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Upregulation of miR-375 level ameliorates morphine analgesic tolerance in mouse dorsal root ganglia by inhibiting the JAK2/STAT3 pathway

Authors Li HQ, Tao R, Wang J, Xia LJ

Received 20 October 2016

Accepted for publication 22 December 2016

Published 26 May 2017 Volume 2017:10 Pages 1279—1287

DOI https://doi.org/10.2147/JPR.S125264

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lucy Goodman

Peer reviewer comments 3

Editor who approved publication: Dr Michael Schatman

Haiqin Li, Rong Tao, Jing Wang, Lingjie Xia

Department of Clinical Pain, The People’s Hospital of Henan Province, Zhengzhou, People’s Republic of China

Abstract: Several lines of evidence indicate that microRNAs (miRNAs) modulate tolerance to the analgesic effects of morphine via regulation of pain-related genes, making dysregulation of miRNA levels a clinical target for controlling opioid tolerance. However, the precise mechanisms by which miRNAs regulate opioid tolerance are unclear. In the present study, we noted that the miR-375 level was downregulated but the expression of Janus kinase 2 (JAK2) was upregulated in mouse dorsal root ganglia (DRG) following chronic morphine treatment. The miR-375 levels and JAK2 expression were correlated with the progression of morphine tolerance, and upregulation of miR-375 level could significantly hinder morphine tolerance. This was ameliorated by JAK2 knockdown. Prolonged morphine exposure induced the expression of brain-derived neurotrophic factor (BDNF) in a time-dependent manner in the DRG. This was regulated by the miR-375 and JAK2–signal transducer and activator of transcription 3 (STAT3) pathway, and inhibition of this pathway decreased BDNF production, and thus, attenuated morphine tolerance. More importantly, we found that miR-375 could target JAK2 and increase BDNF expression in a JAK2/STAT3 pathway-dependent manner.

Keywords: morphine tolerance, miR-375, JAK2, BDNF

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