{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:05:01Z","timestamp":1740146701573,"version":"3.37.3"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["18gm1210005h0001"],"award-info":[{"award-number":["18gm1210005h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Neuropathic pain refers to pain caused by lesions or diseases of the somatosensory nervous system that is characteristically different from nociceptive pain. Moreover, neuropathic pain occurs in the maxillofacial region due to various factors and is treated using tricyclic antidepressants and nerve block therapy; however, some cases do not fully recover. Netrin is a secreted protein crucially involved in neural circuit formation during development, including cell migration, cell death, neurite formation, and synapse formation. Recent studies show Netrin-4 expressed in the dorsal horn of the spinal cord is associated with chronic pain. Here we found involvement of Netrin-4 in neuropathic pain in the maxillofacial region. Netrin-4, along with one of its receptors, Unc5B, are expressed in the caudal subnucleus of the trigeminal spinal tract nucleus. Inhibition of its binding by anti-Netrin-4 antibodies not only shows a behavioral analgesic effect but also neuronal activity suppression. There was increased Netrin-4 expression at 14 days after infraorbital nerve injury. Our findings suggest that Netrin-4 induced by peripheral nerve injury causes neuropathic pain via Unc5B.<\/jats:p>","DOI":"10.1371\/journal.pone.0251013","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T17:47:54Z","timestamp":1619718474000},"page":"e0251013","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Increased expression of Netrin-4 is associated with allodynia in a trigeminal neuropathic pain model rats by infraorbital nerve injury"],"prefix":"10.1371","volume":"16","author":[{"given":"Yuka","family":"Honjo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Niwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4559-7018","authenticated-orcid":true,"given":"Toshihide","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"pone.0251013.ref001","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1016\/j.pain.2011.06.017","article-title":"A new definition of neuropathic pain","author":"TS Jensen","year":"2011","journal-title":"Pain"},{"key":"pone.0251013.ref002","first-page":"1","article-title":"Diagnosis and classification of neuropathic pain","volume":"28","author":"International Association for the Study of P","year":"2010","journal-title":"IASP Pain Clinical Updates"},{"issue":"4","key":"pone.0251013.ref003","first-page":"379","article-title":"(2008) Clinical picture of neuropathic trigeminal pain provoked by dental treatment","volume":"57","author":"M Chiba","year":"2008","journal-title":"Journal of the Japanese Stomatological Society"},{"issue":"8","key":"pone.0251013.ref004","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/S1474-4422(10)70143-5","article-title":"Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment","volume":"9","author":"R Baron","year":"2010","journal-title":"The Lancet Neurology"},{"issue":"3","key":"pone.0251013.ref005","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/0092-8674(94)90421-9","article-title":"Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord","volume":"78","author":"TE Kennedy","year":"1994","journal-title":"Cell"},{"issue":"4","key":"pone.0251013.ref006","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/nrm2142","article-title":"Netrins: beyond the brain","volume":"8","author":"V Cirulli","year":"2007","journal-title":"Nature reviews Molecular cell biology"},{"issue":"2","key":"pone.0251013.ref007","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1083\/jcb.151.2.221","article-title":"A Novel Member of the Netrin Family, \u03b2-Netrin, Shares Homology with the \u03b2 Chain of LamininIdentification, Expression, and Functional Characterization","volume":"151","author":"M Koch","year":"2000","journal-title":"The Journal of cell biology"},{"issue":"17","key":"pone.0251013.ref008","doi-asserted-by":"crossref","first-page":"6540","DOI":"10.1523\/JNEUROSCI.20-17-06540.2000","article-title":"Netrin-G1: a novel glycosyl phosphatidylinositol-linked mammalian netrin that is functionally divergent from classical netrins","volume":"20","author":"T Nakashiba","year":"2000","journal-title":"Journal of Neuroscience"},{"issue":"11","key":"pone.0251013.ref009","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1242\/dev.044529","article-title":"Netrins: versatile extracellular cues with diverse functions","volume":"138","author":"KLW Sun","year":"2011","journal-title":"Development"},{"issue":"1","key":"pone.0251013.ref010","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1460-9568.2004.03094.x","article-title":"Netrin 1\u2010mediated chemoattraction regulates the migratory pathway of LHRH neurons","volume":"19","author":"GA Schwarting","year":"2004","journal-title":"European Journal of Neuroscience"},{"issue":"36","key":"pone.0251013.ref011","doi-asserted-by":"crossref","first-page":"11065","DOI":"10.1523\/JNEUROSCI.0947-09.2009","article-title":"Netrin participates in the development of retinotectal synaptic connectivity by modulating axon arborization and synapse formation in the developing brain","volume":"29","author":"C Manitt","year":"2009","journal-title":"Journal of Neuroscience"},{"issue":"8","key":"pone.0251013.ref012","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1093\/cercor\/bhq265","article-title":"Laminar and areal expression of unc5d and its role in cortical cell survival","volume":"21","author":"M Takemoto","year":"2011","journal-title":"Cerebral