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ReviewGliaandpain:IschronicpainagliopathyRu-RongJia,,TemuginBertaa,MaikenNedergaardbaDepartmentofAnesthesiologyandNeurobiology,DukeUniversityMedicalCenter,Durham,NC,USAbDivisionofGlialDiseaseandTherapeutics,CenterforTranslationalNeuromedicine,UniversityofRochester,Rochester,NY,USAarticleinfoArticlehistory:Received27July2012Receivedinrevisedform23May2013Accepted12June2013AvailableonlinexxxxKeywords:AstrocytesATPreceptorsChemokinesCytokinesHumanMicrogliaRodentsSatelliteglialcellsSpinalcordabstractActivationofglialcellsandneuro–glialinteractionsareemergingaskeymechanismsunderlyingchronicpain.
Accumulatingevidencehasimplicated3typesofglialcellsinthedevelopmentandmain-tenanceofchronicpain:microgliaandastrocytesofthecentralnervoussystem(CNS),andsatelliteglialcellsofthedorsalrootandtrigeminalganglia.
Painfulsyndromesareassociatedwithdifferentglialactivationstates:(1)glialreaction(ie,upregulationofglialmarkerssuchasIBA1andglialbrillaryacidicprotein(GFAP)and/ormorphologicalchanges,includinghypertrophy,proliferation,andmodi-cationsofglialnetworks);(2)phosphorylationofmitogen-activatedproteinkinasesignalingpathways;(3)upregulationofadenosinetriphosphateandchemokinereceptorsandhemichannelsanddownreg-ulationofglutamatetransporters;and(4)synthesisandreleaseofglialmediators(eg,cytokines,che-mokines,growthfactors,andproteases)totheextracellularspace.
Althoughwidelydetectedinchronicpainresultingfromnervetrauma,inammation,cancer,andchemotherapyinrodents,andmorerecently,humanimmunodeciencyvirus-associatedneuropathyinhumanbeings,glialreaction(acti-vationstate1)isnotthoughttomediatepainsensitivitydirectly.
Instead,activationstates2to4havebeendemonstratedtoenhancepainsensitivityviaanumberofsynergisticneuro–glialinteractions.
Glialmediatorshavebeenshowntopowerfullymodulateexcitatoryandinhibitorysynaptictransmis-sionatpresynaptic,postsynaptic,andextrasynapticsites.
Glialactivationalsooccursinacutepaincon-ditions,andacuteopioidtreatmentactivatesperipheralgliatomaskopioidanalgesia.
Thus,chronicpaincouldbearesultof''gliopathy,''thatis,dysregulationofglialfunctionsinthecentralandperiph-eralnervoussystem.
Inthisreview,weprovideanupdateonrecentadvancesanddiscussremainingquestions.
2013InternationalAssociationfortheStudyofPain.
PublishedbyElsevierB.
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Allrightsreserved.
1.
IntroductionItisnowwellestablishedthatchronicpain,suchasinamma-torypain,neuropathicpain,andcancerpain,isanexpressionofneuralplasticity,bothintheperipheralnervoussystem(PNS)asperipheralsensitization[11,78]andinthecentralnervoussystem(CNS)ascentralsensitization[111,139].
Themostwidelystudiedneuronalmechanismsarehyperexcitabilityandsensitizationofprimarysensoryneurons(peripheralsensitization)andenhance-mentofexcitatorysynaptictransmissioninspinalcord,brainstem,andcorticalneurons(centralsensitization),causedbytranscrip-tional,translational,andpost-translationalregulation.
Otherneu-ronalmechanismsincludedisinhibition(reducedinhibitorysynaptictransmission),descendingpathwayfacilitation(eg,fromthebrainstemtothespinalcord),andlong-termpotentiation(LTP)inthecortexandspinalcord.
Theseneuronalmechanismshavebeenstronglyimplicatedinthedevelopmentandmainte-nanceofpersistentpaininrodents[11,142,195,205,317].
CentralsensitizationandLTParealsoinvolvedinhumanpainconditions[134,285].
Inparalleltotheprogressintheseneuronalmecha-nismsistheincreasedrecognitionoftheimportanceofnon-neuro-nalcells,especiallyglialcells,intheinitiationandmaintenanceofchronicpain.
Ofnote,overthelast10years,theeldofpainre-searchhaswitnessedadramaticincreaseinthenumberofpubli-cationsstudyinggliaandpain.
Numerousreviewshavebeenpublishedinhigh-impactjournalstoaddressthistopic[24,52,68,80,160,164,200,209,247,273].
Hereweprovideacom-prehensiveandupdatedreviewofgliaandpainbyintegratingre-centadvancesinboththepainandglialresearchelds.
GlialcellsintheCNSconsistof3majorgroups:astrocytes,microglia,andoligodendrocytes[69].
GlialcellsinthePNScon-sistofsatelliteglialcells(SGCs)inthedorsalrootganglia(DRGs)andtrigeminalganglia(TGs)andSchwanncellsintheperipheralnerves.
Thisreviewwillcover3typesofglia—microglia,0304-3959/$36.
002013InternationalAssociationfortheStudyofPain.
PublishedbyElsevierB.
V.
Allrightsreserved.
http://dx.
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org/10.
1016/j.
pain.
