{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:05:53Z","timestamp":1791270353067,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T00:00:00Z","timestamp":1677801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Neuropathic pain (NP) induced by spinal cord injury (SCI) often causes long-term disturbance for patients, but the mechanisms behind remains unclear. Here, our study showed SCI-induced ectopic expression of Nav1.7 in abundant neurons located in deep and superficial laminae layers of the spinal dorsal horn (SDH) and upregulation of Nav1.7 expression in dorsal root ganglion (DRG) neurons in mice. Pharmacologic studies demonstrated that the efficacy of the blood\u2013brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771. Moreover, more than 20% of Nav1.7-expressing SDH neurons in SCI mice were activated to express FOS when there were no external stimuli, suggesting that the ectopic expression of Nav1.7 made SDH neurons hypersensitive and Nav1.7-expressing SDH neurons participated in central sensitization and in spontaneous pain and\/or walking-evoked mechanical pain. Further investigation showed that NGF, a strong activator of Nav1.7 expression, and its downstream JUN were upregulated after SCI in SDH neurons with similar distribution patterns and in DRG neurons too. In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF\/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI <jats:italic>via<\/jats:italic> selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP.<\/jats:p>","DOI":"10.3389\/fnmol.2023.1091096","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T06:30:35Z","timestamp":1677825035000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model"],"prefix":"10.3389","volume":"16","author":[{"given":"Yan","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liting","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengting","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilong","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changgeng","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/379257a0","article-title":"A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons","volume":"379","author":"Akopian","year":"1996","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/9195","article-title":"The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways","volume":"2","author":"Akopian","year":"1999","journal-title":"Nat. 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Rev."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.expneurol.2004.03.017","article-title":"NGF message and protein distribution in the injured rat spinal cord","volume":"188","author":"Brown","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.expneurol.2007.01.025","article-title":"NGF mRNA is expressed in the dorsal root ganglia after spinal cord injury in the rat","volume":"205","author":"Brown","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1002\/ejp.905","article-title":"Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis","volume":"21","author":"Burke","year":"2017","journal-title":"Eur. J. Pain"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"E792","DOI":"10.1073\/pnas.1713701115","article-title":"Mechanism-specific assay design facilitates the discovery of Nav1.7-selective inhibitors","volume":"115","author":"Chernov-Rogan","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1006\/exnr.1997.6608","article-title":"Spinal cord injury and anti-NGF treatment results in changes in CGRP density and distribution in the dorsal horn in the rat","volume":"147","author":"Christensen","year":"1997","journal-title":"Exp. Neurol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1038\/nature05413","article-title":"An SCN9A channelopathy causes congenital inability to experience pain","volume":"444","author":"Cox","year":"2006","journal-title":"Nature"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"8232","DOI":"10.1523\/JNEUROSCI.2695-04.2004","article-title":"Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy","volume":"24","author":"Cummins","year":"2004","journal-title":"J. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"174480691666608","DOI":"10.1177\/1744806916666083","article-title":"A SCN10A SNP biases human pain sensitivity","volume":"12","author":"Duan","year":"2016","journal-title":"Mol. Pain"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"2585","DOI":"10.1093\/brain\/aws225","article-title":"Neurological perspectives on voltage-gated sodium channels","volume":"135","author":"Eijkelkamp","year":"2012","journal-title":"Brain"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"349","DOI":"10.3389\/fnmol.2017.00349","article-title":"Mechanisms of osteoarthritic pain. Studies in humans and experimental models","volume":"10","author":"Eitner","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/ana.22485","article-title":"Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy","volume":"71","author":"Faber","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"19444","DOI":"10.1073\/pnas.1216080109","article-title":"Gain-of-function Nav1.8 mutations in painful neuropathy","volume":"109","author":"Faber","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0304-3940(02)01251-X","article-title":"Attenuation of mechanical hyperalgesia following spinal cord injury by administration of antibodies to nerve growth factor in the rat","volume":"336","author":"Gwak","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1124\/mol.118.113076","article-title":"The novel activity of carbamazepine as an activation modulator extends from NaV1.7 mutations to the NaV1.8-S242T Mutant Channel from a patient with painful diabetic neuropathy","volume":"94","author":"Han","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1111\/papr.12342","article-title":"NGF\/TrkA Signaling as a therapeutic target for pain","volume":"16","author":"Hirose","year":"2016","journal-title":"Pain Pract."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1097\/00001756-199609020-00033","article-title":"Treatment with genetically engineered fibroblasts producing NGF or BDNF can accelerate recovery from traumatic spinal cord injury in the adult rat","volume":"7","author":"Kim","year":"1996","journal-title":"Neuroreport"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"438","DOI":"10.5535\/arm.20081","article-title":"Prevalence and characteristics of neuropathic pain in patients with spinal cord injury referred to a rehabilitation Center","volume":"44","author":"Kim","year":"2020","journal-title":"Ann. Rehabil. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1007\/s003359900235","article-title":"Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse","volume":"7","author":"Kozak","year":"1996","journal-title":"Mamm. Genome"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"7405","DOI":"10.1523\/JNEUROSCI.19-17-07405.1999","article-title":"Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury","volume":"19","author":"Krenz","year":"1999","journal-title":"J. Neurosci."},{"key":"ref25","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1046\/j.1471-4159.2000.740730.x","article-title":"Nerve growth factor in glia and inflammatory cells of the injured rat spinal cord","volume":"74","author":"Krenz","year":"2000","journal-title":"J. Neurochem."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/S0076-6879(99)14104-1","article-title":"Blockade of neuropathic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons","volume":"314","author":"Lai","year":"2000","journal-title":"Methods Enzymol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"8352","DOI":"10.1523\/JNEUROSCI.22-19-08352.2002","article-title":"Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS\/PN3)-null mice","volume":"22","author":"Laird","year":"2002","journal-title":"J. Neurosci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1007\/s12035-020-02156-1","article-title":"NGF-induced Nav1.7 upregulation contributes to chronic post-surgical pain by activating SGK1-dependent Nedd4-2 phosphorylation","volume":"58","author":"Liu","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0304-3940(99)00040-3","article-title":"The neurotrophins NGF and NT-3 reduce sensory neuronal loss in adult rat after peripheral nerve lesion","volume":"262","author":"Ljungberg","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1097\/j.pain.0000000000001227","article-title":"Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy","volume":"159","author":"McDonnell","year":"2018","journal-title":"Pain"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/ncomms1795","article-title":"Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons","volume":"3","author":"Minett","year":"2012","journal-title":"Nat. Commun."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"12706","DOI":"10.1073\/pnas.0404915101","article-title":"Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain","volume":"101","author":"Nassar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1016\/j.neuroscience.2004.04.036","article-title":"Activation of extracellular signal-regulated protein kinase in the dorsal root ganglion following inflammation near the nerve cell body","volume":"126","author":"Obata","year":"2004","journal-title":"Neuroscience"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1126\/science.aam7671","article-title":"miR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes","volume":"356","author":"Peng","year":"2017","journal-title":"Science"},{"key":"ref0010","doi-asserted-by":"publisher","first-page":"11746","DOI":"10.1007\/BF01187077","article-title":"The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation","volume":"92","author":"Raitano","year":"1995","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/BF01187077","article-title":"The influence of regeneration and nerve growth factor on the neuronal cell body reaction to injury","volume":"18","author":"Rich","year":"1989","journal-title":"J. Neurocytol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"5953","DOI":"10.1074\/jbc.271.11.5953","article-title":"Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons","volume":"271","author":"Sangameswaran","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"14805","DOI":"10.1074\/jbc.272.23.14805","article-title":"A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia","volume":"272","author":"Sangameswaran","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s13311-018-0633-4","article-title":"Neuropathic pain after spinal cord injury: challenges and research perspectives","volume":"15","author":"Shiao","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1111\/papr.12921","article-title":"Prolonged analgesia by spinal cord stimulation following a spinal injury associated with activation of adult neural progenitors","volume":"20","author":"Sun","year":"2020","journal-title":"Pain Pract."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"102024","DOI":"10.1016\/j.pneurobio.2021.102024","article-title":"MicroRNA-96 is required to prevent allodynia by repressing voltage-gated sodium channels in spinal cord","volume":"202","author":"Sun","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1073\/pnas.94.4.1527","article-title":"Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons","volume":"94","author":"Toledo-Aral","year":"1997","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/sj.sc.3102000","article-title":"The prevalence of neuropathic pain after non-traumatic spinal cord lesion","volume":"45","author":"Werhagen","year":"2007","journal-title":"Spinal Cord"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1007\/s40265-017-0747-8","article-title":"Neuropathic pain and spinal cord injury: phenotypes and pharmacological management","volume":"77","author":"Widerstr\u00f6m-Noga","year":"2017","journal-title":"Drugs"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"913990","DOI":"10.3389\/fnmol.2022.913990","article-title":"The human SCN9A (R185H) point mutation induces pain hypersensitivity and spontaneous pain in mice","volume":"15","author":"Xue","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1136\/jmg.2003.012153","article-title":"Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia","volume":"41","author":"Yang","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1159\/000330456","article-title":"Suppressive effects of intrathecal paeoniflorin on bee venom-induced pain-related behaviors and spinal neuronal activation","volume":"88","author":"Yu","year":"2011","journal-title":"Pharmacology"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.1097\/j.pain.0000000000001632","article-title":"Alterations in evoked and spontaneous activity of dorsal horn wide dynamic range neurons in pathological pain: a systematic review and analysis","volume":"160","author":"Zain","year":"2019","journal-title":"Pain"}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1091096\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T06:30:38Z","timestamp":1677825038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2023.1091096\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,3]]},"references-count":48,"alternative-id":["10.3389\/fnmol.2023.1091096"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2023.1091096","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,3]]},"article-number":"1091096"}}