{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:17:32Z","timestamp":1792811852266,"version":"4.5.0"},"reference-count":63,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Primary sensory neurons that sense noxious stimuli (nociceptors) are unusual in possessing two major components of voltage\u2010dependent sodium channel current with different voltage dependence and kinetics. We used pharmacology to characterize the roles of defined sodium channel types in generating action potentials and controlling repetitive firing in putative peptidergic nociceptors, using mice in which CGRP\u2010lineage neurons are fluorescently labelled. We found that the major components of sodium current were carried by Nav1.8 channels, identified by sensitivity to VX\u2010548 (suzetrigine), and by Nav1.7 channels, identified by sensitivity to the toxin GsAF\u20101, with an additional smaller component of current carried by tetrodotoxin\u2010sensitive channels resistant to GsAF\u20101. Action potential clamp experiments were used to quantify the size and time course of the Nav1.8 component of sodium current during firing of single and repetitive action potentials. In most neurons, Nav1.8 current carried the majority of overall sodium entry during action potentials and nearly all of the sodium current supporting action potentials during repetitive firing. Although total tetrodotoxin\u2010sensitive current (mostly but not entirely carried by Nav1.7 channels) activated with smaller depolarizations and much more rapidly than Nav1.8 current, Nav1.8 current was equally important in setting the action potential threshold and was dominant in the action potential upstroke because of its greater size. By comparison with similar experiments in human dorsal root ganglion neurons, the results suggest Nav1.8 channels play a more dominant role in firing of mouse peptidergic nociceptors than in human C\u2010type nociceptors, suggesting limitations of pharmacology of mouse nociceptors for predicting effects on human nociceptor excitability.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70607-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The new Nav1.8 inhibitor VX\u2010548 (suzetrigine) was used to define the role of Nav1.8 currents in generating action potentials in mouse CGRP\u2010lineage dorsal root ganglion neurons.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Nav1.8 current typically carried the majority of sodium current evoked by voltage steps, with remaining current mainly carried by Nav1.7 channels (identified by sensitivity to GsAF\u20101) together with a small component from tetrodotoxin\u2010sensitive channels not inhibited by GsAF\u20101.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Nav1.8 current contributes to determining the action potential threshold, provides the majority of sodium current during the rising phase of the action potential and flows during the shoulder of the action potential typical of C\u2010fibre nociceptors.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Inhibition of Nav1.8 sodium current by VX\u2010548 produces a counter\u2010intuitive decrease in refractory period, probably resulting from reduction of potassium channel activation caused by a smaller peak and narrower action potential when Nav1.8 current is inhibited.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp290574","type":"journal-article","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T02:54:41Z","timestamp":1780196081000},"page":"6104-6127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Functional role of Nav1.8 channels in action potentials of mouse CGRP\u2010lineage dorsal root ganglion neurons"],"prefix":"10.1113","volume":"604","author":[{"given":"Tom\u00e1s","family":"Osorno","sequence":"first","affiliation":[{"name":"Department of Neurobiology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akie","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sooyeon","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5093-3576","authenticated-orcid":false,"given":"Bruce P.","family":"Bean","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Harvard Medical School  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/379257a0"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/9195"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-025-01253-3"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2021.750583"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-01108-x"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-00415-2"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000003411"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00052.2017"},{"issue":"6","key":"e_1_2_5_10_1","first-page":"1085","article-title":"Suzetrigine, a Nonopioid Na V 1.8 Inhibitor for Treatment of Moderate\u2010to\u2010severe Acute Pain: Two phase 3 randomized clinical trials","volume":"142","author":"Bertoch T.","year":"2025","journal-title":"Anesthesiology"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-23-10277.2002"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-32-10338.2003"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201110614"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-24-j0001.1999"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2008.12.005"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.857ba.x"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.042127"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1993.sp019583"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0105895"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02033"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00444-w"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002333"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-3-12"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611364104"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0444-2"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202413719"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.122.000593"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2209870"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-021-02656-6"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202313526"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(81)90088-9"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/eph8702350"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.013086"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200709935"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0104-3"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S509144"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.119.118927"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00232056"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40122-024-00697-0"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.147942"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13092"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.006"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1177\/1744806916660721"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.054718"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2001.86.2.629"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.12-06-02104.1992"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.771bg.x"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.121483"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602813103"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.11.5953"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2503570122"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5011-13.2014"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2023.1336664"},{"key":"e_1_2_5_54_1","first-page":"285","article-title":"Correlation of the electrophysiological profiles and sodium channel transcripts of individual rat dorsal root ganglia neurons","volume":"8","author":"Th\u00e9riault O.","year":"2014","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.124.000944"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202413596"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2507342122"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe2305708"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0468-18.2018"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77558"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.90960.3"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12119"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2010.05.009"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.039"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290574","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP290574","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290574","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:35:01Z","timestamp":1785742501000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP290574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,30]]},"references-count":63,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1113\/JP290574"],"URL":"https:\/\/doi.org\/10.1113\/jp290574","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,30]]},"assertion":[{"value":"2025-11-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}