[Link].
com
PathophysiologicalMechanismsofNeuropathicPain
CaterinaLeoneAntonellaBiasiottaSilviaLaCesaGiuliaDiStefanoGiorgioCruccuAndreaTruini
FutureNeurology.20116(4):497509.
AbstractandIntroduction
Abstract
Neuropathicpainisacommonprobleminclinicalpracticeandonethatadverselyaffectspatients'[Link]
evidencefromanimalandhumanstudiesdemonstratesthatneuropathicpainarisesfromalesioninthesomatosensorysystem.
InjuredperipheralnervefibersgiverisetoanintenseandprolongedectopicinputtotheCNSand,insomecases,alsoto
[Link]
accordingtoamechanismbasedratherthananetiologybasedapproachmighthelpintargetingtherapytotheindividualpatient
[Link]
pathophysiologicalmechanismsunderlyingneuropathicpainandfocusesonhowsymptomstranslateintomechanisms.
Introduction
Thewidelyaccepteddefinitionofneuropathicpainis'painarisingasadirectconsequenceofalesionordiseaseaffectingthe
somatosensorysystem'.[1]
[Link]
causeneuropathicpainaredistalsymmetricperipheralneuropathies(e.g.,diabeticneuropathy)andfocalneuropathiesrelatedto
trauma(e.g.,traumaticbrachialplexusinjuries),aswellassurgicalinterventions(e.g.,breastsurgery).ExemplaryCNSdiseases
causingneuropathicpainincludemultiplesclerosis,[Link]
[Link]
characteristicsinlargecommunitysampleshavereporteda78%prevalenceofneuropathicpaininthegeneralpopulation.[2,3]
[Link]
betweentheunderlyingpathophysiologicalmechanismsandneuropathicpainsymptomsnowsuggeststhatclassifying
neuropathicpainaccordingtoamechanismbasedratherthananetiologybasedapproachmighthelpintargetingtherapytothe
[Link]
peripheralandcentralpathophysiologicalmechanismsunderlyingneuropathicpainandfocusonhowsymptomstranslateinto
mechanisms.
MechanismsUnderlyingNeuropathicPain
AnimalModels
Mostofourcurrentknowledgeonthecomplexpathophysiologicalprocessesthattriggerneuropathicpaincomesfromanimal
modelsofperipheralnerveinjuries,largelydesignedtomimichumandiseases.[4]Althoughthesemodelshavetheimportantmerit
ofimprovingourknowledgeonthemechanismsunderlyingneuropathicpain,theyoftenpoorlypredicttheinvolvementof
particulartargetsorprocessesinhumanneuropathicpain.[4]Severalstudieshaveusedtotalnervetransectionandligationto
simulatetheclinicalconditionsofamputation.[5]Partialnerveligation[6]andsparednerveinjury[7]havebeenusedtosimulatethe
[Link]
lumbardiskherniation.[8]Immuneortoxinmediateddemyelinationsimulatesdemyelinatingneuropathy.[9]Vincristine,paclitaxel
andcisplatinhavebeenusedinanimalmodelstomimicpolyneuropathycausedbytumorchemotherapy.[10]Finally,streptozocin
induceddamagetopancreaticinsulinproducingcellsinratsprovidesanexperimentalmodelofdiabeticneuropathy.[11]
PeripheralSensitization
Followingnervedamage,aneuroma,consistingofregenerativenervesproutsgrowinginalldirections,developsattheproximal
[Link],ongoingspontaneousactivity,abnormal
excitabilityandanincreasedsensitivitytochemical,thermalandmechanicalstimulidevelopatmultiplesites,includingthe
neuroma(thesiteofinjurywithabortedaxongrowth),inthecellbodyofinjureddorsalrootganglianeurons[12]andinneighboring
intactafferents.[13]This'hyperactivity'involvingthenociceptiveprimaryafferentsisdefinedasperipheralsensitization(Figure1).
[4,1418]
Figure1.
[Link],thespikes(A,13)
arealwaystriggeredbyasubthresholdoscillationpeakasseenintheexpandedtimeandvoltagescale(B,13).
Reproducedwithpermissionfrom[123].