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022Correspondingauthor.
Address:DepartmentofAnesthesiology,DukeUniversityMedicalCenter,595LaSalleStreet,GSRB-I,Room1027A,P.
O.
Box3094,NC27710,USA.
Tel.
:+1(919)6849387;fax:+1(919)6842411.
E-mailaddress:ru-rong.
ji@duke.
edu(R.
-R.
Ji).
PAINxxx(2013)xxx–xxxwww.
elsevier.
com/locate/painPleasecitethisarticleinpressas:JiR-Retal.
Gliaandpain:IschronicpainagliopathyPAIN(2013),http://dx.
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022astrocytes,andSGCs—astheirrolesinpainregulationarewelldocumented.
1.
1.
MicrogliaMicrogliaaremacrophage-likecellsintheCNSthatoriginatefrombonemarrow-derivedmonocytesthatmigrateduringperina-taldevelopment.
TheyareheterogeneouslydistributedthroughouttheCNS.
Undernormalconditions,microgliaarenotasquiescentasmanyinvestigatorsoriginallythought,asithasbeenshownthatmicrogliaactivelysensetheirenvironmentwiththeirramiedpro-cesses[93,175,199].
Notably,microgliadynamicallyinteractwithsynapsestomodulatetheirstructuresandfunctionsinhealthybrain[246].
Duringdevelopment,microglialprocessescanengulfsynapses,andsynapticpruningbymicroglia,whichinvolvestheactivationofthecomplementsystem,isnecessaryfornormalbraindevelopment.
[186,221].
Microgliaarefurtheractivatedaftervariousinsultssuchasnerveinjury,bydisplayingmorphologicalchanges,suchasachangefromramiedtoamoeboidshape[57]andupregulationofmicroglialmarkers(CCR3/CD11b,majorhistocompatibilitycom-plexII[MHCII],andionizedcalcium-bindingadaptormolecule-1[IBA1])[93,227](Table1).
Afterperipheralnerveinjury,microgliainthespinalcordundergorapidproliferation[14,23,55,151],andthisproliferationisalreadyveryprominent2daysaftersparednerveinjury[227].
Numerousstudieshavedemonstratedacriticalroleofmicrogliainthedevelopmentofneuropathicpain[43,113,197,252],aswellasacuteinammatorypain[229,311].
Minocycline,anonselectiveinhibitorofmicroglia,hasbeenshowntoreduceneuropathicpain,inammatorypain,andpostoperativepain[13,86,100,197],butitsroleinreducingtheestablishedlate-phaseneuropathicpainislim-ited[197].
Importantly,recentprogresshasidentiedalargenum-berofmoleculesthatareinducedinmicrogliaafterpainfulinjuries,especiallynervetrauma(Tables1–4).
1.
2.
AstrocytesAstrocytesarethemostabundantcellsintheCNSandwerehis-toricallyregardedassupportcells.
Workoverthepastdecadeindi-catesthatastrocytesplaymultipleactiverolesinacuteandchronicneuronaldiseasessuchasseizure,stroke,andischemia[133].
Un-likemicrogliaandoligodendrocytes,astrocytesformphysicallycouplednetworksmediatedbygapjunctions,which,amongotherfunctions,facilitateintercellulartransmissionofCa2+signalingandexchangeofcytosoliccontents,anddisplayoscillationsinionper-meabilitythroughastrocyticnetworks.
Gapjunctioncommunica-tionismediatedbyhomo-andheteromericassociationsofhemichannels,suchasconnexin-43(Cx43),thepredominantconn-exinexpressedinastrocytes[27].
Althoughastrocytesaretypicallyimmunelabeledbyglialbrillaryacidicprotein(GFAP),GFAPimmunoreactivitylabelsonlymajorbranchesandprocessesofastrocytes.
TheactualterritoryoccupiedbyanastrocyteismuchlargerthanthatrevealedbyGFAPimmunostaining.
Ofnote,eachastrocyteformsanon-overlappingterritoryordomain[106,133],whichcollectivelyresemblealatticeframework,appearingcrystal-lineinnature.
Althoughtheimplicationsofthisorganizationarenotfullyunderstood,itbecomeslostwhenastrocytestransitiontoreactivestates[181].
Inaddition,astrocyteshaveextensivecon-tactswithbothsynapsesandcerebralbloodvessels,andcontroltheincreaseinbloodowevokedbysynapticactivity.
Theastro-cyte-mediatedbloodowincreaseisfundamentaltotheblood-oxygen-level-dependent(BOLD)signaldetectedbyfunctionalmagneticresonanceimaging(fMRI)[106].
Itisestimatedthatasingleastrocytecanenwrap140,000syn-apsesand4to6neuronalsomata,andcancontact300to600neu-ronaldendritesinrodents.
[22,69,180].
Aclosecontactwithneuronsandsynapsesmakesitpossibleforastrocytesnotonlytosupportandnourishneuronsbutalsotoregulatetheexternalchemicalenvironmentduringsynaptictransmission.
Thegrowingappreciationforactiverolesofastrocyteshasledtotheproposalofa''tripartitesynapse''theory,basedonthefactsthat(1)gliarespondtoneuronalactivitywithanelevationoftheirinternalCa2+concentrationandtriggerthereleaseofchemicaltransmittersfromgliathemselves,and(2)glialtransmitterscausefeedbackregulationofneuronalactivityandsynapticstrength.
