Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain.
Neuropathic pain, often caused by nerve injury, is a major clinical challenge. Mechanisms that underlie neuropathic pain remain elusive and effective medications are limited. Numerous investigations of pain mechanisms have focused on alterations and phenotypic switches of the nociceptive transmitters and modulators, as well as on their receptors and downstream signaling pathways that have already exerted roles in the pain processes of mature nervous systems. We have demonstrated recently that nerve injury may elicit neuronal alterations that recapitulate events occurring during development. Signaling of the representative activated molecule Wnt thus becomes a trigger for the development of neuropathic pain and is a potential therapeutic target. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status in rats. Peripheral nerve injury causes rapid-onset and long-lasting nuclear accumulation of YAP/TAZ/β-catenin in the spinal dorsal horn. Spinal inhibition or knock-down of either YAP or TAZ suppresses mechanical allodynia induced by nerve injury or the pain initiators lysophosphatidic acid and Wnt3a. Promoting the nuclear accumulation of YAP/TAZ leads to mechanical hypersensitivity in naive animals. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain and the associated neurochemical alterations. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening for potent analgesics for the treatment of neuropathic pain.



Mechanisms that underlie neuropathic pain remain elusive. We have demonstrated recently that nerve injury can activate Wnt signaling, which becomes a trigger for the development of neuropathic pain. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening of potent analgesics for the treatment of neuropathic pain.
Center for Anesthesiology and Pain Medicine and Department of Anesthesiology, Peking University Cancer Hospital and Institute, Center for Pain Medicine, and.
Ni
N
Xu
Center for Anesthesiology and Pain Medicine and Department of Anesthesiology, Peking University Cancer Hospital and Institute, Center for Pain Medicine, and.
Ming-Zheng
MZ
Wu
Neuroscience Research Institute, Peking University Health Science Center, Beijing 100142, China.
Xue-Ting
XT
Deng
Neuroscience Research Institute, Peking University Health Science Center, Beijing 100142, China.
Ping-Chuan
PC
Ma
Center for Pain Medicine, and.
Ze-Hua
ZH
Li
Center for Pain Medicine, and.
Lei
0000-0003-4102-778X
L
Liang
Center for Pain Medicine, and.
Meng-Fan
MF
Xia
Center for Anesthesiology and Pain Medicine and Department of Anesthesiology, Peking University Cancer Hospital and Institute.
Dong
D
Cui
Center for Anesthesiology and Pain Medicine and Department of Anesthesiology, Peking University Cancer Hospital and Institute.
Duan-Duan
DD
He
Center for Pain Medicine, and.
Yuan
Y
Zong
Center for Anesthesiology and Pain Medicine and Department of Anesthesiology, Peking University Cancer Hospital and Institute.
Zhong
Z
Xie
Center for Anesthesiology and Pain Medicine and Department of Anesthesiology, Peking University Cancer Hospital and Institute, Center for Pain Medicine, and Neuroscience Research Institute, Peking University Health Science Center, Beijing 100142, China songxuejun@bjmu.edu.cn xuejunsong@yahoo.com.
Xue-Jun
XJ
Song
D000217:Acyltransferases; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D010147:Pain Measurement; D058748:Pain Perception; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000150:complications / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
D051017:Apoptosis Regulatory Proteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; D000217:Acyltransferases; C544439:Tafazzin protein, rat
TAZ; YAP; beta-catenin; drug discovery; nerve injury; neuropathic pain
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