[Link],voltagegatedsodium
channelexpressionundergoesmarkedchanges.ManystudiesdemonstratedabnormalsodiumchannelNav1.3,Nav1.7,Nav1.8
andNav1.9expression,[19,20]leadingtoprimaryafferenthyperexcitability(aloweredthresholdandhigherfiringrate).[14,21,22]
[Link]
rootganglionthereisaphasicallyactivating,voltagedependentsodiumconductancealternatingwithapassive,voltage
independentpotassiumleak,[Link]
thresholdamplitude,ectopicfiringensues(Figure2).[23,24]
Figure2.
Baselineactivityandresponsestobrush,pressandpinchinonenormalandonediabeticwidedynamicrangeneuron.
TheRFsofthesetwospinothalamictractneuronsareindicatedintheshadedareaoftherathindpaw.
RF:Receptivefield.
Reproducedwithpermissionfrom[124].
AusefulanimalmodelofneuropathicpainthatinvolvesdysregulatedsodiumchannelexpressionindorsalrootgangliAbfibers
(seefortheglossary)onneuronsisstreptozotocininduceddiabetes.InthismodelsodiumchannelsNav1.3,Nav1.6andNav1.9
mRNAandproteinexpressionisupregulated,andNav1.8mRNAisdownregulated.[21,25,26]Wholecellpatchclamprecordings
demonstratedanincreaseinthepeakcurrentdensityandrampcurrentamplitude,consistentwithNav1.3,Nav1.6andNav1.7
channelupregulation,whichproducesrobustrampcurrents.[27]ThetypeIIIembryonicsodiumchannel(Nav1.3)probablyplaysa
[Link]
experimentalnerveinjuryitsexpressionmarkedlyincreases.[2830]Itrapidlyrecoversfrominactivationandhasslowclosedstate
inactivationkinetics,suggestingthatneuronsexpressingNav1.3mayexhibitchangesineitherreducedthresholdorarelatively
highfiringfrequency,orboth.[2830]
[Link].
Afibers:largemyelinatednerveafferentsorpathwaysthatconveynonnociceptiveinput(e.g.,tactilesensation)
Afibers:smallmyelinatednerveafferentsorpathwaysthatconveycoldandnociceptiveinput
Allodynia:painsensationinducedbyastimulusthatnormallydoesnotprovokepain,andthusimpliesachangein
thequalityofasensation
Blinkreflex:neurophysiologicaltoolforassessingtrigeminallargemyelinatedpathway
Cfibers:unmyelinatednerveafferentsorpathwaysthatconveythermalandnociceptiveinput
CatecholOmethyltransferase:enzymethatdegradescatecholaminessuchasdopamine,epinephrineand
norepinephrine
Centralsensitization:increasedbackgroundactivity,enlargedreceptivefieldandincreasedresponsestoall
afferentimpulsesofthesecondordernociceptiveneurons
Dysesthesias:spontaneous,nonconstantsensationsthatareclearlyunpleasant(e.g.,pinsandneedles)
Hyperalgesia:increasedpainresponsetoastimulusthatnormallyprovokespain(e.g.,thepinusedinneurological
examination)
Laserevokedpotentials:scalpsignalsevokedbylaserstimuli,whichselectivelyassessAafferentpathways
NerveConductionStudy:[Link]
assessesonlyAfibers
Paresthesia:spontaneous,nonconstantsensationsthatarenotclearlyunpleasant(e.g.,tingling)
Paroxysmalpain:sudden,veryshortlastingpains(e.g.,electricshocklike,stabbingsensations)
Peripheralsensitization:areductioninthresholdandanincreaseinresponsivenessoftheperipheralendsof
nociceptors.