Table1Distinctreactionofmicroglia,astrocytes,andsatelliteglialcells(SGCs)indifferentpainconditions,asexaminedbyupregulationoftheglialmarkersIBA1,CD11b,andglialbrillaryacidicprotein(GFAP).
PainconditionsMicrogliaAstrocytesSGCsNerveinjury%%%Spinalcordinjury%%Pawincision%%InammationM/%%%Jointarthritis%%%BonecancerM/%%%SkincancerM%ChemotherapyM/%%%Diabetes%%HIVneuropathyM%Chronicopioid%%AcuteopioidMM%Detailed,withrelatedreferences,inSection2.
1.
Symbols:Right-upwarddiagonalarrow(%)denotesupregulation;right&lefthori-zontalarrow(M)denotesnoregulation;right-downwarddiagonalarrow(&)denotesdownregulation.
Table2Phosphorylationofmitogen-activatedproteinkinases(MAPKs;ERK,p38,JNK,ERK5)inmicroglia,astrocytes,andsatelliteglialcells(SGCs)indifferentpainconditions.
PainconditionsMicrogliaAstrocytesSGCsNerveinjuryP-ERK%%%P-p38%%P-JNK%P-ERK5%SCIP-ERK%P-p38%PawincisionP-p38%InammationP-ERK%%P-p38%P-JNK%BonecancerPERK%%P-p38%P-JNK%SkincancerP-JNK%DiabetesP-ERK%P-p38%ChronicopioidP-ERK%P-p38%Detailed,withrelatedreferences,inSection2.
2.
SCI=spinalcordinjury.
Symbols:Right-upwarddiagonalarrow(%)denotesupregulation;right&lefthori-zontalarrow(M)denotesnoregulation;right-downwarddiagonalarrow(&)denotesdownregulation.
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022Accordingtothistheory,astrocyticprocessesareactivecomponentsofsynapses,inadditiontopre-andpost-synapticcomponents[7].
Althoughactivecontributiontosynapticactivityremainsapossibility,severalrecentstudieshavechallengedthetheoryofthetripartitesynapse,bydemonstratingthatalterationsinastrocyticCa2+donotmodulatesynaptictransmission[4,172,193].
Inreviewingtheseconclusions,however,itisimportanttonotethatmostoftheclassicalstudiesofthetripartitesynapsearebasedonelectrophysiologicalanalysisofacuteslicespreparedfromrodentpups.
Sincetheexpressionofmembraneproteinsaswellasneuralcircuitsundergosignicantchangesduringdevelopment[16,61],itispossiblethattheconceptofreceptor-mediatedCa2+signalingasakeyfeaturedeningastrocyticparticipationinhigherneuralfunctionwillbeexpandedtoincludeotherintracellularsignalingpathways.
Ofnote,gluta-mate-dependentneuroglialCa2+signalingdiffersbetweentheyoungandadultrodentbrain[223].
Thus,alternativepathwaysforastrocyticmodulationofsynaptictransmissionexist:1oftheessentialhousekeepingdutiesofastrocytesistomaintainpotassiumhemostasis.
Recently,ithasbeenshownthatreceptor-mediatedincreasesinastrocyticCa2+canmodulateneuralnetworkactivitybyactiveuptakeofextracellularK+[263].
BecausetheextracellularconcentrationofK+isanimportantdeterminantoftherestingmembranepotentialandtherebyofneuronalactivity,activeuptakeofK+representsasimpleyetpowerfultoolforrapidmodulationofneuralnetworks.
Studiesusingastroglialtoxins(eg,urocitrateanda-aminoadi-pate),astroglialaconitaseinhibitor(sodiumuoroacetate),orinhibitorsoftheastroglialenzymeglutaminesynthetase(eg,methioninesulfoximine)inadultanimalssuggestthatastrocytesareimportantbothfortheinductionandmaintenanceofinamma-toryandforneuropathicpain[30,31,69,83,110,161,184,200,272].
Proliferationofspinalcordastrocyteshasbeendemonstratedinmodelsofneuropathicpain,suchasrhizotomy[151]andspinalnerveligation[248].
Conversely,inhibitingastrocyteproliferationinthespinalcordwasshowntoreduceneuropathicpain[248].
1.
3.
SatelliteglialcellsSatelliteglialcells(SGCs)areprominentglialcellsinthePNS.
Theyarefoundnotonlyinsensoryglia(DRGsandTGs)butalsoinsympatheticandparasympatheticganglia.
LikeSchwanncells,SGCsarederivedfromneuralcrestcells.
SGCsarecharacterizedbythincellularsheathsthatsurroundtheindividualneurons.
Theyexhibitmanysimilaritiestoastrocytes:(1)bothexpresstheglialmarkersGFAP,S100,andglutaminesynthetase;and(2)bothformgapjunctions[89].
ThenumberofSGCsinDRGsandTGsismuchTable3Regulationofreceptors,channels,transporters,enzymes,andtranscriptionalfactorsinmicroglia,astrocytes,andsatelliteglialcells(SGCs)indifferentpainconditions.
