Netrin-1 Contributes to Myelinated Afferent Fiber Sprouting and Neuropathic Pain.
Netrin-1 is a neuronal guidance molecule implicated in the development of spinal cord neurons and cortical neurons. In the adult spinal cord, UNC5H (repulsive receptor of netrin-1), but not deleted in colorectal cancer (DCC) (attractive receptor of netrin-1), constitutes a major mode of netrin-1 signal transduction, which may be involved in axon repulsion and inhibits neurite outgrowth. Abnormal sprouting of myelinated afferent fibers in the spinal dorsal horn can cause mechanical allodynia associated with postherpetic neuralgia (PHN, Shingles) and other neuropathic pains. However, whether netrin-1 participates in sprouting of myelinated afferent fibers and mechanical allodynia remains unknown. In an ultropotent TRPV1 agonist resiniferatoxin (RTX)-induced PHN-like model, RTX treatment for 6 weeks increased netrin-1 expression in dorsal horn neurons, including NK-1-positive projection neurons. In human neuroblastoma SH-SY5Y cells, we found that TRPV1 antagonist capsazepine antagonized RTX-induced upregulation of netrin-1. After RTX treatment, UNC5H2 expression was gradually decreased, whereas DCC expression was significantly increased. Silencing netrin-1 in the spinal dorsal horn significantly attenuated RTX-induced mechanical allodynia and sprouting of myelinated fibers into the spinal lamina II. Our results suggest that RTX treatment upregulates netrin-1 expression through activation of TRPV1 receptors and change UNC5H2-rich spinal dorsal horn into a growth-permissive environment by increasing DCC expression, thus enhancing the sprouting of myelinated afferent nerves. Netrin-1 may be targeted for reducing primary afferent sprouting and mechanical allodynia in PHN and other neuropathic pain conditions.
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Cai-Hua
CH
Wu
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Xiao-Cui
XC
Yuan
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Fang
F
Gao
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Hong-Ping
HP
Li
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Jie
J
Cao
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Yan-Shen
YS
Liu
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Wei
W
Yu
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Bo
B
Tian
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Xian-Fang
XF
Meng
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Jing
J
Shi
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.|Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Hui-Lin
HL
Pan
Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. liman73@mails.tjmu.edu.cn.
Man
M
Li
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D000075389:DCC Receptor / Q000378:metabolism; D004224:Diterpenes / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D000075388:Netrin-1 / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
D015415:Biomarkers; D000075389:DCC Receptor; C501912:Dcc protein, rat; D004224:Diterpenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C524887:Unc5b protein, rat; D000075388:Netrin-1; C024353:resiniferatoxin
Axon growth; Netrin-1; Neuropathic pain; Postherpetic neuralgia; TRPV1 receptor