cortex"},{"issue":"42","key":"pone.0251013.ref013","doi-asserted-by":"crossref","first-page":"15226","DOI":"10.1073\/pnas.1402095111","article-title":"Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion","volume":"111","author":"Y Hayano","year":"2014","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1\u20132","key":"pone.0251013.ref014","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.molbrainres.2004.07.009","article-title":"Identification of a novel alternative splicing form of human netrin-4 and analyzing the expression patterns in adult rat brain","volume":"130","author":"C Zhang","year":"2004","journal-title":"Molecular brain research"},{"issue":"5","key":"pone.0251013.ref015","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/jnr.20199","article-title":"Developmental shift in expression of netrin receptors in the rat spinal cord: Predominance of UNC\u20105 homologues in adulthood","volume":"77","author":"C Manitt","year":"2004","journal-title":"Journal of neuroscience research"},{"issue":"13","key":"pone.0251013.ref016","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1084\/jem.20160877","article-title":"Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B.","volume":"213","author":"Y Hayano","year":"2016","journal-title":"Journal of Experimental Medicine"},{"issue":"5","key":"pone.0251013.ref017","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1523\/JNEUROSCI.14-05-02708.1994","article-title":"Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat\u2019s infraorbital nerve","volume":"14","author":"BP Vos","year":"1994","journal-title":"Journal of Neuroscience"},{"issue":"14","key":"pone.0251013.ref018","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1177\/0333102416678387","article-title":"Trigeminal nervous system sensitization by infraorbital nerve injury enhances responses in a migraine model","volume":"37","author":"M Toyama","year":"2017","journal-title":"Cephalalgia"},{"issue":"6","key":"pone.0251013.ref019","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1177\/0022034511401406","article-title":"PKC\u03b3 in Vc and C1\/C2 is Involved in Trigeminal neuropathic Pain","volume":"90","author":"A Nakajima","year":"2011","journal-title":"Journal of dental research"},{"issue":"2","key":"pone.0251013.ref020","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0057278","article-title":"Involvement of ERK phosphorylation of trigeminal spinal subnucleus caudalis neurons in thermal hypersensitivity in rats with infraorbital nerve injury","volume":"8","author":"I Suzuki","year":"2013","journal-title":"PLoS One."},{"issue":"3","key":"pone.0251013.ref021","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/0304-3940(89)90125-0","article-title":"Application of the formalin test to the study of orofacial pain in the rat","volume":"103","author":"P Clavelou","year":"1989","journal-title":"Neuroscience letters"},{"issue":"1","key":"pone.0251013.ref022","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/PL00005748","article-title":"Characterization of heat-hyperalgesia in an experimental trigeminal neuropathy in rats","volume":"116","author":"Y Imamura","year":"1997","journal-title":"Experimental brain research"},{"issue":"2","key":"pone.0251013.ref023","first-page":"158","article-title":"(2007) Formalin Stimulation to Rat Infraorbital Nerve CCI Mode1","volume":"35","author":"T Sanuki","year":"2007","journal-title":"Journal of Japanese Dental Society of Anestheology"},{"issue":"11","key":"pone.0251013.ref024","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1038\/nn942","article-title":"Can we conquer pain?","volume":"5","author":"J Scholz","year":"2002","journal-title":"Nature neuroscience"},{"issue":"1","key":"pone.0251013.ref025","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/nbdi.2000.0360","article-title":"Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain","volume":"8","author":"R-R Ji","year":"2001","journal-title":"Neurobiology of disease"},{"issue":"12","key":"pone.0251013.ref026","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.tins.2003.09.017","article-title":"Central sensitization and LTP: do pain and memory share similar mechanisms","volume":"26","author":"R-R Ji","year":"2003","journal-title":"Trends in neurosciences"},{"issue":"1","key":"pone.0251013.ref027","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.brainresrev.2008.12.011","article-title":"MAP kinase and pain","volume":"60","author":"R-R Ji","year":"2009","journal-title":"Brain research reviews"},{"issue":"5472","key":"pone.0251013.ref028","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1126\/science.288.5472.1765","article-title":"Neuronal plasticity: increasing the gain in pain","volume":"288","author":"CJ Woolf","year":"2000","journal-title":"science"},{"issue":"7","key":"pone.0251013.ref029","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1111\/j.1460-9568.2004.03656.x","article-title":"Brain\u2010derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord","volume":"20","author":"SE Slack","year":"2004","journal-title":"European Journal of Neuroscience"},{"issue":"17","key":"pone.0251013.ref030","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1523\/JNEUROSCI.5349-07.2008","article-title":"Bradykinin enhances AMPA and NMDA receptor activity in spinal cord dorsal horn neurons by activating multiple kinases to produce pain hypersensitivity","volume":"28","author":"T Kohno","year":"2008","journal-title":"Journal of Neuroscience"},{"issue":"1\u20132","key":"pone.0251013.ref031","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.pain.2004.12.022","article-title":"ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model","volume":"114","author":"Z-Y