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Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats

Liu, Su; Liu, Yue-Peng; Huang, Zhi-Jiang; Zhang, Yan-Kai; Song, Angela A.; Ma, Ping-Chuan; Song, Xue-Jun

doi: 10.1097/j.pain.0000000000000366
Research Paper
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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 Ca2+ 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 Ca2+-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.

Ryk receptor-mediated Wnt signaling pathway is critical to sensitization of the peripheral sensory neurons and spinal dorsal horn neurons after nerve injury.

aNeuroscience Research Institute, Peking University, Beijing, China

bCenter for Pain Medicine, Peking University Health Science Center, Beijing, China

cDepartment of Neurobiology, Parker University Research Institute, Dallas, TX, USA

Corresponding author. Address: Neuroscience Research Institute and Center for Pain Medicine, Peking University, 38 Xueyuan Rd, Beijing 100191, China; or Parker University Research Institute, 2540 Walnut Hill Lane, Dallas, TX 75229, USA. E-mail address: xuejunsong@yahoo.com (X.-J. Song).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received January 30, 2015

Received in revised form September 03, 2015

Accepted September 16, 2015

© 2015 International Association for the Study of Pain
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