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Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn

Authors Sun KF, Feng WW, Liu YP, Dong YB, Gao L, Yang HL

Received 18 August 2017

Accepted for publication 30 January 2018

Published 21 March 2018 Volume 2018:11 Pages 599—609

DOI https://doi.org/10.2147/JPR.S149470

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Katherine Hanlon


Ke-fu Sun,1–3 Wan-wen Feng,2,3 Yue-peng Liu,4 Yan-bin Dong,4 Li Gao,2,3 Hui-lin Yang1

1Department of Orthopedic Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; 2Department of Orthopedics, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China; 3Department of Orthopedics, Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, China; 4Center for Clinical Research and Translation Medicine, Lianyungang Oriental Hospital, Lianyungang, Jiangsu, China


Objective:
The analgesic effect on chronic pain of peripheral nerve stimulation (PNS) has been proven, but its underlying mechanism remains unknown. Therefore, this study aimed to assess the analgesic effect of PNS on bone cancer pain in a rat model and to explore the underlying mechanism.
Materials and methods: PNS on sciatic nerves with bipolar electrode was performed in both naïve and bone cancer pain model rats. Then, the protein levels of activity-regulated cytoskeleton-associated protein (Arc), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptor 1 (GluA1), and phosphate N-methyl-d-aspartic acid-type glutamate receptor subunit 2B (pGluNR2B) in spinal cord were evaluated by immunohistochemistry and Western blotting. Thermal paw withdraw latency and mechanical paw withdraw threshold were used to estimate the analgesic effect of PNS on bone cancer pain. Intrathecal administration of Arc shRNA was used to inhibit Arc expression in the spinal cord.
Results: PNS at 60 and 120 Hz for 20 min overtly induced Arc expression in the spinal cord, increased thermal pain thresholds in naïve rats, and relieved bone cancer pain; meanwhile, 10 Hz PNS did not achieve those results. In addition, PNS at 60 and 120 Hz also reduced the expression of GluA1, but not pGluNR2B, in the spinal cord. Finally, the anti-nociceptive effect and GluA1 downregulation induced by PNS were inhibited by intrathecal administration of Arc shRNA.
Conclusion: PNS (60 Hz, 0.3 mA) can relieve bone-cancer-induced allodynia and hyperalgesia by upregulating Arc protein expression and then by decreasing GluA1 transcription in the spinal cord dorsal horn.

Keywords: peripheral nerve stimulation, Arc, GluA1, bone cancer pain

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