2024
TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization
Gualdani R, Barbeau S, Yuan J, Jacobs D, Gailly P, Dib-Hajj S, Waxman S. TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2406186121. PMID: 39226353, PMCID: PMC11406256, DOI: 10.1073/pnas.2406186121.Peer-Reviewed Original ResearchConceptsLaser-assisted in situ keratomileusisPhotorefractive keratectomyOcular Surface Disease Index scoreCapsaicin-induced desensitizationPhotorefractive keratectomy enhancementDisease Index scorePhysiological membrane potentialsCorneal neuralgiaTRPV1 variantsCorneal painRefractive surgeryRefractive errorCapsaicin desensitizationPersistent painBradykinin sensitivityNerve injuryM mutationPatch clampChannel activitySurgical techniqueLeftward shiftInflammatory mediatorsM-channelPainIndex scoreDisordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders
Dib-Hajj S, Waxman S. Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders. Journal Of Clinical Investigation 2024, 134: e182198. PMID: 38949022, PMCID: PMC11213459, DOI: 10.1172/jci182198.Peer-Reviewed Original ResearchConceptsTetrodotoxin-sensitiveHyperexcitability disordersSensory neuronsExcitability of sensory neuronsGene therapy modalitiesPeripheral sensory neuronsVoltage-gated sodiumMinimal side effectsGene therapyInduce analgesiaTherapy modalitiesSide effectsTherapeutic strategiesNav channelsAttenuating excitationIn vivoHyperexcitabilityAnalgesiaNeuronsDisordersPainTherapyGenesBiodistributionRats
2023
NaV1.7: A central role in pain
Waxman S, Dib-Hajj S. NaV1.7: A central role in pain. Neuron 2023, 111: 2615-2617. PMID: 37678164, DOI: 10.1016/j.neuron.2023.08.011.Peer-Reviewed Original ResearchTRPA1 rare variants in chronic neuropathic and nociplastic pain patients
Marchi M, Salvi E, Andelic M, Mehmeti E, D'Amato I, Cazzato D, Chiappori F, Lombardi R, Cartelli D, Devigili G, Bella E, Gerrits M, Almomani R, Malik R, Ślęczkowska M, Mazzeo A, Gentile L, Dib-Hajj S, Waxman S, Faber C, Vecchio E, de Tommaso M, Lauria G. TRPA1 rare variants in chronic neuropathic and nociplastic pain patients. Pain 2023, 164: 2048-2059. PMID: 37079850, PMCID: PMC10443199, DOI: 10.1097/j.pain.0000000000002905.Peer-Reviewed Original ResearchConceptsNociplastic painPainful neuropathyPain patientsHealthy controlsRare variantsChronic neuropathic painChronic pain disordersChronic widespread painChronic pain patientsMolecular profilePainless neuropathyNeuropathic painPain disordersWidespread painChronic painPatient's molecular profileIndependent cohortPainPatientsClinical diagnosisDisease riskNeuropathyTRPA1 variantsNew risk genesPain genesConserved but not critical: Trafficking and function of NaV1.7 are independent of highly conserved polybasic motifs
Tyagi S, Sarveswaran N, Higerd-Rusli G, Liu S, Dib-Hajj F, Waxman S, Dib-Hajj S. Conserved but not critical: Trafficking and function of NaV1.7 are independent of highly conserved polybasic motifs. Frontiers In Molecular Neuroscience 2023, 16: 1161028. PMID: 37008789, PMCID: PMC10060856, DOI: 10.3389/fnmol.2023.1161028.Peer-Reviewed Original ResearchSensory axonsPeripheral voltage-gated sodium channelsMajor unmet clinical needFunction of Nav1.7Non-addictive treatmentsUnmet clinical needVoltage-clamp recordingsVoltage-gated sodium channelsPain therapyChronic painPrimary afferentsNoxious stimuliTherapeutic modalitiesAction potentialsAxonal transportClinical needVesicular packagingSodium channelsHuman painPainAxonal traffickingAxonal surfaceAxonal membraneAxonsAttractive targetIntegrative miRNA–mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy
Andelic M, Salvi E, Marcuzzo S, Marchi M, Lombardi R, Cartelli D, Cazzato D, Mehmeti E, Gelemanovic A, Paolini M, Pardo C, D'Amato I, Hoeijmakers J, Dib-Hajj S, Waxman S, Faber C, Lauria G. Integrative miRNA–mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy. Brain 2023, 146: 3049-3062. PMID: 36730021, PMCID: PMC10316770, DOI: 10.1093/brain/awad025.Peer-Reviewed Original ResearchConceptsNeuropathic painPain-related mechanismsCohort of patientsSmall nerve fibersUnmet clinical needPainful neuropathyTargeted molecular profilingNeuropathy painPathophysiological mechanismsAvailable therapiesPreclinical modelsNerve fibersLimited efficacyHealthy individualsPersonalized managementPotential drug candidatesTranslational gapPainClinical needGene targetsPatientsImmunofluorescence assaysMolecular profilingMiR-30 familyProtein expression
2022
Maximizing treatment efficacy through patient stratification in neuropathic pain trials
Baron R, Dickenson A, Calvo M, Dib-Hajj S, Bennett D. Maximizing treatment efficacy through patient stratification in neuropathic pain trials. Nature Reviews Neurology 2022, 19: 53-64. PMID: 36400867, DOI: 10.1038/s41582-022-00741-7.Peer-Reviewed Original ResearchConceptsNeuropathic painPain medicineOutcome measuresClinical practiceNeuropathic pain etiologyNeuropathic pain trialsPatient stratification approachesMultiple pathophysiological mechanismsSubgrouping of patientsRoutine clinical practiceNovel outcome measuresPain etiologyBaseline characteristicsPain trialsPathophysiological mechanismsClinical trialsTreatment successTherapeutic approachesAnimal modelsPatient stratificationTreatment efficacyPainHuman painTherapeutic compoundsPatientsNon-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol
Ghovanloo M, Dib-Hajj S, Goodchild S, Ruben P, Waxman S. Non-psychotropic phytocannabinoid interactions with voltage-gated sodium channels: An update on cannabidiol and cannabigerol. Frontiers In Physiology 2022, 13: 1066455. PMID: 36439273, PMCID: PMC9691960, DOI: 10.3389/fphys.2022.1066455.Peer-Reviewed Original Research
2017
Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav1.7 mutation I234T
Yang Y, Adi T, Effraim PR, Chen L, Dib‐Hajj S, Waxman SG. Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav1.7 mutation I234T. British Journal Of Pharmacology 2017, 175: 2261-2271. PMID: 28658526, PMCID: PMC5980548, DOI: 10.1111/bph.13935.Peer-Reviewed Original ResearchConceptsUse-dependent inhibitionSensory neuronsDorsal root ganglion sensory neuronsIntact sensory neuronsDRG sensory neuronsMulti-electrode array recordingsTreatment of painTargeting Ion ChannelsEffects of carbamazepineMutant channelsT mutationChronic painActivation of NaSodium channel variantsSection visitPainPharmacogenomic approachPharmacological analysisPatch clampPatientsNeuronsHigher firingCarbamazepineThemed sectionChannel variants
2016
Familial gain-of-function Nav1.9 mutation in a painful channelopathy
Han C, Yang Y, Morsche R, Drenth JP, Politei JM, Waxman SG, Dib-Hajj SD. Familial gain-of-function Nav1.9 mutation in a painful channelopathy. Journal Of Neurology Neurosurgery & Psychiatry 2016, 88: 233. PMID: 27503742, DOI: 10.1136/jnnp-2016-313804.Peer-Reviewed Original ResearchConceptsPain disordersPainful small fiber neuropathyDorsal root ganglion neuronsSmall fiber neuropathyPotential therapeutic targetVoltage-clamp recordingsFunction mutationsPain symptomsGastrointestinal disturbancesGanglion neuronsClinical examinationHyperpolarising shiftFunctional assessmentTherapeutic targetDistal extremitiesPhenotypic spectrumElectrophysiological recordingsPatientsBlood relativesFirst arginine residuePainAcceleration of activationSegment 4ChannelopathiesDisorders
2010
