{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:52:43Z","timestamp":1792201963571,"version":"4.4.0"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004489","name":"Mitacs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004489","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The Voltage-gated sodium channel NaV1.8 is a critical determinant of nociceptive signaling in primary sensory neurons. Here, we evaluated the analgesic potential of suzetrigine, a potent clinically approved NaV1.8 blocker, using electrophysiological, behavioral, and tolerance paradigms in mice. Whole-cell recordings from dorsal root ganglion neurons revealed that suzetrigine inhibited tetrodotoxin (TTX)-resistant sodium currents in a concentration-dependent manner (IC\n                    <jats:sub>50<\/jats:sub>\n                    = 0.35\u2009\u00b1\u20090.17\u00a0\u03bcM), consistent with high-affinity NaV1.8 inhibition. In vivo, intraperitoneal administration of suzetrigine significantly reduced nocifensive behaviors in the formalin test, attenuated CFA-induced thermal hypersensitivity, and reversed mechanical hyperalgesia in the partial sciatic nerve injury-induced neuropathy model. Importantly, repeated dosing did not produce tolerance in a chronic administration paradigm. Although suzetrigine showed limited efficacy in clinical trials for neuropathic pain, its robust analgesic effects in mouse models underscore the challenges of translating preclinical findings to human neuropathic pain, while still supporting the potential of NaV1.8-targeted therapies.\n                  <\/jats:p>","DOI":"10.1186\/s13041-025-01253-3","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T08:38:41Z","timestamp":1763023121000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pharmacological inhibition of NaV1.8 by suzetrigine reveals potent analgesic potential without tolerance development in mice"],"prefix":"10.1186","volume":"18","author":[{"given":"Md Yousof","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia T.T.","family":"Antunes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald W.","family":"Zamponi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"issue":"2","key":"1253_CR1","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1152\/physrev.00052.2017","volume":"99","author":"DL Bennett","year":"2019","unstructured":"Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD. The role of voltage-gated sodium channels in pain signaling. Physiol Rev. 2019;99(2):1079\u2013151.","journal-title":"Physiol Rev"},{"issue":"2","key":"1253_CR2","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1152\/jn.2001.86.2.629","volume":"86","author":"M Renganathan","year":"2001","unstructured":"Renganathan M, Cummins TR, Waxman SG. Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol. 2001;86(2):629\u201340.","journal-title":"J Neurophysiol"},{"issue":"5","key":"1253_CR3","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s41573-024-01108-x","volume":"24","author":"M Alsaloum","year":"2025","unstructured":"Alsaloum M, Dib-Hajj SD, Page DA, Ruben PC, Krainer AR, Waxman SG. Voltage-gated sodium channels in excitable cells as drug targets. Nat Rev Drug Discov. 2025;24(5):358\u201378.","journal-title":"Nat Rev Drug Discov"},{"issue":"2","key":"1253_CR4","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1007\/s40122-024-00697-0","volume":"14","author":"JD Osteen","year":"2025","unstructured":"Osteen JD, Immani S, Tapley TL, Indersmitten T, Hurst NW, Healey T, et al. Pharmacology and mechanism of action of Suzetrigine, a potent and selective Na V 1.8 pain signal inhibitor for the treatment of moderate to severe pain. Pain Ther. 2025;14(2):655\u201374.","journal-title":"Pain Ther"},{"issue":"5","key":"1253_CR5","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1056\/NEJMoa2209870","volume":"389","author":"J Jones","year":"2023","unstructured":"Jones J, Correll DJ, Lechner SM, Jazic I, Miao X, Shaw D, et al. Selective inhibition of Na V 1.8 with VX-548 for acute pain. N Engl J Med. 2023;389(5):393\u2013405.","journal-title":"N Engl J Med"},{"issue":"6","key":"1253_CR6","first-page":"1085","volume":"142","author":"T Bertoch","year":"2025","unstructured":"Bertoch T, D\u2019Aunno D, McCoun J, Solanki D, Taber L, Urban J, et al. Suzetrigine, a nonopioid Na V 1.8 inhibitor for treatment of moderate-to-severe acute pain: two phase 3 randomized clinical trials. Anesthesiology. 