Painisoneoftheleadingcharacteristicsofmanydiseasesandpresentsamajorhealthburdenworldwide1,2.Despitethelargenumberofapprovedanalgesics,manypatientswhoareinpainareinadequatelytreated,withaconsequentreductionintheirqualityoflife.Effectiveandsafeanalgesicsarestillurgentlyneeded,andthedevelopmentofsuchdrugsdependsondetailedknowledgeofthecellularandmolecularmechanismsofpainprocessing.AlthoughongoinginflammationortissueandnervedamagearewellknowntocausemolecularchangesintheCNSandPNSthatareassociatedwithpainhypersensitivity(causedbycentralandperipheralsensitizationmechanisms,respectively),thedetailedsensitizationmechanisms,particularlywithregardtopainchronification,remainunclear.Epigeneticshasbeendefinedasthecellularmechanismsthatenable“thestructuraladaptationofchromosomalregionssoastoregister,signalorperpetuatealteredactivitystates”(REF.3),withregardtomodulatedgeneexpression.Moreover,thisalteredactivitystateissustained,evenwhentheoriginalstimulushasfadedand,consequently,adaptationscanbelonglasting,andarethoughttohavearoleinprocessessuchasmemoryformation4–7.Accordingly,epigeneticadaptationsprobablyregulatepainsensitization,whichcouldresultinchronicallyincreasednociceptiveresponsestonoxiousstimulation(thatis,hyperalgesia)ornociceptivereactionstononnoxiousstimuli(thatis,allodynia)8,9.Withoutpharmacologicaltreatment,suchpathophysiologicalpaincanbecomechronicordevelopintostimulusindependentpain.Thefieldofepigeneticshasattractedincreasingattentionoverthepastdecade10,notonlyinrelationtogeneralepigeneticmechanisms,butalsoinrelationtotranslationofepigeneticconceptstootherresearchfields,suchaspainandpaintherapy11–15.InthisReview,wecriticallydiscussthestatusofepigeneticresearchinpain.Thisresearchlargelyconsistsofpreclinicalproofofconceptstudies,predominantlyinmodelsofacuteorsubacutepain.Incontrasttopreviousreviewsinthisfield,weaddressthelackofclinicalstudiesandthechallengestothedevelopmentofwelltoleratedepigeneticmodifiersforclinicaltherapiesofch...