Skinbiopsy:aminimallyinvasivetechniquethatassessesthedensityofintraepidermalfibers,whichmainlyconsist
ofCfibers
TRPV1:thetransientreceptorpotentialcationchannel,subfamilyV,[Link]
receptor,TRPV1isanonselectivecationchannelexpressedpredominantlyinunmyelinatedCfibers
Widedynamicrangeneurons:secondorderneuronslocatedinthespinalcorddorsalhorn,responsivetoall
sensorymodalities(thermal,chemicalandmechanical)andabroadrangeofintensityofstimulationfromprimary
afferentsm
Thesedata,togetherwithexperimentalandclinicalobservationsonthepartialeffectivenessofsodiumchannelblockingagentsin
neuropathicpain,establishedalinkbetweensodiumchannelactivityandprimaryafferenthyperexcitabilityproducingpain.[31]
RecentstudieshavelinkedgainoffunctionmutationsinSCN9A,thegenethatencodesNav1.7,totwohumaninheritedpain
syndromes,inheritederythromelalgiaandparoxysmalextremepaindisorder,whereaslossoffunctionmutationsinSCN9Ahave
beenlinkedtocompleteinsensitivitytopain.[32,33]
Althoughpotassiumchannelexpressionhasbeenstudiedlessthansodiumchannelexpressioninanimalmodelsofneuropathic
pain,[Link]
inpotassiumchanneltranscriptexpressioninthedorsalrootganglionafterperipheralnervelesions.[3436]Furthermore,
potassiumchannelopenersactasanalgesicsinanimalmodelsofneuropathicpain.[37,38]
Thedevelopmentandmaintenanceofperipheralsensitizationismodulatedbycytokines,smallproteinsinvolvedininflammatory
processes.VariousanimalexperimentsdemonstratethatperipheralnerveinjuryincreasesTNFandIL1immunoreactivityin
dorsalrootgangliaofbothinjuredanduninjuredipsilateraladjacentafferents.[39]Theincreasedcytokinelevelisassociatedwith
reducedmechanicalandthermalwithdrawalthresholdsinrats.[4044]EpineuriallyappliedTNFelicitedacutemechanical
hyperalgesiaintheawakerat[40]andantibodiesneutralizingtheTNFreceptorinjectedatthesiteofnerveinjuryreducepain
behaviorinmice.[41]ExogenousTNFinjectedintodorsalrootgangliaofdamagedrootsistransportedintothedorsalhorn,
precipitatingallodyniainboththeligatedandadjacentuninjurednerves.[42,43]Nervebiopsiesofpatientswithpainfulneuropathies
demonstratedhigherTNFimmunoreactivitiesinmyelinatingSchwanncellsandserumsolubleTNFreceptorlevelsarehigherin
patientswithcentrallymediatedmechanicalallodynia.[44]AnendogenousIL1receptorantagonist,experimentallyinjectedin
mice,preventsinflammatoryhyperalgesia,andantibodiesneutralizingIL1receptorsreducepainassociatedbehaviorinmice
withexperimentalnervedamage.[4547]Afterunilateralchronicconstrictioninjury,IL1alsoincreasesinthecontralateral
homolognerve.[48,49]ThisselectivecontralateralcytokineinductionisprobablymediatedbyNMDAreceptorsandreflectsaspinal
mechanism.
Peripheralsensitizationalsoinvolvestheupregulationofvariousproteins,someofthemonlymarginallyexpressedunder
[Link]
(TRP)[Link]
forsensorysignalingintheperipheralnervoussystem.Severalanimalstudiesinvestigatedtheroleofthevanilloidreceptor1
(TRPV1),amemberoftheTRPfamily,inthedevelopmentofneuropathicpain.[5053]Totalorpartialsciaticnervetransection,or
spinalnerveligation,reduceTRPV1expressioninthesomataofalldamageddorsalrootganglia.[5053]Followingpartialnerve
lesionorspinalnerveligation,TRPV1expressionisgreaterintheundamageddorsalrootganglionsomatathanincontrols.[5053]
EvidencethathyperalgesiadoesnotdevelopinTRPV1deficientmiceandthatTRPV1antagonistsreducepainbehaviorinmice
afterspinalnerveligationfurthersupportstheideathatTRPV1playsacrucialroleinthedevelopmentofneuropathicpain.[5053]
[Link]
thedorsalrootganglioncellbodythesesignalsubstancesmodifygenetranscriptionandproteinsynthesis.[54,55]Afternerve
damage,[Link],nervedamage,throughcomplexsignalingmechanisms
(cAMPdependentPKAandCa2+/phospholipiddependentPKC)[Link]
afternervedamage,thereisaninductionofcjun,p38andERK.[5660]Theencodedproteinsofthesegenesareinvolvedin
inflammatoryresponses,neuronaldegenerationandneuronalplasticity,whichmaintainpainsensation.[14,5660]Therefore,the
importanceofgeneticfactorsinneuropathicpainremainsaninterestingquestionforfurtherresearch,especiallyfortheirpossible
useastargetsfornew,moreselectivedrugs.
Inaccordancewithfindingsfromanimalstudies,microelectroderecordingsfromtransectednervesinhumanamputeeswith
phantomlimbpain,displayedspontaneousafferentactivity(i.e.,peripheralsensitization).Inthesepatients,tappingtheneuroma
increasespainandafferentdischarges.[61]Theinjectionoflidocaineintotheneuromablocksnerveactivityowingtothetapofthe
neuromaanditsrelatedpain.[16]Bycontrast,perineuromalinjectionofgallamine,apotassiumchannelblocker,increasespain.
