{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T17:33:33Z","timestamp":1789320813735,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"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. Med."],"abstract":"<jats:p>\n                    Gain-of-function mutations in\n                    <jats:italic>SCN9A<\/jats:italic>\n                    , which encodes the Nav1.7 voltage-gated sodium channel, are known to cause primary erythromelalgia (PEM). This condition is characterized by recurrent episodes of erythema, burning pain, and warmth in the extremities. These genetic insights have spurred the development of Nav1.7 blockers as a promising therapeutic strategy for PEM. However, translating these findings into effective clinical treatments has remained challenging. In this study, we demonstrate that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients. Using voltage-clamp recordings in human embryonic kidney (HEK) 293 cells, we demonstrated that mepyramine inhibits hNav1.7 channels carrying three distinct PEM mutations, I848T, L858F, and L1267V, which differentially affect the gating properties of hNav1.7. Importantly, mepyramine\u2019s efficacy was consistent regardless of how these mutations altered channel activation or inactivation properties. To evaluate its clinical potential, we administered a high-dose topical formulation of mepyramine to a group of PEM patients suffering from severe pain that was unresponsive to conventional analgesics, including cases with identified\n                    <jats:italic>SCN9A<\/jats:italic>\n                    mutations. This treatment rapidly and durably reduced burning pain and erythema, providing meaningful relief for patients who had not responded to, or could not tolerate, previous therapies. These results suggest that mepyramine can inhibit PEM-associated Nav1.7 channel mutants and may offer a new therapeutic approach for PEM patients.\n                  <\/jats:p>","DOI":"10.3389\/fmed.2025.1744968","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T06:32:22Z","timestamp":1765521142000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Mepyramine targets mutant Nav1.7 channels to relieve pain and erythema in primary erythromelalgia patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Myriam","family":"Ducrocq","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Penalba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Bodemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Delmas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.jaad.2023.02.071","article-title":"Erythromelalgia. Part I: pathogenesis, clinical features, evaluation, and complications","volume":"90","author":"Caldito","year":"2024","journal-title":"J Am Acad Dermatol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.jaad.2023.02.070","article-title":"Erythromelalgia. Part II: differential diagnoses and management","volume":"90","author":"Caldito","year":"2024","journal-title":"J Am Acad Dermatol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1186\/s13023-015-0347-1","article-title":"Primary erythromelalgia: a review","volume":"10","author":"Tang","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1001\/archderm.139.10.1337","article-title":"Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia","volume":"139","author":"Davis","year":"2003","journal-title":"Arch Dermatol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1001\/archderm.136.3.330","article-title":"Natural history of erythromelalgia: presentation and outcome in 168 patients","volume":"136","author":"Davis","year":"2000","journal-title":"Arch Dermatol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1016\/j.pain.2011.12.012","article-title":"Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling","volume":"153","author":"Segerdahl","year":"2012","journal-title":"Pain"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1590\/abd1806-4841.20187535","article-title":"Erythromelalgia: a cutaneous manifestation of neuropathy?","volume":"93","author":"Leroux","year":"2018","journal-title":"An Bras Dermatol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/ijd.13760","article-title":"Secondary erythromelalgia: a tryptophan dietary supplement-induced case associated with elevated 5-hydroxyindoleacetic acid (5HIAA) urinary levels","volume":"57","author":"Michelerio","year":"2018","journal-title":"Int J Dermatol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1024\/0301-1526\/a000162","article-title":"Erythromelalgia: incidence and clinical experience in a single centre in Sweden","volume":"41","author":"Alhadad","year":"2012","journal-title":"Vasa"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/j.1468-3083.2008.02938.x","article-title":"Incidence of erythromelalgia: a population based study in Olmsted County, Minnesota","volume":"23","author":"Reed","year":"2009","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"ref11","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":"ref12","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0065-2660(08)01004-3","article-title":"Genetics and molecular pathophysiology of Nav1.7-related pain syndromes","volume":"63","author":"Dib-Hajj","year":"2008","journal-title":"Adv Genet"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1093\/brain\/aww007","article-title":"Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile","volume":"139","author":"Mcdonnell","year":"2016","journal-title":"Brain"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.tips.2017.11.010","article-title":"NaV1.7 as a pharmacogenomic target for pain: moving toward precision medicine","volume":"39","author":"Yang","year":"2018","journal-title":"Trends Pharmacol Sci"},{"key":"ref15","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":"ref16","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 USA"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1002\/cne.21450","article-title":"Na(v)1.7 and Na(v)1.3 are the only tetrodotoxin-sensitive sodium channels expressed by the adult guinea pig enteric nervous system","volume":"504","author":"Sage","year":"2007","journal-title":"J Comp Neurol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"9607","DOI":"10.1523\/JNEUROSCI.18-23-09607.1998","article-title":"Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE\/PN1 sodium channel","volume":"18","author":"Cummins","year":"1998","journal-title":"J Neurosci"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1113\/jphysiol.2006.121483","article-title":"Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons","volume":"579","author":"Rush","year":"2007","journal-title":"J Physiol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.tins.2007.08.004","article-title":"From genes to pain: Nav1.7 and human pain disorders","volume":"30","author":"Dib-Hajj","year":"2007","journal-title":"Trends Neurosci"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1007\/s00424-020-02419-9","article-title":"Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels","volume":"472","author":"Baker","year":"2020","journal-title":"Pflugers Arch"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1111\/j.1365-2133.2006.07727.x","article-title":"Mutation hotspots of SCN9A in primary erythermalgia","volume":"156","author":"Zhang","year":"2007","journal-title":"Br J