title: Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B.
abstract: Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4-mutant rats. Transient suppression of Netrin-4 or its receptor Unc5B after injury could also prevent allodynia. Conversely, intrathecal administration of Netrin-4 protein to naive rats enhanced excitatory synaptic transmission in the dorsal horn and induced allodynia, suggesting that Netrin-4 is involved in spinal sensitization. Furthermore, the Unc5B receptor and subsequent activation of the tyrosine phosphatase SHP2 mediated Netrin-4-induced pain signaling in the spinal cord. These results identify Netrin-4 as a novel protein regulating spinal sensitization leading to chronic pain. Our findings provide evidence for the function of Netrin in the adult nervous system, as well as a previously unknown function in inducing pain signals from dorsal horn interneurons.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yasufumi
authors.identifier: 0000-0002-1238-7690
authors.initials: Y
authors.lastname: Hayano
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Takasu
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Koyama
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Minami
authors.affiliation: Pain and Neuroscience, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Asaki
authors.affiliation: Department of Biological Sciences, Graduate School of Science, Hokkaido University, Kita-ku, Sapporo 060-0810, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kitada
authors.affiliation: Department of Neurology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan yamashita@molneu.med.osaka-u.ac.jp.
authors.forename: Toshihide
authors.identifier: 0000-0003-4559-7018
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; C524887:Unc5b protein, rat; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11