[62]Someinvestigatorsdemonstratedaninverserelationshipbetweenongoingpainandheatpaindeficitinpatientswith
postherpeticneuralgia.[63]Inthesepatients,lidocaineappliedtothepainfulskininpatientswithpostherpeticneuralgiaproduces
effectivepainrelief.[64]Microneurographicstudiesdemonstratedthatinpatientswithperipheralneuropathies,painisassociated
withongoingspontaneousfiringofunmyelinatedCfibers.[6567]
CentralSensitization
Despitetheincreasingevidenceunderlyingtheimportanceofperipheralsensitization,manyinvestigatorsconsidercentral
sensitizationthemainpathophysiologicalmechanismresponsibleforneuropathicpain.[14,6870]Theprimaryafferentpathways
[Link]
nociceptivespecificneuronsandwidedynamicrangeneurons.[71,72]Nociceptivespecificneuronsarelocatedintheouterlayers
(laminaeIII)ofthedorsalhornwidedynamicrangeneuronslieindeeperlaminae(mostoflaminaVneuronsarewidedynamic
neurons).[Link]
neuronsexcitedbothbynoxiousandnonnoxiousstimuli,receivebothlargemyelinatedAfibersaswellasAandCfibers.
Widedynamicrangeneuronscanencodeandprojectdifferenttypesofsensoryinformation,nociceptiveandnonnociceptive,
varyingtheirfiringrate(higherfornoxiousandlowerfornonnoxiousstimuli).Nociceptiveneuronshaveafairlylocalizedreceptive
[Link],sincewidedynamicrangeneurons
havealargereceptivefieldandastimulusresponsefunction(thehigherthestimulusintensity,thehigherthefiringrateoftheir
output),theirmainfunctionistodetectanddiscriminatetheintensityofnoxiousstimuli.[73,74]
Animalstudiesdemonstratedthatafternervedamage,owingtotheongoingspontaneousactivityarisingfromprimarynociceptors
(peripheralsensitization),backgroundactivityinsecondordernociceptiveneuronsincreases,receptivefieldsenlargeand
responsestoafferentimpulses,includinginnocuoustactilestimuli,increase(Figure2).Inthispathologicalcondition,Alow
thresholdmechanoreceptorscanactivatesecondordernociceptiveneurons,thusgainingaccesstothepainsignalingpathway.
Thisphenomenonistermedcentralsensitization.[4,16,68,75]Centralsensitizationhasbeendocumentedinanimalsandmay
explainpersistentneuropathicpaininpatients.[14,69,70]
[Link],
thecentralterminalsofprimarynociceptiveafferentsinthedorsalhornofthespinalcordreleasetheneurotransmittersglutamate
andsubstanceP,[Link],themajorexcitatoryneurotransmitter
foundthroughoutthewholenervoussystem,[Link]
releaseglutamateinresponsetoacuteandpersistentnoxiousstimuli,andthroughAMPacid(AMPA)receptoractivation,setthe
[Link]
[Link]
[Link]
normalphysiologicalconditionsthemagnesiumion(Mg2+)levelsfoundinnervoustissuesblockthereceptor'sionchannel.A
sustainedmembranedepolarizationisrequiredtoactivateandopentheNMDAreceptorchannel.[72]Thecontactbetween
neurotransmittersandreceptorsproduceanincreaseofintracellularCa2+andcAMPconcentrations,whichactivatesprotein
[Link](i.e.,cfos,cjun).[69,76]
Likeperipheralsensitizationinneuropathicpain,recentstudiesdemonstratethatcentralsensitizationarisesalsothroughchanges
[Link],
[Link],experimental
[Link]
ordernociceptiveneuronsandpain.AntisenseknockdownofNav1.3reducessecondordernociceptiveneuronalhyperexcitability
andpainbehaviorinspinalcordinjuredrats.[77,78]Severallinesofevidencesuggestthatthemechanismsunderlyingcentral
sensitizationatthedorsalhornlevelalsoinvolvemolecularmechanismsotherthansodiumchannels,forexample,prostaglandins
andcytokines,theproinflammatorysubstancesthatfacilitatepaintransmission.[14,22,79]
Althoughmostinvestigatorsconsidercentralandperipheralsensitizationasthemainmechanismsunderlyingneuropathicpain,
peripheralnervedamagealsoleadstoothercentralchanges.[79]Forexample,mildafferentsignallossmightinducemajor
[Link],theinterneuronsthatinhibitnociceptiveneurons
becomehypoactive(lossofafferentinhibition).[80]Earlierresearchsuggestedchangesinthedescendingmodulatorysystems[81]
subsequentlyconfirmedbytheefficacyofserotoninandnoradrenalinreuptakeblockingantidepressantsinneuropathicpain.[14]
Duringmassivedeafferentation,afterpresynapticterminalbuttonsarelost,thepostsynapticreceptorsonspinothalamictract
