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 vivoHyperexcitabilityAnalgesiaNeuronsDisordersPainTherapyGenesBiodistributionRatsA multi-ancestry genetic study of pain intensity in 598,339 veterans
Toikumo S, Vickers-Smith R, Jinwala Z, Xu H, Saini D, Hartwell E, Pavicic M, Sullivan K, Xu K, Jacobson D, Gelernter J, Rentsch C, Stahl E, Cheatle M, Zhou H, Waxman S, Justice A, Kember R, Kranzler H. A multi-ancestry genetic study of pain intensity in 598,339 veterans. Nature Medicine 2024, 30: 1075-1084. PMID: 38429522, DOI: 10.1038/s41591-024-02839-5.Peer-Reviewed Original ResearchPain intensityChronic painTreat chronic painCalcium channel blockersCross-ancestry meta-analysisGenome-wide association studiesExperience of painSamples of European ancestryPain phenotypesFunctional genomics dataGABAergic neuronsCalcium channelsAnalgesic effectB-blockersDrug groupMillion Veteran ProgramPainSubstance use disordersQuality of lifeDrug repurposing analysisOpioid crisisGenetic architectureCausal genesGenetic lociGenomic data
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 ResearchTargeting a Peripheral Sodium Channel to Treat Pain
Waxman S. Targeting a Peripheral Sodium Channel to Treat Pain. New England Journal Of Medicine 2023, 389: 466-469. PMID: 37530829, DOI: 10.1056/nejme2305708.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 expressionGene therapy for chronic pain: emerging opportunities in target-rich peripheral nociceptors
Ovsepian S, Waxman S. Gene therapy for chronic pain: emerging opportunities in target-rich peripheral nociceptors. Nature Reviews Neuroscience 2023, 24: 252-265. PMID: 36658346, DOI: 10.1038/s41583-022-00673-7.Peer-Reviewed Original Research
2022
Dendritic Spines and Pain Memory
Benson C, King J, Reimer M, Kauer S, Waxman S, Tan A. Dendritic Spines and Pain Memory. The Neuroscientist 2022, 30: 294-314. PMID: 36461773, DOI: 10.1177/10738584221138251.Peer-Reviewed Original ResearchNeuropathic painDendritic spinesSynaptic transmissionSpinal cord dorsal hornForm of painNew therapeutic approachesSurface of neuronsDorsal hornIntractable painDeep laminaePain memoryTherapeutic approachesPainNervous systemNew therapeuticsSpineMillions of peopleInjuryDiseaseRecent studiesReview articlePrevalenceNeuronsImportant rolePeripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy
Ślęczkowska M, Almomani R, Marchi M, Salvi E, de Greef B, Sopacua M, Hoeijmakers J, Lindsey P, Waxman S, Lauria G, Faber C, Smeets H, Gerrits M. Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy. International Journal Of Molecular Sciences 2022, 23: 14095. PMID: 36430572, PMCID: PMC9696564, DOI: 10.3390/ijms232214095.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyNeuropathic painIon channel genesPainful small fiber neuropathyPain score VASPathogenic heterozygous variantGenetic variantsIon channelsCohort studyDiabetic neuropathySevere painDifferent etiologiesPainPatientsVoltage-gated sodium ion channelsHeterozygous variantsNeuropathySodium ion channelsGene screeningGeneration sequencingPrevious findingsSuch variantsEtiologySCN1BVariantsNon-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
2018
Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury
Guo Y, Benson C, Hill M, Henry S, Effraim P, Waxman S, Dib-Hajj S, Tan AM. Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury. Molecular Pain 2018, 14: 1744806918788648. PMID: 29956587, PMCID: PMC6053256, DOI: 10.1177/1744806918788648.Peer-Reviewed Original ResearchConceptsDendritic spine dysgenesisNeuropathic painSpine dysgenesisBurn injurySignificant tactile allodyniaDorsal horn neuronsChronic disease burdenActivity-dependent expressionCutaneous burn injurySecond-degree burn injuryBurn injury modelC-fos expressionPotential molecular targetsDrug discontinuationHeat hyperalgesiaTactile allodyniaDorsal hornPain outcomesChronic painNociceptive activityLower painDisease burdenInjury modelCognitive dysfunctionPain
2016
Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia
Cao L, McDonnell A, Nitzsche A, Alexandrou A, Saintot PP, Loucif AJ, Brown AR, Young G, Mis M, Randall A, Waxman SG, Stanley P, Kirby S, Tarabar S, Gutteridge A, Butt R, McKernan RM, Whiting P, Ali Z, Bilsland J, Stevens EB. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Science Translational Medicine 2016, 8: 335ra56. PMID: 27099175, DOI: 10.1126/scitranslmed.aad7653.Peer-Reviewed Original ResearchConceptsSensory neuronsPain conditionsSodium channelsClinical phenotypeSensory neuronal activityChronic pain conditionsHeat-induced painPeripheral nervous systemUnmet clinical needSodium channel Nav1.7Nav1.7 sodium channelNav1.7 blockersPharmacological reversalPain phenotypesExtreme painNeuronal activityHeat stimuliNervous systemChannel Nav1.7PainClinical needPatientsAberrant responsesSensory conditionsInduced pluripotent stem cell lineVoltage-Gated Ion Channels as Molecular Targets for Pain
Zamponi G, Han C, Waxman S. Voltage-Gated Ion Channels as Molecular Targets for Pain. 2016, 415-436. DOI: 10.1007/978-1-4899-7654-3_22.Peer-Reviewed Original ResearchVoltage-gated ion channelsDorsal root ganglion neuronsIon channelsMolecular targetsAction potential firing propertiesTreatment of painVoltage-gated sodiumImportant ion channelsNerve injuryGanglion neuronsPain signalingPeripheral afferentsPainFiring propertiesPharmacological modulatorsPotassium channelsTranslational researchDevelopment of modulatorsFunction changesHyperexcitabilityAfferentsInflammationMajor roleMajor themesInjury
2014
Epidermal Nerve Fibers
Lauria G, Merkies I, Waxman S, Faber C. Epidermal Nerve Fibers. 2014, 76-79. DOI: 10.1016/b978-0-12-385157-4.00656-4.Peer-Reviewed Original ResearchEpidermal nerve fibersNerve fibersNeuropathic painSkin biopsiesProtein gene product 9.5Severity of neuropathySmall fiber neuropathySmall nerve fibersDistinct clinical syndromeSensory nervesClinical syndromeProduct 9.5Unmyelinated axonsNeuropathyPainAvailability of antibodiesBiopsySomatic functionsInnervationNociceptorsNerveSyndromeAxonsDegenerationDiagnosis
2013
Approach to Small Fiber Neuropathy
Lauria G, Merkies I, Waxman S, Faber C. Approach to Small Fiber Neuropathy. 2013, 507-517. DOI: 10.1007/978-1-4614-6567-6_25.Peer-Reviewed Original Research
2012
Genetic aspects of sodium channelopathy in small fiber neuropathy
Hoeijmakers J, Merkies I, Gerrits M, Waxman S, Faber C. Genetic aspects of sodium channelopathy in small fiber neuropathy. Clinical Genetics 2012, 82: 351-358. PMID: 22803682, DOI: 10.1111/j.1399-0004.2012.01937.x.Peer-Reviewed Original ResearchConceptsSmall fiber neuropathyEtiology of SFNSmall-diameter peripheral axonsIntraepidermal nerve fiber densityDorsal root ganglion neuronsAbnormal thermal thresholdsNerve fiber densityQuantitative sensory testingUnmyelinated C-fibersSFN patientsAutonomic dysfunctionNeuropathic painAδ fibersGanglion neuronsC-fibersPeripheral axonsSensory testingSpecific treatmentSodium channelopathiesApparent causeFiber densitySodium channelsLogical targetNeuropathyPainUnderstanding chronic inflammatory and neuropathic pain
Hughes J, Chessell I, Malamut R, Perkins M, Bačkonja M, Baron R, Farrar J, Field M, Gereau R, Gilron I, McMahon S, Porreca F, Rappaport B, Rice F, Richman L, Segerdahl M, Seminowicz D, Watkins L, Waxman S, Wiech K, Woolf C. Understanding chronic inflammatory and neuropathic pain. Annals Of The New York Academy Of Sciences 2012, 1255: 30-44. PMID: 22564068, DOI: 10.1111/j.1749-6632.2012.06561.x.Peer-Reviewed Original Research
2008
Multiple sodium channel isoforms and mitogen‐activated protein kinases are present in painful human neuromas
Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG. Multiple sodium channel isoforms and mitogen‐activated protein kinases are present in painful human neuromas. Annals Of Neurology 2008, 64: 644-653. PMID: 19107992, DOI: 10.1002/ana.21527.Peer-Reviewed Original ResearchConceptsMultiple sodium channel isoformsHuman neuromasSodium channel isoformsPainful neuromasMitogen-activated protein kinaseERK1/2 MAP kinasesNeuronal voltage-gated sodium channelsChannel isoformsSodium channel Nav1.3Sodium channelsSpontaneous ectopic dischargeTreatment of painSodium channel Nav1.1Possible therapeutic targetVoltage-gated sodium channelsMAP kinase p38Ectopic dischargesChronic painTraumatic neuromaChannel Nav1.1MAP kinaseExtracellular signal-regulated kinases 1NeuromaTherapeutic targetPain