A new Nav1.7 sodium channel mutation I234T in a child with severe pain
Ahn H, Dib‐Hajj S, Cox JJ, Tyrrell L, Elmslie FV, Clarke AA, Drenth JP, Woods CG, Waxman SG. A new Nav1.7 sodium channel mutation I234T in a child with severe pain. European Journal Of Pain 2010, 14: 944-950. PMID: 20385509, DOI: 10.1016/j.ejpain.2010.03.007.Peer-Reviewed Original ResearchConceptsSevere painSevere pain symptomsYear old patientAvoidance of triggersWhole-cell voltage-clamp analysisPain episodesPain symptomsOlder patientsDrug treatmentVoltage-clamp analysisPainRamp depolarizationIEM patientsPatient's genomic DNAMild warmthPatientsSodium channelsFunction mutationsT mutationLimited reliefMonthsActivation shiftActivationRednessMutations
2009
A sodium channel gene SCN9A polymorphism that increases nociceptor excitability
Estacion M, Harty TP, Choi J, Tyrrell L, Dib‐Hajj S, Waxman SG. A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Annals Of Neurology 2009, 66: 862-866. PMID: 20033988, DOI: 10.1002/ana.21895.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArginineBiophysical PhenomenaCell Line, TransformedElectric StimulationGanglia, SpinalGreen Fluorescent ProteinsHumansMembrane PotentialsMiceNAV1.7 Voltage-Gated Sodium ChannelNociceptorsPatch-Clamp TechniquesPolymorphism, Single NucleotideSensory Receptor CellsSensory ThresholdsSodium ChannelsTransfectionTryptophanConceptsNonsynonymous single nucleotide polymorphismsNociceptive primary sensory neuronsDorsal root ganglion neuronsPrimary sensory neuronsCurrent-clamp analysisSingle nucleotide polymorphismsSCN9A geneDRG neuronsNociceptor excitabilityGanglion neuronsUnaffected family membersControl chromosomesSensory neuronsSmall depolarizationSodium channelsMembrane potentialNeuronsAffected probandPolymorphismFamily membersDepolarizationChromosomesGenesErythromelalgiaPainA novel Nav1.7 mutation producing carbamazepine‐responsive erythromelalgia
Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, Dib‐Hajj S, Waxman SG. A novel Nav1.7 mutation producing carbamazepine‐responsive erythromelalgia. Annals Of Neurology 2009, 65: 733-741. PMID: 19557861, PMCID: PMC4103031, DOI: 10.1002/ana.21678.Peer-Reviewed Original ResearchConceptsSteady-state inactivationDorsal root ganglion neuron hyperexcitabilityWhole-cell patch-clamp recordingsRamp currentsHuman therapeutic rangeWhole-cell patch-clamp studiesPatch-clamp recordingsPatch-clamp studiesErythromelalgia mutationV400MNeuron hyperexcitabilityNeuropathic painM cell lineNav1.7 mutationPainful disordersSympathetic neuronsTherapeutic rangeBlood samplesAnimal studiesNormalizing effectPharmacological studiesErythromelalgiaPainSodium channelsCarbamazepine
2008
Voltage‐Gated Sodium Channels: Multiple Roles in the Pathophysiology of Pain
Dib‐Hajj S, Hains B, Black J, Waxman S. Voltage‐Gated Sodium Channels: Multiple Roles in the Pathophysiology of Pain. 2008, 67-104. DOI: 10.1002/9780470429907.ch3.Chapters
2006
Mutations in the sodium channel Nav1.7 underlie inherited erythromelalgia
Dib-Hajj S, Rush A, Cummins T, Waxman S. Mutations in the sodium channel Nav1.7 underlie inherited erythromelalgia. Drug Discovery Today Disease Mechanisms 2006, 3: 343-350. DOI: 10.1016/j.ddmec.2006.09.005.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsSympathetic ganglion neuronsDorsal root gangliaHigh-frequency firingSingle action potentialSodium channel Nav1.7Mild thermal stimuliSevere painDRG neuronsPainful conditionsGanglion neuronsRoot gangliaChannel Nav1.7Action potentialsModel diseaseThermal stimuliErythromelalgiaNeuronsMutant channelsFunctional studiesIEMPainGangliaNav1.7MutationsDisease
2005
Erythromelalgia: A hereditary pain syndrome enters the molecular era