(STT)neuronsbecomeexposedtoneurotransmitters,andSTTneuronsbegintofirespontaneously(deafferentation
supersensitivity).[14]
[Link],includingmicrogliaandastrocytes,arenon
[Link],releasemediatorsthatmodulate
neuronalactivityandalteraxonalanddendriticgrowth.Undernormalconditionstheyaccountfor70%ofCNScells.[82]Several
linesofevidenceindicatethatspinalcordmicrogliaandastrocytesareimplicatedincreatingexaggeratedpainstates.[8387]Glial
cellsplayacrucialroleinmaintainingneuronalhomeostasisintheCNSandimmunefactorsproducedbymicrogliaarebelieved
[Link]
underneuropathicpainconditionsinducesthereleaseofproinflammatorycytokinesandothersubstancesthatfacilitatepain
transmission.[8387]GlialcellsalsoenhancethereleaseofsubstancePandexcitatoryaminoacidsfromnerveterminals,
includingprimaryafferentsinthespinalcord.[83,84]Glialcellactivationcanalsoleadtoalteredopioidsystemactivity.[8587]
Duringstrongneuronalexcitation,suchasthatinducedbyneuropathicpain,fractalkine,aproteinexpressedbyneurons,breaks
free.[88]Thesolubleportionoffractalkinediffusesawayandbindstoandactivatesglialcells.[89]Intrathecalfractalkinecreates
boththermalhyperalgesiaandmechanicalallodynia,andfractalkinereceptorblockadeblocksinflammatoryneuropathyinduced
pain.[90]
MechanismbasedSymptoms
Atthebedsideexamination,neuropathicpaincanbeendistinguishedfromspontaneouspain,(i.e.,stimulusindependent)and
provokedpain.[70][Link]
(usuallysuperficialburningordeeppressingpain,orboth),andparoxysmalpain(electricalshocklike,stabbingpain).[79,91]
Provokedpainincludesallodynia,paininresponsetoanormallynonpainfulstimulus,andhyperalgesia,anincreasedresponseto
[Link],unlikeanimalstudies,neuropathicpainmechanismsinhumansremainlargelyunclear
currentclinicalandneurophysiologicalresearchhasproposedvariousmechanismsforeachtypeofpain.
Ausefulwaytodrawparallelsbetweensymptomandmechanismistocombinepatients'sensoryprofiles,obtainedbyspecific
questionnairessuchastheNeuropathicPainSymptomInventory(NPSI),usingdataobtainedwithneurophysiologicaltools(blink
reflex,nerveconductionstudiesandlaserevokedpotentials).
Patientswithneuropathicpainsyndromestypicallydescribetheirpainasconstantandburning.Inagroupof150patientswith
varioustypesofpolyneuropathy(68withneuropathicpain)approximately90%complainedofburningpain.[92]Previous
neurophysiologicalstudiesdemonstratedthatinpatientswithvariousneuropathicpainconditions(postherpeticneuralgia,carpal
tunnelsyndromeandpolyneuropathy)burningpainisassociatedwithnociceptivepathwaydamageasassessedbylaserevoked
potentialrecordings(Figure3).[9294]Microneurographicstudiesdemonstratedthatinpatientswithperipheralneuropathiesthe
spontaneousburningpainwasassociatedwiththeongoingspontaneousfiringofCfibers.[6567]Skinbiopsystudiesdescribed
reducedintraepidermalnociceptiveterminalsinpatientswithongoingpainrelatedtoperipheralneuropathy.[95,96]Thesedata
suggestthatongoingburningpainisprobablyduetotheabnormalspontaneousactivityoriginatingindamagednociceptivefiber
[Link]
fromaxonalsprouts,aconcurrentmechanismmightincludelongtermCNSchangesprovokedbynociceptivepathwaydamage,
suchashyperactivityinthesecondorderneurons(centralsensitization).[22,97]Arecentmicroneurographicstudyprovidednew
evidenceofaspecificCfibersetthathaveabimodalthermoreceptivepropertiesandareactivatedbycooling,heatingand
menthol.[98]ActivityofthisspecificsetofCfiberscouldberesponsibleforthestinging,hotandburningsensationsevokedby
innocuouscoldstimuli.[99][Link]
patientswithpostherpeticneuralgia,theongoingburningpainisassociatedwithasevereheatpaindeficit,thussuggestinga
[Link]
neuralgiatodetermineCfiberactivity,demonstratinganabolishedresponseintheareaofmaximumpain.[16]Ongoingburning
painfrequentlymanifestassequelaerelatedtodeafferentation,[Link]
spinalneuronactivityinapatientwithinjurytothedorsalrootsofthecaudaequinadisclosedhighfrequency,regularand
paroxysmalburstingdischarges.[16]Thepatientsufferedfromspontaneousburningpaininaregionwherethelesionhadcaused
anesthesia(anaesthesiadolorosa).