Zhuang","year":"2005","journal-title":"Pain"},{"key":"pone.0251013.ref032","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2174\/1876386300902010011","article-title":"c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury?","volume":"2","author":"Y-J Gao","year":"2009","journal-title":"The open pain journal"},{"issue":"12","key":"pone.0251013.ref033","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/16040","article-title":"Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity","volume":"2","author":"R-R Ji","year":"1999","journal-title":"Nature neuroscience"},{"key":"pone.0251013.ref034","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.brainres.2012.02.023","article-title":"Organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis and upper cervical spinal cord associated with orofacial neuropathic pain","volume":"1451","author":"K Shibuta","year":"2012","journal-title":"Brain research"},{"issue":"4","key":"pone.0251013.ref035","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1111\/j.0953-816X.2004.03203.x","article-title":"Enhancement of stimulation\u2010induced ERK activation in the spinal dorsal horn and gracile nucleus neurons in rats with peripheral nerve injury","volume":"19","author":"H Wang","year":"2004","journal-title":"European Journal of Neuroscience"},{"issue":"2","key":"pone.0251013.ref036","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/j.1471-4159.2010.06946.x","article-title":"Light touch induces ERK activation in superficial dorsal horn neurons after inflammation: involvement of spinal astrocytes and JNK signaling in touch\u2010evoked central sensitization and mechanical allodynia","volume":"115","author":"YJ Gao","year":"2010","journal-title":"Journal of neurochemistry"},{"issue":"44","key":"pone.0251013.ref037","doi-asserted-by":"crossref","first-page":"40917","DOI":"10.1074\/jbc.M103872200","article-title":"Netrin stimulates tyrosine phosphorylation of the UNC-5 family of netrin receptors and induces Shp2 binding to the RCM cytodomain","volume":"276","author":"J Tong","year":"2001","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0251013.ref038","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/S0896-6273(03)00645-7","article-title":"The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1","volume":"40","author":"G Krapivinsky","year":"2003","journal-title":"Neuron"},{"issue":"5","key":"pone.0251013.ref039","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.neuron.2005.04.031","article-title":"Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking","volume":"46","author":"MJ Kim","year":"2005","journal-title":"Neuron"},{"issue":"3","key":"pone.0251013.ref040","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/j.1471-4159.2006.03789.x","article-title":"The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS\/MAPK pathway by brain-derived neurotrophic factor","volume":"97","author":"JB Easton","year":"2006","journal-title":"J Neurochem"},{"issue":"1","key":"pone.0251013.ref041","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.conb.2007.01.003","article-title":"Netrin signaling leading to directed growth cone steering","volume":"17","author":"J Round","year":"2007","journal-title":"Curr Opin Neurobiol"},{"issue":"5","key":"pone.0251013.ref042","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.pain.2012.02.006","article-title":"Spinal SIRP\u03b11-SHP2 interaction regulates spinal nerve ligation-induced neuropathic pain via PSD-95-dependent NR2B activation in rats","volume":"153","author":"HY Peng","year":"2012","journal-title":"Pain"},{"key":"pone.0251013.ref043","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fncel.2018.00085","article-title":"Regulation of Brain-Derived Neurotrophic Factor and Growth Factor Signaling Pathways by Tyrosine Phosphatase Shp2 in the Retina: A Brief Review.","volume":"12","author":"M Abbasi","year":"2018","journal-title":"Front Cell Neurosci"},{"issue":"34","key":"pone.0251013.ref044","doi-asserted-by":"crossref","first-page":"12491","DOI":"10.1073\/pnas.0804008105","article-title":"Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B","volume":"105","author":"E Lejmi","year":"2008","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"1","key":"pone.0251013.ref045","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.neulet.2007.03.068","article-title":"Down-regulation of UNC5 homologue expression after the spinal cord injury in the adult rat","volume":"419","author":"KJ Ahn","year":"2007","journal-title":"Neuroscience letters"},{"issue":"33","key":"pone.0251013.ref046","doi-asserted-by":"crossref","first-page":"23750","DOI":"10.1074\/jbc.M703137200","article-title":"Binding of netrin-4 to laminin short arms regulates basement membrane assembly","volume":"282","author":"FI Schneiders","year":"2007","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"pone.0251013.ref047","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms13515","article-title":"Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes","volume":"7","author":"R Reuten","year":"2016","journal-title":"Nature communications"},{"issue":"1","key":"pone.0251013.ref048","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0925-4773(00)00369-5","article-title":"Identification and expression of mouse netrin-4","volume":"96","author":"Y Yin","year":"2000","journal-title":"Mechanisms of development"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251013","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T17:48:48Z","timestamp":1619718528000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251013"}},"subtitle":[],"editor":[{"given":"Masabumi","family":"Minami","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0251013","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2021,4,29]]}}}