PainconditionsMicrogliaAstrocytesSGCsNerveinjuryP2X4%MP2X7%P2Y6%P2Y12%%TLR2MTLR3MTLR4%C1q,3,4,5%MCX3CR1%MCCR2%IFN-cR%Cx43%%Kir4.
1%&TRPM2MMGLT-1&GLAST&COX-1%COX-2%NF-kB%%NOX-2%STAT3%%c-Jun%CB2%SCICx43%InammationTLR3MTLR4%Cx43%TRPM2%GRK2&ALX&JointarthritisCX3CR1%BonecancerCX3CR1%HIVTLR2%TLR9&ChronicopioidP2X4%P2X7%TLR2%TLR4MDetailed,withrelatedreferences,inSection2.
3.
Symbols:Right-upwarddiagonalarrow(%)denotesupregulation;right&lefthori-zontalarrow(M)denotesnoregulation;right-downwarddiagonalarrow(&)denotesdownregulation.
Table4Regulationoftheglialmediatorscytokines,chemokines,growthfactors,andproteasesinmicroglia,astrocytes,andsatelliteglialcells(SGCs).
PainconditionsMicrogliaAstrocytesSGCsNerveinjuryTNF-a%IL-1b%%%IL-6%IL-18%CCL2%BDNF%bFGF%%MMP-2%%tPA%%CatS%TSP4%SCIIL-1b%InammationTNF-a%IL-1b%%IL-6%BonecancerTNF-a%IL-1b%IL-6%ChronicopioidTNF-a%IL-1b%IL-6%AcutemorphineIL-1b%Detailed,withrelatedreferences,inSection2.
4.
Symbols:Right-upwarddiagonalarrow(%)denotesupregulation;right&lefthori-zontalarrow(M)denotesnoregulation;right-downwarddiagonalarrow(&)denotesdownregulation.
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Unlikeastrocytes,eachSGCcontactsonly1neuron.
Strikingly,thegapofextracellu-larspacebetweentheSGCsheathandtheassociatedneuronalplasmamembranemeasuresonly20nm,allowingforcloseinter-actionsandeffectivesignalingbetweenneuronsandSGCs[89].
EmergingevidencesuggeststhatSGCsareactivatedafterpainfulinjuriesandplayanactiveroleinthedevelopmentofpersistentpain[29,54,91,107,150].
SGCsalsoexhibitenhancedcouplinginpersistentinammatoryandneuropathicpain[54,295].
2.
DifferentactivationstatesofgliaafterpainfulstimuliandinjuriesAfterpainfulstimuliandinjuries,gliaexhibitvariablealtera-tionsinfunctionsandmorphologies,includingthefollowing:(1)ionicchanges(eg,intracellularCa2+risesinastrocytes);(2)post-translationalregulation(eg,phosphorylationofmitogen-activatedproteinkinases[MAPK]);(3)translationalandtranscriptionalmodulation(eg,modulationofsurfacemolecules,glialmarkers,pro-andanti-inammatorymediators);(4)morphologicalchanges(eg,hypertrophy);and(5)proliferation.
Thesechangesareassoci-atedwithdifferentactivationstatesofglia(Fig.
1).
Belowwedis-cussactivationstatesthatarefrequentlymeasuredinthepainresearcheld.
2.
1.
Glialreaction:Changesinglialmarkersand/ormorphologyMoststudiesdeneglialactivationasupregulationoftheglialmarkerssuchasCCR3/CD11b,IBA1,andGFAP,whichareoften,butnotalways,associatedwithmorphologicalchanges(eg,hyper-trophyorprocessretraction/extension).
Thus,werefertothisglialactivationstateasglialreaction.
Observationsthatnerveinjuryinducesmicroglialresponsesdatebacktothe1970s[3].
Microglialreaction(microgliosis)inthespinalcordhasbeenintensivelyinvestigatedafterperipheralnerveinjury.
Nervetraumainducesveryrobustmicroglialreaction,suchashypertrophyandupregulationofthemicroglialmarkersCD11b,IBA1,andCD68inthespinalcordandbrainstem[118,252,300](Fig.
2).
IBA1isprobablythemostwidelyusedmar-kerformicroglialreactioninthepaineld,partlybecausetheIBA1antibodyfromWakoChemicalsworksbetterthanotherantibodiesofmicroglialmarkers.
Asexpected,microglialreactionisalsoveryrobustafterspinalcordinjury[86,102].
Furthermore,chronicopi-oidexposure,streptozotocin-induceddiabeticneuropathy,andsurgicalincisionresultinmicroglialreaction[49,192,275,310].
However,microglialreactionislessevidentafterbonecancer[98]andchemotherapy-inducedneuropathy[297,307],dependingonthedosesofchemotherapydrugsandseverityofnervedamageaftertumorgrowth(asshownbyATF-3expressioninDRGneu-rons)[23,303].
Intra-articularbutnotintraplantarinjectionofcompleteFreund'sadjuvant(CFA)inducesmicroglialreaction[222],becauseofdeeptissue(joint)injuryandpossibleaxonalinjury(Table1).
Interestingly,inyoungrats(P10),nerveFig.
1.
Differentactivationstatesofglia.
Gliaexhibitdifferentactivationstatesafterpainfulinjuries.
