{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:10:09Z","timestamp":1790313009689,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001173"],"award-info":[{"award-number":["82001173"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471279"],"award-info":[{"award-number":["82471279"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017940","name":"Zhejiang Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["ZJ2024076"],"award-info":[{"award-number":["ZJ2024076"]}],"id":[{"id":"10.13039\/100017940","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Voltage-gated sodium channels in primary sensory neurons are essential mediators of nociceptive signal transmission and represent promising therapeutic targets for pain management. Here, we demonstrate that Nav1.5, which is traditionally known to be a cardiac sodium channel, as a major determinant of mechanical sensitivity in the somatosensory system. Immunostaining and single-cell RNA sequencing analyses revealed that Nav1.5 is predominantly expressed in myelinated TrkB-positive A-fibre neurons within the dorsal root ganglion.<\/jats:p>\n                  <jats:p>Through conditional knockout studies, we found that Nav1.5 deletion in TrkB neurons or dorsal root ganglion tissue specifically impairs mechanical sensitivity while preserving other sensory and motor functions. Notably, Nav1.5 ablation significantly attenuated mechanical hypersensitivity in both neuropathic and visceral pain models. Mechanistically, Nav1.5 contributes to action potential generation and firing patterns in TrkB-positive neurons.<\/jats:p>\n                  <jats:p>In summary, these findings establish Nav1.5 as a critical regulator of mechanical hypersensitivity.<\/jats:p>","DOI":"10.1093\/brain\/awaf438","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:54:02Z","timestamp":1763470442000},"page":"2516-2532","source":"Crossref","is-referenced-by-count":6,"title":["Nav1.5 in the dorsal root ganglion plays a crucial role in mechanical hypersensitivity"],"prefix":"10.1093","volume":"149","author":[{"given":"Chen-Jing","family":"Zhang","sequence":"first","affiliation":[{"name":"Center for General Practice Medicine, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College , Hangzhou, Zhejiang 310014 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-Jun","family":"Ji","sequence":"additional","affiliation":[{"name":"Center for General Practice Medicine, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College , Hangzhou, Zhejiang 310014 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Lu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for General Practice Medicine, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College , Hangzhou, Zhejiang 310014 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR) , Singapore 138634 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Fei","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for General Practice Medicine, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College , Hangzhou, Zhejiang 310014 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Women's Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310006 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Women's Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310006 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2587-1198","authenticated-orcid":false,"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London WC1E 6BT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Zhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London WC1E 6BT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9129-8011","authenticated-orcid":false,"given":"James J","family":"Cox","sequence":"additional","affiliation":[{"name":"Wolfson Institute for Biomedical Research, Division of Medicine, University College London , London WC1E 6BT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9219-1681","authenticated-orcid":false,"given":"Xue-Long","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia, Women's Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310006 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"2026070619582066100_awaf438-B1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41587-025-02590-3","article-title":"Vertex's opioid-free drug for acute pain wins FDA approval","volume":"43","author":"Harrison","year":"2025","journal-title":"Nat Biotechnol"},{"key":"2026070619582066100_awaf438-B2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1056\/NEJMoa2209870","article-title":"Selective inhibition of Na(V)1.8 with VX-548 for acute pain","volume":"389","author":"Jones","year":"2023","journal-title":"N Engl J Med"},{"key":"2026070619582066100_awaf438-B3","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1152\/physrev.00052.2017","article-title":"The role of voltage-gated sodium channels in pain signaling","volume":"99","author":"Bennett","year":"2019","journal-title":"Physiol Rev"},{"key":"2026070619582066100_awaf438-B4","doi-asserted-by":"crossref","first-page":"4880","DOI":"10.1093\/brain\/awad328","article-title":"Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies","volume":"146","author":"Lischka","year":"2023","journal-title":"Brain"},{"key":"2026070619582066100_awaf438-B5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-022-00365-7","article-title":"Genetic pain loss disorders","volume":"8","author":"Lischka","year":"2022","journal-title":"Nat Rev Dis Primers"},{"key":"2026070619582066100_awaf438-B6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev-pharmtox-010617-052554","article-title":"The genetics of pain: Implications for therapeutics","volume":"58","author":"Sexton","year":"2018","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"2026070619582066100_awaf438-B7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.mcn.2007.03.002","article-title":"The