Waxman SG, Dib‐Hajj S. Erythromelalgia: A hereditary pain syndrome enters the molecular era. Annals Of Neurology 2005, 57: 785-788. PMID: 15929046, DOI: 10.1002/ana.20511.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPain syndromeGanglion neuronsCentral nervous system neuronsDorsal root ganglion neuronsChronic neuropathic painSodium channelsSympathetic ganglion neuronsIon channel mutationsChannel functionSodium channel functionAutosomal dominant disorderNeuropathic painPain disordersChronic painAltered excitabilityModerate exerciseSystem neuronsPrimary erythermalgiaRational therapyErythromelalgiaPainFirst human disorderModel diseaseWarm stimuliSyndrome
2002
Sodium channels and the molecular basis for pain
Black J, Cummins T, Dib-Hajj S, Waxman S. Sodium channels and the molecular basis for pain. Progress In Inflammation Research 2002, 23-50. DOI: 10.1007/978-3-0348-8129-6_2.ChaptersPrimary sensory neuronsSensory neuronsAction potentialsSpontaneous action potentialsHigh-frequency activityInflammatory painTrigeminal neuronsNociceptive responsesAscending pathwaysPeripheral nervesTissue injuryNoxious stimuliPeripheral targetsPainNeuronsSodium channelsTemperature sensationBrainHigh thresholdNerveMolecular basisInjuryAxonsDRG
2000
Sodium channels and the molecular pathophysiology of pain
Cummins T, Dib-Hajj S, Black J, Waxman S. Sodium channels and the molecular pathophysiology of pain. Progress In Brain Research 2000, 129: 3-19. PMID: 11098678, DOI: 10.1016/s0079-6123(00)29002-x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsDorsal root gangliaTrigeminal neuronsSodium channelsAction potentialsDorsal root ganglion neuronsSpontaneous action potential activityMolecular pathophysiologyPrimary sensory neuronsPeripheral target tissuesAction potential activitySodium channel expressionChain of neuronsPathological burstingNerve injuryNociceptive pathwaysChronic painGanglion neuronsRoot gangliaSensory neuronsChannel expressionSomatosensory systemPainNeuronsTarget tissuesPathophysiology
1999
Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain
Dib-Hajj S, Fjell J, Cummins TR, Zheng Z, Fried K, LaMotte R, Black JA, Waxman S. Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. Pain 1999, 83: 591-600. PMID: 10568868, DOI: 10.1016/s0304-3959(99)00169-4.Peer-Reviewed Original ResearchConceptsTTX-R sodium channelsChronic constriction injury modelDRG neuronsSodium currentSodium channelsNeuropathic painInjury modelAxotomized dorsal root ganglion (DRG) neuronsSmall-diameter DRG neuronsTTX-R sodium currentsDorsal root ganglion neuronsTTX-S currentsSodium channel expressionGanglion neuronsSciatic nerveChannel expressionSodium channel transcriptsNeuronsNa currentPainChannel transcriptsSignificant changesLevels of transcriptsHyperalgesiaPrevious studiesSodium channels, excitability of primary sensory neurons, and the molecular basis of pain
Waxman S, Cummins T, Dib‐Hajj S, Fjell J, Black J. Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. Muscle & Nerve 1999, 22: 1177-1187. PMID: 10454712, DOI: 10.1002/(sici)1097-4598(199909)22:9<1177::aid-mus3>3.0.co;2-p.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPrimary sensory neuronsDRG neuronsSodium channel expressionSodium channel gene expressionSensory neuronsChannel gene expressionSodium channelsChannel expressionSodium currentTTX-sensitive sodium currentAbnormal burst activityNormal DRG neuronsSNS/PN3Resistant sodium currentsDistinct sodium channelsSodium channel geneChannel genesInflammatory painNerve injuryAxonal transectionElectrophysiological abnormalitiesSelective blockadePharmacological approachesBurst activityPain