Figure3.
Correlationsbetweentheseverityofongoingburningpainandlaserevokedpotentialabnormalitiesinvarious
neuropathicpainconditions.(A)[Link].
(B)40patients(75hands)[Link](mediannerveterritory).(C)150patientswith
[Link],themoreabnormaltheLEPs,changesthatreflect
nociceptivepathwaydamage.
LEP:Laserevokedpotential.
Previousneurophysiologicalstudiesinpatientswithpostherpeticneuralgiaandcarpaltunnelsyndromedemonstratedthat
paroxysmalpainisassociatedwithabnormalitiesinvolvingnonnociceptiveAfibers.[93,94]Morespecifically,inpatientswith
postherpeticneuralgiaandcarpaltunnelsyndrome,thecorrelationbetweentheblinkreflexdelayandmediannervesensory
conductionvelocityslowing,[Link]
studiesinanimalsdescribingspontaneousectopicdischargesrecordedinlargemyelinatedAfiberaxonsafternerveinjuries,
[9,100,101][Link]
thesehighfrequencyburstsindemyelinatedAfibersaresufficienttoprovokepainperseordosoonlyafterephaptic
transmissiontotheneighbouringunmyelinatedCfibers,orbyinvolvingwidedynamicrangeneurons.[94]Althoughmost
investigatorsconsiderparoxysmsasperipheralphenomenarelatedtospontaneousfiring,aclinicalstudyprovidedevidencethat
paroxysmalpainisassociatedwithdecreasedsmallfiberfunction,thusraisingthepossibilitythatparoxysmsoriginatecentrallyin
thesecondorderneurons.[102]
Nogeneralagreementexistsregardingthepathophysiologicalmechanismunderlyingallodynia.[18]Twoopposingviewscurrently
exist,oneperipheral[67,103]andtheothercentral.[104]Accordingtosomeinvestigators,allodyniareflectsperipheralsensitization.
[105]Overthepastdecades,apossibleroleforhyperexcitableperipheralnociceptorsasprimarydeterminantsofpaininhumans
[Link]
relatedtoCnociceptorfiring.[67]Arecentstudyinpatientswithpolyneuropathyfoundthatallodyniawasassociatedwitharelative
sparingofnociceptivefibers,asassessedwithlaserevokedpotentials.[92]Thesefindingssuggestthatallodyniareflectsan
abnormalreductioninthemechanicalthresholdinsensitizedperipheralnociceptors.[79,92,106]
Accordingtomanyinvestigators,allodyniaisgeneratedatacentrallevel.[16,18]Thespontaneousfiringindamagednociceptive
afferentsmayevokeongoingpainand,asasecondaryeffect,sensitizecentralnociceptiveneurons.[68,107109]Asaresult,a
largeskinareasurroundingtheinitiallesionsitemaybecomehypersensitivetolighttouch(i.e.,allodynia).Microneurographic
studiesdemonstratedthatallodyniaismediatedbylargemyelinatedAfiberlowthresholdmechanoreceptors.[110]Inchronic
neuropathicpain,differentialnerveblocksdemonstratethatallodyniaisabolishedconcomitantlywithlossofinnocuoustactile
sensationatatimewhenAandCfibermediatedmodalitiesareunaffected.[107,111]Inpatientswithneuropathicpain,a
selectiveAfiberblockeliminatesallodynia[107,112]butongoingburningpainpersists,indicatingthatitismediatedbyC
nociceptors.[16]Centralsensitizationasthemainmechanismunderlyingallodyniaalsoreceivessupportfromthelinkbetweenthis
painsymptomandabnormalpainsummationonrepetitivemechanicalstimulation,asignofcentralsensitization.[16]Future
researchefforts,designedtotranslatemechanismsintosymptoms,shouldthereforeseekmoreinformationtoclarifythe
peripheralmechanismsunderlyingneuropathicpain.