(1)Glialreactionreferstoupregulationofglialmarkersandmorphologicalchangesofglia(gliosis);(2)upregulationofglialreceptorssuchasadenosinetriphosphate(ATP)receptors,chemokinereceptors,andToll-likerecep-tors,whichwillleadtothethirdactivationstate:(3)activationofintracellularsignalingpathways,suchasmitogen-activatedproteinkinase(MAPK)pathways.
PhosphorylationofMAPKswillleadtothenextactivationstate:(4)upregulationofglialmediators,suchascytokines,chemokines,andgrowthfactors.
Uponrelease,theseglialmediatorscaninteractwithneuronstoelicitpainviacentralandperipheralsensitization.
Unlikeglialreaction(state1),theotheractivationstates(states2–4)havebeenshowntoinducepain.
Fig.
2.
Activationofmicrogliainthespinalcorddorsalhorn3daysaftersparednerveinjury(SNI)inrats.
(A)IB4staininginthespinalcorddorsalhornipsilateralandcontralateraltotheinjuryside.
NotealossofIB4staininginthedorsalhornregioninnervatedbytheinjurednervebranches.
(BandC)CD11b(OX-42)andphosphorylatedp38(p-p38)immunostaininginthedorsalhornipsilateralandcontralateraltotheinjuryside.
NoteoverlappingexpressionpatternsofOX-42andp-p38intheinjuryside.
(D)Doublestainingofp-p38(red)andOX-42(green)intheipsilateraldorsalhorn.
Lowerpanelpresentshigh-magnicationimagesof2microglialcells(indicatedbyarrowandarrowhead)fromtheupperpanel.
Notethatp-p38iscompletelyco-localizedwithOX-42.
Scale,100lm.
ImagesaremodiedfromWenetal.
[276],withpermission.
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022injury-evokedspinalmicroglialreactionisnotsoevident,inparal-lelwiththeabsenceofnerveinjury-inducedneuropathicpainintheseyounganimals[170,256].
Furthermore,priorneonatalinjurycan''prime''thespinalmicroglialresponsetoadultinjury,result-inginenhancedmicroglialreactivity[13].
Microgliacanalsobeprimedbypreviousinsultinadults,leadingtoenhancedpainintensityanddurationofthesecondinsult[87].
Comparedtomicroglialreaction,astrocytereactioninthespinalcordismoregeneralandevidentafterpainfulinjuries[69].
Robustastrocytereactionisinducednotonlybynervetraumaandspinalcordinjury[75,76,173,316],butalsobychronicopioidexposure[214],intraplantarorintra-articularCFAinjection[70,83,198,222],bone[98]andskincancer[67],chemotherapy,andhumanimmunodeciencyvirus(HIV)-inducedneuropathy[297].
Inaddition,itappearsthatastrocyticreactionismorepersis-tentthanmicroglialreaction.
IthasbeenshownthatGFAPandCD11bupregulationpeaksat150and14daysafternerveinjury,respectively,althoughCD11bupregulationremainsafter150days[298].
GFAPupregulationisalsoprominent9monthsafterspinalcordinjury[85,173].
Althoughmoststudieshavefocusedonglialreactioninthespinalcordandbrainstem,astrocytereactionhasalsobeenfoundintheforebrain,suchastheanteriorcingulatecor-tex,whichcontributestoaffectivepain[28].
OnecaveatisthatimmunohistochemistryofsomeGFAPantibodiesmaydetectcon-formationalorsolubilitychangesorpost-translationalmodica-tionsoftheproteinbutnotactualchangesinproteinexpression,becauseofdifferentxationconditions[15,56].
Thus,itisidealtovalidatetheresultsofGFAPimmunohistochemistrywithdiffer-entantibodiesanddifferentmethodssuchasWesternblotandquantitativepolymerasechainreaction(PCR).
LessisknownaboutSGCreaction(GFAPupregulation)afterpainfulinjuries.
SGCreactionisinducednotonlybynerveinjury[150,295]butalsobyinammation[235,236]inDRGsandTGs.
NerveinjuryfurtherresultsinSGCproliferation[107].
SGCsreac-tionafternerveinjuryandDRGcompressionisveryrapid,becom-ingevidentwithin4hours.
Thisreactionpeaksat1weekbutdeclinesafter3weeks.
ThistimecourseofSGCreactionsuggestsapossibleroleofSCGsintheinductionandearlymaintenanceofneuropathicpain[150,295].
AdministrationofglialtoxintoDRGshasbeenshowntoreduceneuropathicpain[150].
Also,thereisin-creasedcouplingbetweenSGCsafternerveinjury[185,295]andinammation[54].
Interestingly,evenacuteopioidtreatmentafterasubcutaneousinjectionresultsinmarkedSGCreactioninDRGsat2hourswhenmorphineanalgesiadeclines[18](Table1).
2.
2.
PhosphorylationofMAPKsandSrcingliaTheMAPKfamilyincludes3majormembers:extracellularsig-nal-regulatedkinase1and2(ERK1andERK2,respectively),p38,andc-JunN-terminalkinases(JNK)).
ERK5isanewfamilymemberandwasshowntobeactivatedinspinalmicrogliaafternervein-jury[177].
MAPKpathwaysplayanimportantroleinintracellularsignalinginneuronsandglia,andbotharerequiredforthegenesisofpersistentpain[109,178].
