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Electroacupuncture decreases Netrin-1-induced myelinated afferent fiber sprouting and neuropathic pain through μ-opioid receptors

Authors Li HP, Su W, Shu Y, Yuan XC, Lin LX, Hou TF, Xiang HC, Zhu H, Hu XF, Pan L, Wu JN, Meng XF, Pan HL, Wu CH, Li M

Received 25 October 2018

Accepted for publication 21 February 2019

Published 23 April 2019 Volume 2019:12 Pages 1259—1268

DOI https://doi.org/10.2147/JPR.S191900

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Michael Schatman


Hong-Ping Li,1 Wen Su,2 Yang Shu,3 Xiao-Cui Yuan,1 Li-Xue Lin,1 Teng-Fei Hou,1 Hong-Chun Xiang,1 He Zhu,1 Xue-Fei Hu,1 Li Pan,1 Jing-Nan Wu,1 Xian-Fang Meng,1 Hui-Lin Pan,4 Cai-Hua Wu,1,2 Man Li1

1Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Acupuncture, Wuhan First Hospital, Wuhan, People’s Republic of China; 3Department of Central Laboratory, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, People’s Republic of China; 4Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Purpose: We determined whether electroacupuncture (EA) reduces Netrin-1-induced myelinated primary afferent nerve fiber sprouting in the spinal cord and pain hypersensitivity associated with postherpetic neuralgia (PHN) through activation of μ-opioid receptors.
Methods: PHN was induced by systemic injection of resiniferatoxin (RTX) in rats. Thirty-six days after RTX injection, a μ-opioid receptor antagonist, beta-funaltrexamine (β-FNA) or a κ-opioid receptor antagonist, nor Binaltorphimine (nor-BNI), was injected intrathecally 30 mins before EA, once every other day for 4 times. Mechanical allodynia was tested with von Frey filaments. The protein expression level of Netrin-1 and its receptors (DCC and UNC5H2) were quantified by using western blotting. The myelinated primary afferent nerve fiber sprouting was mapped with the transganglionic tracer cholera toxin B-subunit (CTB).
Results: Treatment with 2 Hz EA at “Huantiao” (GB30) and “Yanglingquan” (GB34) decreased the mechanical allodynia at 22 days and the myelinated primary afferent nerve fiber preternatural sprouting into the lamina II of the spinal dorsal horn at 42 days after RTX injection. Also, treatment with 2 Hz EA reduced the protein levels of DCC and Netrin-1 and promoted the expression of UNC5H2 in the spinal dorsal horn 42 days after RTX injection. Furthermore, the μ-opioid receptor antagonist β-FNA, but not the κ-opioid receptor antagonist nor-BNI, reversed the effect of EA on neuropathic pain caused by RTX. In addition, morphine inhibited the Netrin-1 protein level induced by RTX in SH-SY5Y cells.
Conclusions: Through activation of μ-opioid receptors, treatment with EA reduces the expression level of DCC and Netrin-1 and changes a growth-permissive environment in spinal dorsal horn into an inhibitory environment by increasing UNC5H2, thus decreasing RTX-caused primary afferent nerve sprouting in the spinal dorsal horn and neuropathic pain.

Keywords: postherpetic neuralgia, analgesia, mechanical hyperalgesia, rat, μ-opioid receptors

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