic pain continues to be a major clinical challenge and underlying mechanisms of neuropathic pain remain elusive. We have recently demonstrated that Wnt signaling, which is important in developmental processes of the nervous systems, plays critical roles in the development of neuropathic pain through the β-catenin-dependent pathway in the spinal cord and the β-catenin-independent pathway in primary sensory neurons after nerve injury. Here, we report that Wnt signaling may contribute to neuropathic pain through the atypical Wnt/Ryk signaling pathway in rats. Sciatic nerve injury causes a rapid-onset and long-lasting expression of Wnt3a, Wnt5b, and Ryk receptors in primary sensory neurons, and dorsal horn neurons and astrocytes. Spinal blocking of the Wnt/Ryk receptor signaling inhibits the induction and persistence of neuropathic pain without affecting normal pain sensitivity and locomotor activity. Blocking activation of the Ryk receptor with anti-Ryk antibody, in vivo or in vitro, greatly suppresses nerve injury-induced increased intracellular Ca and hyperexcitability of the sensory neurons, and also the enhanced plasticity of synapses between afferent C-fibers and the dorsal horn neurons, and activation of the NR2B receptor and the subsequent Ca-dependent signals CaMKII, Src, ERK, PKCγ, and CREB in sensory neurons and the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the Wnt/Ryk signaling may be an effective approach for treating neuropathic pain.
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing, China Center for Pain Medicine, Peking University Health Science Center, Beijing, China Department of Neurobiology, Parker University Research Institute, Dallas, TX, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Yue-Peng
authors.initials: YP
authors.lastname: Liu
authors.forename: Zhi-Jiang
authors.initials: ZJ
authors.lastname: Huang
authors.forename: Yan-Kai
authors.initials: YK
authors.lastname: Zhang
authors.forename: Angela A
authors.initials: AA
authors.lastname: Song
authors.forename: Ping-Chuan
authors.initials: PC
authors.lastname: Ma
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Song
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000378:metabolism*; D011493:Protein Kinase C; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051153:Wnt Proteins; D060509:Wnt3A Protein; C502524:Wnt5b protein, rat; C087857:protein kinase C gamma; D020794:Receptor Protein-Tyrosine Kinases; C485555:Ryk protein, rat; D019061:src-Family Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2