Interestingly,differentMAPKsexhibitdistinctactivation(phosphorylation)patternsinglialcellsafterpainfulinjuries[109](Table2).
Numerousstudieshaveshownincreasedphosphorylation(acti-vation)ofp38(P-p38)inspinalcordmicrogliaafternerveinjury[118,136,251](Fig.
2),spinalcordinjury[46,86],formalin-inducedacuteinammatorypain[229],surgery-evokedpostoperativepain[192,275],andchronicopioidexposure[47].
Nerveinjuryalsoacti-vatesmicroglialp38inthetrigeminalnucleus[194].
Ithasbeenshownthatthebisoformofp38(p38b)isexpressedinmicroglia[228].
Inaddition,P-p38isinducedinneuronsandSGCsofDRGsfollowingnerveinjury[118,179]andalsoinSGCsofTGsafterinammationinthetemporomandibularjoint[65].
P-JNKisinducedinspinalastrocytesafternerveinjury[316],CFA-inducedpersistentinammatorypain[70],bonecancer[267],andmelanoma-inducedskincancer[67].
Consistently,nerveinjuryalsoactivatestheupstreamactivatorofJNK,thetransform-inggrowthfactor-activatedkinase-1(TAK1),andthedownstreameffectorofJNK,c-Juninspinalastrocytes[125,316].
AmongseveralJNKisoforms(JNK1,2,3),JNK1wasshowntobeexpressedinspinalastrocytes[70].
P-ERKinductioningliaafterinjuryishighlydynamic:inductioninspinalmicrogliacorrespondstotheearly-phase(rstweek),andgraduallytransitionstoastrocytesinthelatephaseafternervein-juryandbonecancer[268,314].
CFAalsoinducesP-ERKinspinalastrocytesinthelatephase[279].
Furthermore,nerveinjuryevokesP-ERKinSGCsofDRGs[314],andtemporomandibularjointinammationelicitsP-ERKinSGCsofTGs[65].
MAPKsareactivatedbyproinammatorymediators[109]andinactivatedbyphosphatases,suchasMAPKphosphatase(MKP1,2,3).
Forexample,P-p38expressioninspinalmicrogliaafternerveinjurycanbesuppressedbyMKP3[171].
ActivationofCB2inmicrogliawasshowntoupregulateMKP1andMKP3,leadingtoareductionofP-ERKinmicroglia[202].
InammationinducesrapidupregulationofMKP1,MKP2,andMKP3inSGCsofTGs[65],whichmayregulatetheresolutionofinammatorypain.
MountingevidenceindicatesthatactivationofMAPKsinspinalcordglialcellsisessentialforthedevelopmentofpersistentpain[109].
Thus,intrathecalinjection(s)ofselectiveinhibitorsofMEK(ERKkinase),p38,andJNK,aswellasantisenseknockdownofERK5,attenuatedinammatory,neuropathic,andcancerpaininratsandmice[109].
Systemicinjectionofp38inhibitoralsore-ducedspinalnerveligation-inducedmechanicalallodyniainmice[113].
UpregulationofspinalMKP-3viagenetherapyattenuatesneuropathicpainbysuppressingP-p38[171].
TheimportanceofMAPKpathwaysforneuropathicpainhasalsobeendemonstratedinhumanbeings.
InHIVpatientswithneuropathicpain,P-ERK,P-p38,andP-JNKlevelsinthedorsalhornsaresignicantlyincreased,comparedtothoseinHIVpa-tientswithoutneuropathicpain[211].
Inadouble-blind,pla-cebo-controlledclinicaltrial,oraldeliveryofaselectivep38inhibitor,dilmapimod(SB-681323)attenuatedneuropathicpaininpatientswithnervetrauma,radiculopathy,orcarpaltunnelsyn-drome[6].
NerveinjuryalsoinducesphosphorylationofSrcfamilykinases(Src,Lyn,Fyn)inspinalmicroglia[126,250].
IntrathecalinfusionofaSrcinhibitor(PP2)reducednerveligation-elicitedneuropathicpain.
Ofinterest,PP2suppressedtheactivationofERKbutnotp38inspinalmicroglia[126].
2.
3.
Regulationofreceptors,channels,andtransportersingliaAsshowninTable3,multiplereceptors,channels,andtrans-portersareexpressedinglialcellsandareregulatedindifferentpainconditions.
Althoughthesemoleculesarenotsecreted,theyplayactiverolesinglialintracellularsignalingbyactivatingtheMAPKpathwaysandinducingthesynthesis,release,anduptakeofthesecretedmolecules(Table4).
ATPmodulatesglialactivationviaactivatingP2X(ionchannels)andP2Yreceptors(GPCR-coupled),andtheseATPreceptorsgatemicroglialsignalingforneuropathicpain[244,253].
PeripheralnerveinjuryupregulatesP2X4,P2X7,P2Y6,andP2Y12inspinalmicroglia;and,furthermore,neuropathicpainisreducedafterphar-macologicalinhibition,antisenseknockdown,orgeneticdeletionofP2X4,P2X7,P2Y6,orP2Y12[135–137,215,243,244,252,253].
MicelackingtheP2x4genedisplaydiminishedinammatorypainandbluntedneuropathicpain[249].
