Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain.

Ni Xu; Ming-Zheng Wu; Xue-Ting Deng; Ping-Chuan Ma; Ze-Hua Li; Lei Liang; Meng-Fan Xia; Dong Cui; Duan-Duan He; Yuan Zong; Zhong Xie; Xue-Jun Song

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 eitherYAPor 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 thatYAPandTAZare core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening for potent analgesics for the treatment of neuropathic pain.

SPINAL cord physiology; NEUROPATHY; NERVOUS system injuries; PAIN perception; DEVELOPMENTAL neurobiology

Journal of Neuroscience, 2016, Vol 36, Issue 39, p10128

0270-6474

Academic Journal

10.1523/JNEUROSCI.0800-16.2016