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Contribution of dorsal root ganglion octamer transcription factor 1 to neuropathic pain after peripheral nerve injury

Yuan, Jingjinga,b; Wen, Jinga,b; Wu, Shaogenb; Mao, Yuanyuana,b; Mo, Kaib; Li, Zhisonga,c; Su, Songxuec; Gu, Hanwena; Ai, Yanqiua,c; Bekker, Alexb; Zhang, Weia,c; Tao, Yuan-Xiangb,*

doi: 10.1097/j.pain.0000000000001405
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Neuropathic pain genesis is related to gene alterations in the dorsal root ganglion (DRG) after peripheral nerve injury. Transcription factors control gene expression. In this study, we investigated whether octamer transcription factor 1 (OCT1), a transcription factor, contributed to neuropathic pain caused by chronic constriction injury (CCI) of the sciatic nerve. Chronic constriction injury produced a time-dependent increase in the level of OCT1 protein in the ipsilateral L4/5 DRG, but not in the spinal cord. Blocking this increase through microinjection of OCT1 siRNA into the ipsilateral L4/5 DRG attenuated the initiation and maintenance of CCI-induced mechanical allodynia, heat hyperalgesia, and cold allodynia and improved morphine analgesia after CCI, without affecting basal responses to acute mechanical, heat, and cold stimuli as well as locomotor functions. Mimicking this increase through microinjection of recombinant adeno-associated virus 5 harboring full-length OCT1 into the unilateral L4/5 DRG led to marked mechanical allodynia, heat hyperalgesia, and cold allodynia in naive rats. Mechanistically, OCT1 participated in CCI-induced increases in Dnmt3a mRNA and its protein and DNMT3a-mediated decreases in Oprm1 and Kcna2 mRNAs and their proteins in the injured DRG. These findings indicate that OCT1 may participate in neuropathic pain at least in part by transcriptionally activating Dnmt3a and subsequently epigenetic silencing of Oprm1 and Kcan2 in the DRG. OCT1 may serve as a potential target for therapeutic treatments against neuropathic pain.

Dorsal root ganglion octamer transcription factor 1 participates in neuropathic pain by transcriptionally activating Dnmt3a and subsequently epigenetic silencing of Oprm1 and Kcan2 in the dorsal root ganglion.

aDepartment of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

bDepartment of Anesthesiology, New Jersey Medical School, Rutgers the State University of New Jersey, Newark, NJ, United States

cNeuroscience Research Institute, Zhengzhou University Academy of Medical Sciences, Zhengzhou, Henan, China

Corresponding author. Address: Department of Anesthesiology, New Jersey Medical School, Rutgers the State University of New Jersey, 185 S. Orange Ave, MSB, E-661, Newark, NJ 07103, United States. Tel.: +1-973-972-9812; fax: +1-973-972-1644. E-mail address: yuanxiang.tao@njms.rutgers.edu (Y.-X. Tao).

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

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

J. Yuan and J. Wen contributed equally to this work.

Received April 15, 2018

Received in revised form July 28, 2018

Accepted August 16, 2018

© 2019 International Association for the Study of Pain
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