SensoryProfiles
Patientsexperiencingneuropathicpainsufferfromsensorydeficits,aswellasvarioustypesanddifferentcombinationsofpain.
Neuropathicpainmaybeongoing(e.g.,burningandpressing),paroxysmalpain(e.g.,stabbingandelectricshocklikesensations)
orpainprovokedbyvariousstimuli(e.g.,gentlebrushing[allodynia]orcoldwater[coldallodynia]).Specifictypesofpainmay
predominateinsomeneuropathicpainconditionsbutnoneofthemareetiologicspecific.[113,114]Thus,patientssufferingfromthe
[Link],theaimofdiagnosticworkup
shouldbetodefinespecificsensoryprofilesthroughclinicalexamination,questionnairesdedicatedtoneuropathicpainand
laboratorytools.
Currentresearchfindingsstronglyindicatethatthedifferentprofileofsensorysignsandsymptoms,(includingprovokedpainand
spontaneouspain)[Link],neurophysiologicalandneuropathological
investigationsshowthatinpatientswithperipheralneuropathyofvariousetiologies,spontaneousburningpainisinvariablyrelated
tothenociceptivepathwaydamage.[9295]Bycontrast,recentneurophysiologicalstudiessuggestthatspontaneousparoxysmal
painreflectsdemyelinationofnonnociceptive,largemyelinatedfibers(asdescribedpreviously).[93,94]Overall,thesefindings
suggestthatneuropathicpaincanbeclassifiedbysensoryprofiles(qualityofpain)ratherthanetiology,astherecentEuropean
guidelinesrecommend.[115]Classifyingneuropathicpainaccordingtoamechanismbasedratherthananetiologybased
approachmightminimizepathophysiologicalheterogeneitywithinthegroupsunderstudyandthushelpintargetingtherapytothe
individualpatient.
GeneticInheritanceofNeuropathicPain
Becausenotallpatientswithnerveinjuryexperienceneuropathicpain,theheritablepredispositionforneuropathicpainprobably
[Link],[116]
hencegeneticriskfactorsareprobablyimportantinthevariousclinicalneuropathicpainconditions.[117]
[Link],Fabry
diseaseisarareXlinkedrecessive(inherited)lysosomalstoragediseasethatcausespainfulneuropathy.[118]Gainoffunction
mutationsinSCN9A,thegenethatencodesNav1.7,causetwoextremelyrareinheritedneuropathicpainconditions,
erythromelalgiaandparoxysmalextremepaindisorder.[32]Intheserareconditionstraditionalgenetictechniquescanbeapplied
[Link],becausethenervoussystemdiseasesthatmostcommonlycauseneuropathicpainare
sporadic,neitherfamilyhistorynorclassicgenetictechniquescanbereliedupontoevaluatetheheritablesusceptibilitytothis
[Link],thegeneticriskofdevelopingneuropathicpainafternervoussystemdamageresultsfrommultiplerisk
[Link],Costiganandcolleagues(2010)
investigatedasinglenucleotidepolymorphismassociationofthepotassiumchannelsubunit,KCNS1,inhumanswith
neuropathicpain.[117]Theyfoundthatacommonaminoacidchangingallele,the'valineriskallele',wassignificantlyassociated
[Link]
dysfunctionaltemporomandibularjointdisorderpain.[119,120]Arecentstudydemonstratedthatasinglenucleotidepolymorphism
inSCN9AincreasedfiringfrequencyofDRGneuronsthissinglenucleotidepolymorphismwassubsequentlyshowntobe
associatedwithchronicpain.[121,122]Therefore,indefiningsensoryprofilesweneedtotakeintoaccounttheincreasingevidence
[Link]
analysisamongthemoreconventionaldiagnostictools.