Dermatol"},{"key":"ref23","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":"ref24","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1213\/01.ane.0000252965.83347.25","article-title":"Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy","volume":"104","author":"Paticoff","year":"2007","journal-title":"Anesth Analg"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1001\/archderm.135.12.1447","article-title":"Lidocaine and mexiletine therapy for erythromelalgia","volume":"135","author":"Kuhnert","year":"1999","journal-title":"Arch Dermatol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e640","DOI":"10.1111\/j.1365-2230.2009.03355.x","article-title":"Treatment with carbamazepine and gabapentin of a patient with primary erythermalgia (erythromelalgia) identified to have a mutation in the SCN9A gene, encoding a voltage-gated sodium channel","volume":"34","author":"Natkunarajah","year":"2009","journal-title":"Clin Exp Dermatol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1002\/ana.21678","article-title":"A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia","volume":"65","author":"Fischer","year":"2009","journal-title":"Ann Neurol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1001\/jamaneurol.2016.0389","article-title":"Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling","volume":"73","author":"Geha","year":"2016","journal-title":"JAMA Neurol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.1111\/bph.13935","article-title":"Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav 1.7 mutation I234T","volume":"175","author":"Yang","year":"2018","journal-title":"Br J Pharmacol"},{"key":"ref30","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":"ref31","doi-asserted-by":"publisher","first-page":"1744806918815007","DOI":"10.1177\/1744806918815007","article-title":"A novel gain-of-function Nav1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy","volume":"14","author":"Adi","year":"2018","journal-title":"Mol Pain"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.mayocp.2022.08.005","article-title":"Erythromelalgia: a review of medical management options and our approach to management","volume":"98","author":"Ma","year":"2023","journal-title":"Mayo Clin Proc"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.2147\/JPR.S154462","article-title":"Current pain management strategies for patients with erythromelalgia: a critical review","volume":"11","author":"Tham","year":"2018","journal-title":"J Pain Res"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1124\/pr.114.010249","article-title":"International union of basic and clinical pharmacology. XCVIII. Histamine receptors","volume":"67","author":"Panula","year":"2015","journal-title":"Pharmacol Rev"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e22025","DOI":"10.1096\/fj.202100976RR","article-title":"The widely used antihistamine mepyramine causes topical pain relief through direct blockade of nociceptor sodium channels","volume":"35","author":"Hao","year":"2021","journal-title":"FASEB J"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"3745","DOI":"10.1172\/JCI43158","article-title":"Pain as a channelopathy","volume":"120","author":"Raouf","year":"2010","journal-title":"J Clin Invest"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"4253","DOI":"10.1038\/s41467-019-12197-3","article-title":"Maladaptive activation of Nav1.9 channels by nitric oxide causes triptan-induced medication overuse headache","volume":"10","author":"Bonnet","year":"2019","journal-title":"Nat Commun"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"24283","DOI":"10.1038\/s41598-021-03608-x","article-title":"Contributions of NaV1.8 and NaV1.9 to excitability in human induced pluripotent stem-cell derived somatosensory neurons","volume":"11","author":"Alsaloum","year":"2021","journal-title":"Sci Rep"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.jpain.2007.09.005","article-title":"Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations","volume":"9","author":"Dworkin","year":"2008","journal-title":"J Pain"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1093\/brain\/awaa016","article-title":"Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy","volume":"143","author":"Labau","year":"2020","journal-title":"Brain"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1111\/ced.13891","article-title":"Review of primary and secondary erythromelalgia","volume":"44","author":"Mann","year":"2019","journal-title":"Clin Exp Dermatol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1113\/jphysiol.2006.127027","article-title":"A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity","volume":"581","author":"Sheets","year":"2007","journal-title":"J Physiol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"12328","DOI":"10.1523\/JNEUROSCI.2773-14.2014","article-title":"Depolarized inactivation overcomes impaired activation to produce DRG neuron hyperexcitability in a Nav1.7 mutation in a patient with distal limb pain","volume":"34","author":"Huang","year":"2014","journal-title":"J Neurosci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"9270","DOI":"10.1073\/pnas.93.17.9270","article-title":"Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated sodium channels","volume":"93","author":"Ragsdale","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.expneurol.2008.12.012","article-title":"Mexiletine-responsive erythromelalgia due to a new Na(v)1.7 mutation showing use-dependent current fall-off","volume":"216","author":"Choi","year":"2009","journal-title":"Exp Neurol"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e55212","DOI":"10.1371\/journal.pone.0055212","article-title":"A novel SCN9A mutation responsible for primary erythromelalgia and is resistant to the treatment of sodium channel blockers","volume":"8","author":"Wu","year":"2013","journal-title":"PLoS One"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jvn.2009.11.002","article-title":"Erythromelalgia: a rare microvascular disease","volume":"28","author":"Latessa","year":"2010","journal-title":"J Vasc Nurs"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"e2023191","DOI":"10.5826\/dpc.1303a191","article-title":"Clinical challenges in primary erythromelalgia: a real-life experience from a single center and a diagnostic-therapeutic flow-chart proposal","volume":"13","author":"Michelerio","year":"2023","journal-title":"Dermatol Pract Concept"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/bph.12266","article-title":"The role of histamine in neurogenic inflammation","volume":"170","author":"Rosa","year":"2013","journal-title":"Br J Pharmacol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"335ra56","DOI":"10.1126\/scitranslmed.aad7653","article-title":"Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia","volume":"8","author":"Cao","year":"2016","journal-title":"Sci Transl Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1744968\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T06:32:22Z","timestamp":1765521142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1744968\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":50,"alternative-id":["10.3389\/fmed.2025.1744968"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1744968","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]},"article-number":"1744968"}}