P2Y12isalsoinducedinSGCsofTGafternerveinjury,andinjectionofaP2Y12RantagonistintoTGreducestrigeminalneuropathicpain[124].
Moreover,chronicR.
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Jietal.
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022opioidtreatmentupregulatesP2X4andP2X7inspinalmicroglia,andopioidtoleranceispreventedafterspinalknockdownofP2X4orP2X7[99,108,310].
However,arecentstudydemonstratedthatopioid-inducedhyperalgesiabutnottoleranceismediatedbyopioidreceptor-dependentexpressionofP2X4inmicroglia[60].
Toll-likereceptors(TLRs)areknowntoregulateinnateimmu-nityandhavebeenstronglyimplicatedinglialactivation[152,174].
Lipopolysaccride(LPS),anagonistofTLR4,ishighlypo-tentinactivatingmicroglia.
ItalsoactivatesTLR4inastrocytes[152].
Ofnote,spinalmicroglialreactionandneuropathicpainafternerveinjuryarereducedinTlr2knockoutmice[130]andTlr4mutantmice[238].
Arthriticpaininthelatephaseisalsore-ducedinTlr4knockoutmice[33].
Strikingly,malebutnotfemalemicewithTlr4mutationexhibitreducedneuropathicpain[168],suggestingsexdifferencesinTLR4andmicroglialsignaling.
Chronicmorphinewasshowntoinduceglialresponsesviaactiva-tionofTLR4[271].
Ofnote,opioid-inactiveisomerswereshowntoinducespinalproinammatoryresponsesviaactivationofTLR4[104].
PharmacologicalblockadeofTLR4signalinginvivoattenu-ateddevelopmentofanalgesictolerance,hyperalgesia,andopioidwithdrawalbehaviorsinrats[105].
Incontrast,Ferrinietal.
showedthatchronicmorphine-inducedhyperalgesiaisintactinTlr4mutantmice[60].
Microarrayanalysisrevealsthatthecomplementcomponents(eg,C1q,C3,C4,C5)areamongthemostregulatedtranscriptsinthespinalcordfollowingnerveinjury.
Inparticular,thesecompli-mentcomponentsareupregulatedinspinalmicroglia.
InductionofC5aRinspinalmicrogliahasbeenimplicatedinneuropathicpainsensitization[82].
Increasingevidencesuggeststhatchemokinereceptorscontrib-utetothepathogenesisofchronicpainviamodulatingglialactiva-tionandneuralplasticity[1,35,68,280].
CX3CL1(fractalkine)andCCL2(MCP-1)are2ofthemostwell-studiedchemokinesforpainmodulation.
Althoughachemokinenormallyactivatesmultiplereceptors,CX3CR1appearstobetheonlyknownreceptorforCX3CL1andisexclusivelyexpressedinmicroglia.
Thus,Cx3cr1-GFPmicehavebeenusedforstudyingthelocalizationandactiva-tionofmicroglia[175].
NerveinjuryandjointinammationinducearobustupregulationofCX3CR1inspinalmicroglia,andspinalblockadeofCX3CR1withaneutralizingantibodyinhibitedinam-matoryandneuropathicpain[165,222,257,315].
Consistently,micelackingCx3cr1exhibitedreducedinammatoryandneuro-pathicpain[219].
ComparedtoselectivemicroglialexpressionofCX3CR1,CCR2,amajorreceptorforCCL2,isexpressedinbothneu-ronsandmicroglia[2,72,81,84,121,305].
Nerveinjury-inducedspinalmicroglialreactionisabolishedinCcr2knockoutmice[300],whereasintrathecalCCL2causesmicrogliosisinthespinalcord[239,300].
NeuropathicpainisimpairedinCcr2knockoutmiceorafterspinalinjectionofCCR2antagonist[2,300,305].
Acti-vationofCCR2byCCL2alsorapidlymodulatesDRGneuronalsen-sitivityandspinalcordsynapticplasticity[72,81,315].
LikeLPS,interferon-c(IFN-c)isastrongactivatorofmicroglia,bymeansofinducingmicroglialreaction,P2X4upregulation,andLynphosphorylation[250].
NerveinjuryupregulatesINF-crecep-torsinspinalmicroglia,andnerveinjury-inducedmicroglialreac-tionandmechanicalallodyniaareabrogatedinIfncreceptorknockoutmice[250].
AstrocytesandSGCsarecharacterizedbyforminggapjunction-couplednetworks,leadingtothetransmissionofCa2+signalingthroughnetworks[7,54].
Connexinsarethemajorstructuralcom-ponentsofgapjunctions,andCx30andCx43areknowntobeex-pressedbyastrocytes[27].
Cx43isupregulatedinastrocytesafternervelesion,spinalcordinjury,andinammation[27,62,77,83,145].
Inhibitionofgapjunctionfunctionbycarbenox-olone(CBX),anonselectivegapjunctioninhibitor,reducesinam-matoryandneuropathicpain[140,218].
Inadditiontomodulatinggapjunctioncommunication,recentstudiesalsoproposedapara-crinesignalingofCx43toreleasekeyastrocyticmediatorssuchasATPandglutamate[123,148,240,262].
UnopposedCx43hemichan-nelsareidealformodulatingATPreleasepathways,asthebiophys-icalpropertiesofthesehemichannelsenablethemtoconducthighlevelsofATPefux[17,42,190].