2025;142(6):1085\u201399.","journal-title":"Anesthesiology"},{"key":"1253_CR7","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.2147\/JPR.S509144","volume":"18","author":"J McCoun","year":"2025","unstructured":"McCoun J, Winkle P, Solanki D, Urban J, Bertoch T, Oswald J, et al. Suzetrigine, a non-opioid Na(V) inhibitor with broad applicability for moderate-to-severe acute pain: A phase 3 single-arm study for surgical or non-surgical acute pain. J Pain Res. 2025;18:1569\u201376.","journal-title":"J Pain Res"},{"key":"1253_CR8","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20241877","author":"FTT Antunes","year":"2025","unstructured":"Antunes FTT, Gandini MA, Garcia-Caballero A, Huang S, Ali MY, Gambeta E, et al. A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain. J Exp Med. 2025. https:\/\/doi.org\/10.1084\/jem.20241877.","journal-title":"J Exp Med"},{"issue":"6","key":"1253_CR9","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1124\/molpharm.124.000944","volume":"106","author":"P Vaelli","year":"2024","unstructured":"Vaelli P, Fujita A, Jo S, Zhang HB, Osorno T, Ma X, et al. State-dependent inhibition of Nav1.8 sodium channels by VX-150 and VX-548. Mol Pharmacol. 2024;106(6):298\u2013308.","journal-title":"Mol Pharmacol"},{"issue":"22","key":"1253_CR10","doi-asserted-by":"publisher","first-page":"e2503570122","DOI":"10.1073\/pnas.2503570122","volume":"122","author":"RG Stewart","year":"2025","unstructured":"Stewart RG, Osorno T, Fujita A, Jo S, Ferraiuolo A, Carlin K, et al. Modulation of human dorsal root ganglion neuron firing by the Nav1.8 inhibitor suzetrigine. Proc Natl Acad Sci U S A. 2025;122(22):e2503570122.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"1253_CR11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/0165-0270(85)90116-5","volume":"14","author":"S Hunskaar","year":"1985","unstructured":"Hunskaar S, Fasmer OB, Hole K. Formalin test in mice, a useful technique for evaluating mild analgesics. J Neurosci Methods. 1985;14(1):69\u201376.","journal-title":"J Neurosci Methods"},{"issue":"8","key":"1253_CR12","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/S0028-3908(01)00142-3","volume":"41","author":"J Ferreira","year":"2001","unstructured":"Ferreira J, Campos MM, Pesquero JB, Ara\u00fajo RC, Bader M, Calixto JB. Evidence for the participation of kinins in Freund\u2019s adjuvant-induced inflammatory and nociceptive responses in kinin B1 and B2 receptor knockout mice. Neuropharmacology. 2001;41(8):1006\u201312.","journal-title":"Neuropharmacology"},{"issue":"1\u20132","key":"1253_CR13","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/S0304-3959(98)00045-1","volume":"76","author":"AB Malmberg","year":"1998","unstructured":"Malmberg AB, Basbaum AI. Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain. 1998;76(1\u20132):215\u201322.","journal-title":"Pain"},{"key":"1253_CR14","unstructured":"Evaluation of efficacy and safety of VX-548 for painful lumbosacral radiculopathy (PLSR). ClinicalTrials.gov ID NCT0617619; 2024."},{"key":"1253_CR15","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.2147\/JPR.S509144","volume":"18","author":"J McCoun","year":"2025","unstructured":"McCoun J, Winkle P, Solanki D, Urban J, Bertoch T, Oswald J, et al. Suzetrigine, a non-opioid Na. J Pain Res. 2025;18:1569\u201376.","journal-title":"J Pain Res"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-025-01253-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-025-01253-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-025-01253-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T08:38:43Z","timestamp":1763023123000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-025-01253-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,13]]},"references-count":15,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1253"],"URL":"https:\/\/doi.org\/10.1186\/s13041-025-01253-3","relation":{},"ISSN":["1756-6606"],"issn-type":[{"value":"1756-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,13]]},"assertion":[{"value":"9 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the University of Calgary\u2019s ethics committees.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"86"}}