Conclusion
[Link]
[Link]
afteraperipheralnerveinjury,spontaneousactivitydevelopsindamagedaxons,excitabilitybecomesabnormalandsensitivityto
chemical,thermalandmechanicalstimuliincreases,[Link]
activityarisingfromprimaryafferents,backgroundactivityinsecondordernociceptiveneuronsincreases,receptivefieldsenlarge
andresponsestoallafferentimpulsesincrease,resultinginthedevelopmentofcentralsensitization.
Althoughanimalmodelshelptounderstandthemechanismsresponsibleforneuropathicpain,theypoorlyreflectclinical
[Link],[Link],differentpathophysiological
mechanismsareresponsibleforthedevelopmentofneuropathicpainthatmanifestswithheterogeneoussensorydisturbances.
Althoughspecifictypesofpainmaypredominateinsomeetiologicalcategoriesofneuropathicpain,noneofthemareetiology
[Link],regardlessofthedisease,patientssufferingmaypresentwithheterogeneoussensorysignsandsymptoms,even
[Link]
accordingtoamechanismbased,ratherthananetiologybased,approachandtargetingtherapytotheindividualpatient.
FuturePerspective
[Link]
changethewayweclassify,[Link]
clinicalpractice,thediagnosticworkupshouldaimatdefiningspecificsensoryprofiles,thustargetingtherapytotheindividual
[Link]
basedtherapy,clinicalexperimentalstudiesindicatethataspecificsymptommightbegeneratedbyseveralentirelydifferent
underlyingpathophysiologicalmechanisms,[Link]
[Link]
involvedinneuropathicpainconditionsmighthelpusintargetingnovelanalgesicsandbiomarkersofneuropathicpain.
Sidebar
ExecutiveSummary
MechanismsUnderlyingNeuropathicPain
ElectrophysiologicalrecordingsdemonstratethattheregeneratingCfibersofdamagedaxonsdevelopongoing
spontaneousactivity,abnormalexcitabilityandanincreasedsensitivitytochemical,[Link]
phenomenonistermedperipheralsensitization.
Followingnervedamage,asaconsequenceoftheperipheralsensitization,secondordernociceptiveneuronsdevelopan
increasedbackgroundactivity,[Link]
istermedcentralsensitization.
MechanismbasedSymptoms
Neuropathicpainmaybeongoing(e.g.,burningpain),paroxysmal(e.g.,electricalshocklikesensations)orprovokedby
[Link].
Burningpainprobablyreflectstheabnormal,spontaneousactivityoriginatingindamagednociceptivefiberaxons.
ParoxysmalpainmayberelatedtohighfrequencyburstsgeneratedindemyelinatedAfibers.
Allodyniamaybeduetoaperipheralmechanism,reflectinganabnormalreductionofthemechanicalthresholdin
sensitisednociceptors,ortoacentralmechanism,reflectingthesensitizationofcentralnociceptiveneuronsto
mechanicallyevokedinput.
[Link]
aimatfindingspecificsensoryprofilesthroughclinicalexamination,questionnairesdedicatedtoneuropathicpainand
laboratorytools.
Aclassificationpersensoryprofileratherthanetiologymightminimizepathophysiologicalheterogeneityandincreasethe
powertodetectapositivetreatmentresult.
GeneticInheritanceofNeuropathicPain
Reasonably,thegeneticriskofdevelopingneuropathicpainafternervoussystemdamageresultsfrommultiplerisk
conferringgenes.
FuturePerspective
Anincreasedknowledgeofthemechanismsunderlyingpainandtheirtranslationintosignsandsymptomsinpatients
mightleadtoanoptimaltherapeuticapproach,withdrugsthataddressthespecificcombinationofmechanismsoccurring
ineachpatient.
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Papersofspecialnotehavebeenhighlightedas:
ofinterest
ofconsiderableinterest
Financial&competinginterestsdisclosure
ATruinihasbeenaconsultantforthefollowingcompanies:BoehringerIngelheim,EliLilly,Pfizer,MundipharmaandGrunenthal.
GCruccuhasbeenaconsultantforthefollowingcompanies:BoehringerIngelheim,EliLilly,[Link]
havenootherrelevantaffiliationsorfinancialinvolvementwithanyorganizationorentitywithafinancialinterestinorfinancial
[Link],consultancies,honoraria,
stockownershiporoptions,experttestimony,grantsorpatentsreceivedorpending,orroyalties.
Nowritingassistancewasutilizedintheproductionofthismanuscript.
FutureNeurology.20116(4):497509.2011FutureMedicineLtd.