sodium channel Nav1.5a is the predominant isoform expressed in adult mouse dorsal root ganglia and exhibits distinct inactivation properties from the full-length Nav1.5 channel","volume":"35","author":"Kerr","year":"2007","journal-title":"Mol Cell Neurosci"},{"key":"2026070619582066100_awaf438-B8","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0169-328X(02)00411-4","article-title":"Na(v)1.5 underlies the \u2018third TTX-R sodium current\u2019 in rat small DRG neurons","volume":"106","author":"Renganathan","year":"2002","journal-title":"Brain Res Mol Brain Res"},{"key":"2026070619582066100_awaf438-B9","first-page":"2225","article-title":"Downregulation of adult and neonatal Nav1.5 in the dorsal root ganglia and axon of peripheral sensory neurons of rats with spared nerve injury","volume":"41","author":"Wang","year":"2018","journal-title":"Int J Mol Med"},{"key":"2026070619582066100_awaf438-B10","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1053\/j.gastro.2014.02.054","article-title":"Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome","volume":"146","author":"Beyder","year":"2014","journal-title":"Gastroenterology"},{"key":"2026070619582066100_awaf438-B11","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1111\/j.1572-0241.2006.00507.x","article-title":"Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: Evidence of an intestinal channelopathy","volume":"101","author":"Locke","year":"2006","journal-title":"Am J Gastroenterol"},{"key":"2026070619582066100_awaf438-B12","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0014-2999(80)90515-4","article-title":"Intrathecal morphine in mice: A new technique","volume":"67","author":"Hylden","year":"1980","journal-title":"Eur J Pharmacol"},{"key":"2026070619582066100_awaf438-B13","doi-asserted-by":"crossref","first-page":"9424","DOI":"10.1073\/pnas.0914725107","article-title":"Deletion of PIK3C3\/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway","volume":"107","author":"Zhou","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026070619582066100_awaf438-B14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0304-3959(87)90088-1","article-title":"The formalin test in mice: Dissociation between inflammatory and non-inflammatory pain","volume":"30","author":"Hunskaar","year":"1987","journal-title":"Pain"},{"key":"2026070619582066100_awaf438-B15","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0304-3959(00)00276-1","article-title":"Spared nerve injury: An animal model of persistent peripheral neuropathic pain","volume":"87","author":"Decosterd","year":"2000","journal-title":"Pain"},{"key":"2026070619582066100_awaf438-B16","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0304-3959(93)90059-X","article-title":"Streptozocin-induced diabetic rats: Behavioural evidence for a model of chronic pain","volume":"53","author":"Courteix","year":"1993","journal-title":"Pain"},{"key":"2026070619582066100_awaf438-B17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.pain.2007.03.029","article-title":"Visceral and somatic hypersensitivity in a subset of rats following TNBS-induced colitis","volume":"134","author":"Zhou","year":"2008","journal-title":"Pain"},{"key":"2026070619582066100_awaf438-B18","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41467-023-36014-0","article-title":"Cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function","volume":"14","author":"Jung","year":"2023","journal-title":"Nat Commun"},{"key":"2026070619582066100_awaf438-B19","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41583-021-00489-x","article-title":"The mechanosensory neurons of touch and their mechanisms of activation","volume":"22","author":"Handler","year":"2021","journal-title":"Nat Rev Neurosci"},{"key":"2026070619582066100_awaf438-B20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1085\/jgp.200609665","article-title":"Pharmacological dissection and distribution of NaN\/Nav1.9, T-type Ca2 + currents, and mechanically activated cation currents in different populations of DRG neurons","volume":"129","author":"Coste","year":"2007","journal-title":"J Gen Physiol"},{"key":"2026070619582066100_awaf438-B21","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1016\/S0006-3495(99)77131-6","article-title":"Effects of channel cytoplasmic regions on the activation mechanisms of cardiac versus skeletal muscle Na(+) channels","volume":"77","author":"Bennett","year":"1999","journal-title":"Biophys J"},{"key":"2026070619582066100_awaf438-B22","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1113\/jphysiol.1981.sp013879","article-title":"Sodium current in single rat heart muscle cells","volume":"318","author":"Brown","year":"1981","journal-title":"J Physiol"},{"key":"2026070619582066100_awaf438-B23","doi-asserted-by":"crossref","first-page":"5233","DOI":"10.1523\/JNEUROSCI.0057-14.2014","article-title":"Specialized functions of Nav1.5 and Nav1.9 channels in electrogenesis of myenteric neurons in intact mouse ganglia","volume":"34","author":"Osorio","year":"2014","journal-title":"J Neurosci"},{"key":"2026070619582066100_awaf438-B24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nn.3881","article-title":"Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing","volume":"18","author":"Usoskin","year":"2015","journal-title":"Nat Neurosci"},{"key":"2026070619582066100_awaf438-B25","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1136\/gutjnl-2017-315631","article-title":"Single-cell RNAseq reveals seven classes of colonic sensory neuron","volume":"68","author":"Hockley","year":"2019","journal-title":"Gut"},{"key":"2026070619582066100_awaf438-B26","doi-asserted-by":"crossref","first-page":"eabh2557","DOI":"10.1126\/scitranslmed.abh2557","article-title":"GPR177 in A-fiber sensory neurons drives diabetic neuropathic pain via WNT-mediated TRPV1 