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Int J Mol Sci. 2018 Aug 16;19(8). pii: E2421. doi: 10.3390/ijms19082421.

Intrathecal Injection of Dual Zipper Kinase shRNA Alleviating the Neuropathic Pain in a Chronic Constrictive Nerve Injury Model.

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Institute of Biomedical Science, National Chung-Hsing University, Taichung 40244, Taiwan.
Department of Neurosurgery, Taichung Veterans General Hospital, Taichung 40754, Taiwan.
Department Life Sciences, Agriculture Biotechnology Center, National Chung Hsing University, Taichung 40244, Taiwan.
Department of Medical Research, Taichung Veterans General Hospital, Taichung 40754, Taiwan.
Department of Neurosurgery, University of Virginia, Charlottesville, VA 22901, USA.
Department of Neurosurgery, Taichung Veterans General Hospital, Taichung 40754, Taiwan.
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, 11257, Taiwan.


Dual leucine zipper kinase (DLK) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family mainly involved in neuronal degeneration. However, the role of DLK signaling in the neuropathic pain has not yet been fully determined. Chronic constrictive injury (CCI) was conducted by four 3-0 chromic gut ligatures loosely ligated around the sciatic nerve. Escalated DLK expression over the dorsal root ganglion was observed from one to four rings of CCI. Remarkable expression of DLK was observed in primary dorsal root ganglion cells culture subjected to electrical stimulation and attenuated by DLK short hairpin RNA (shRNA) treatment. Intrathecal injection of DLK shRNA attenuates the expression of DLK over the dorsal root ganglion and hippocampus neurons and increased the threshold of mechanical allodynia and decreased thermal hyperalgesia. In CatWalk gait analysis, significant decreases of print area, maximum contact maximum intensity, stand phase, single stance, and regular index by CCI were alleviated by the DLK shRNA administration. In conclusion, the expression of DLK was up-regulated in chronic constrictive injury and attenuated by the administration of DLK shRNA, which paralleled the improvement of neurobehavior of neuropathic pain. The modulation of DLK expression is a potential clinic treatment option for neuropathic pain.


chronic constrictive injury; dual zipper kinase; neuropathic pain

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