activation","volume":"14","author":"Xie","year":"2022","journal-title":"Sci Transl Med"},{"key":"2026070619582066100_awaf438-B27","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/j.cell.2014.11.003","article-title":"Identification of spinal circuits transmitting and gating mechanical pain","volume":"159","author":"Duan","year":"2014","journal-title":"Cell"},{"key":"2026070619582066100_awaf438-B28","doi-asserted-by":"crossref","first-page":"4050","DOI":"10.1172\/JCI70026","article-title":"A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia","volume":"123","author":"Lu","year":"2013","journal-title":"J Clin Invest"},{"key":"2026070619582066100_awaf438-B29","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.neuron.2015.07.029","article-title":"Dorsal horn circuits for persistent mechanical pain","volume":"87","author":"Peirs","year":"2015","journal-title":"Neuron"},{"key":"2026070619582066100_awaf438-B30","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41583-021-00444-w","article-title":"The physiological function of different voltage-gated sodium channels in pain","volume":"22","author":"Goodwin","year":"2021","journal-title":"Nat Rev Neurosci"},{"key":"2026070619582066100_awaf438-B31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0169-328X(96)00163-5","article-title":"Spinal sensory neurons express multiple sodium channel alpha-subunit mRNAs","volume":"43","author":"Black","year":"1996","journal-title":"Brain Res Mol Brain Res"},{"key":"2026070619582066100_awaf438-B32","doi-asserted-by":"crossref","first-page":"6077","DOI":"10.1523\/JNEUROSCI.21-16-06077.2001","article-title":"Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons","volume":"21","author":"Benn","year":"2001","journal-title":"J Neurosci"},{"key":"2026070619582066100_awaf438-B33","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/326603a0","article-title":"Spontaneous and evoked activity of fetal primary afferents in vivo","volume":"326","author":"Fitzgerald","year":"1987","journal-title":"Nature"},{"key":"2026070619582066100_awaf438-B34","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1126\/science.274.5290.1133","article-title":"Synaptic activity and the construction of cortical circuits","volume":"274","author":"Katz","year":"1996","journal-title":"Science"},{"key":"2026070619582066100_awaf438-B35","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/0896-6273(90)90333-B","article-title":"Impulse activity and the patterning of connections during CNS development","volume":"5","author":"Shatz","year":"1990","journal-title":"Neuron"},{"key":"2026070619582066100_awaf438-B36","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1113\/jphysiol.1987.sp016851","article-title":"Post-natal development of electrophysiological properties of rat cerebral cortical pyramidal neurones","volume":"393","author":"McCormick","year":"1987","journal-title":"J Physiol"},{"key":"2026070619582066100_awaf438-B37","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1038\/s41467-018-04049-3","article-title":"Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons","volume":"9","author":"Dhandapani","year":"2018","journal-title":"Nat Commun"},{"key":"2026070619582066100_awaf438-B38","doi-asserted-by":"crossref","first-page":"9858","DOI":"10.1523\/JNEUROSCI.22-22-09858.2002","article-title":"Selective mediation of nerve injury-induced tactile hypersensitivity by neuropeptide Y","volume":"22","author":"Ossipov","year":"2002","journal-title":"J Neurosci"},{"key":"2026070619582066100_awaf438-B39","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1038\/nm.3978","article-title":"Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade","volume":"21","author":"Xu","year":"2015","journal-title":"Nat Med"},{"key":"2026070619582066100_awaf438-B40","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1126\/science.3764416","article-title":"Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin","volume":"234","author":"Sugiura","year":"1986","journal-title":"Science"},{"key":"2026070619582066100_awaf438-B41","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/j.cell.2011.11.027","article-title":"The functional organization of cutaneous low-threshold mechanosensory neurons","volume":"147","author":"Li","year":"2011","journal-title":"Cell"},{"key":"2026070619582066100_awaf438-B42","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nn.2312","article-title":"Coding of pleasant touch by unmyelinated afferents in humans","volume":"12","author":"Loken","year":"2009","journal-title":"Nat Neurosci"},{"key":"2026070619582066100_awaf438-B43","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.neuron.2014.05.001","article-title":"Discriminative and affective touch: Sensing and feeling","volume":"82","author":"McGlone","year":"2014","journal-title":"Neuron"},{"key":"2026070619582066100_awaf438-B44","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/j.cell.2024.02.006","article-title":"A mouse DRG genetic toolkit reveals morphological and physiological diversity of somatosensory neuron subtypes","volume":"187","author":"Qi","year":"2024","journal-title":"Cell"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awaf438\/67299594\/awaf438.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/149\/7\/2516\/67299594\/awaf438.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/149\/7\/2516\/67299594\/awaf438.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T23:58:49Z","timestamp":1783382329000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/149\/7\/2516\/8514142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,11]]},"references-count":44,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,3,11]]},"published-print":{"date-parts":[[2026,7,7]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awaf438","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7]]},"published":{"date-parts":[[2026,3,11]]}}}