Ofnote,SCI-inducedATPreleaseinthespinalcordisdiminishedafterCx43blockade[45].
IndoubleknockoutmicelackingCx30/Cx43,thedevelopmentofneuropathicpain(heathyperalgesiaandmechanicalallodynia)isprevented,andspinalastroglialreactionisreduced[27].
NerveinjurywasshowntoupregulateCx43inSGCsofTGs.
Ofinterest,reducingCx43expressioninSGCsviaRNAireducedneuropathicpaininnerve-injuredratsbutinducedpain-likebehaviorsinnormalrats,suggestingdifferentrolesofSGCs-Cx43inpainmodulationinnon-injuredvsinjuredanimals[183].
Notably,thegapjunctionblockerCBXalsoinhibitspannexin-1(PNX1),whichisexpressedinastro-cytesandmodulatesATPrelease[74].
TheroleofPNX1inpaincontrolneedsfurtherinvestigation.
Thefollowingionchannelshavealsobeenimplicatedforglialsignalinginpain.
TheK+channelsubunitKir4.
1isexpressedinSGCs,andsilencingthisK+subunitwithRANileadstopainhyper-sensitivity[261].
Thewaterchannelaquaporin-4(AQP4)isinducedinspinalcordastrocytesafterspinalcordinjury[173],andmicelackingAqp4displaydecreasedpainsensitivity(hypoalgesia)[9].
TRPM2isexpressedinmicrogliaandcontributestospinalcordmicroglialactivation.
Inammatoryandneuropathicpainareim-pairedinTrpm2knockoutmice[95].
TheglutamatetransporterssuchasGLT-1andGLASTareex-pressedinastrocytes(Table3)andregulatetheclearanceofgluta-matefromsynapticcleftsandextracellularspace,leadingtoalteredglutamatergictransmissionandneuronalplasticity[203,204].
Nerveinjuryandchronicmorphineelicitasustaineddown-regulation,afteraninitialupregulation,ofglutamatetrans-porter-1(GLT1)andglutamateandasparticacidtransporter(GLAST)inthespinalcord[158,224,288].
Inhibitionofglutamatetransportersresultsinanelevationinspinalextracellulargluta-mateandspontaneouspain[147,278].
Consistently,GLT-1genedeliverytothespinalcordattenuatesinammatoryandneuro-pathicpain[157],supportingaroleofastroglialglutamatetrans-portersintheresolutionofchronicpain.
Severalenzymesarealsoactivelyinvolvedinglialsignalinginpain.
Cyclooxygenase-1and-2(COX-1andCOX-2,respectively)areinducedinmicrogliaaftersurgicalincisionandnerveinjurytofacili-tatepostoperativeandneuropathicpain[306,312,313].
NADPHoxi-dase2(Nox2)expressionisinducedindorsalhornmicrogliaafterL5spinalnervetransection,andNox2-decientmiceshowedde-creasesinoxidativestress,microglialreaction,andproinammatorycytokineexpressioninthespinalcord,aswellasneuropathicpain[131].
Ofinterest,G-protein-coupledreceptorkinase(GRK2)inmicrogliawasimplicatedinthetransitionfromacutetochronicinammatorypain.
Spinalmicroglia/macrophageGRK2expressionisreducedafterinammation,leadingtotheactivationofmicrogliaandpersistentpainviap38andinterleukin-1b(IL-1b)signaling[283].
Furthermore,nerveinjuryupregulatesthetranscriptionalfac-torsinspinalcordglia,includingc-Juninastrocytes[316],signaltransducersandactivatorsoftranscription3(STAT3)inmicroglia[53]andastrocytes[248],andnuclearfactor-jB(NF-jB)inmicroglia[227]andastrocytes[167],toenhanceandmaintainneuropathicpain.
Finally,painfulinjuriesalsoinduceupregulationofanti-inam-matoryreceptorsingliafortheresolutionofacutepain.
Inamma-tionincreaseslipoxinreceptorALXexpressioninspinalcordastrocytes,andlipoxinA4reducesinammatorypainviainhibitingJNKphosphorylationinastrocytes[231].
LipoxinA4alsoattenu-atesmorphinetoleranceviamodulatingglialactivationandcyto-kineexpression[117].
Nerveinjuryincreasedcannabinnoid6R.
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022receptorCB2expressioninspinalmicroglia[299],andCB2agonistssuppressedmicroglialreactionandneuropathicpain[282].
OfinterestCb2knockoutmicedisplayedincreasedmicroglialandastrocyticreactivityinthespinalcordandenhancedneuropathicpain,whereastransgenicmiceoverexpressingCb2showedattenu-atedglialreactivityandneuropathicpain[196].
2.
4.
Regulationofcytokines,chemokines,growthfactors,andproteasesingliaAkeyissueregardingglialcontrolofpainistounderstandhowglialmediatorsareproducedandreleased.
AsshowninTable4,gliaproducebothlargemolecules(cytokines,chemokines,growthfactors,andproteases)andsmallmolecules(glutamate,ATP,D-serine,andprostaglandinE2(PGE2).
Theseglialmediatorscanmodulateneuronalandsynapticactivityandpainsensitivity.
Proinammatorycytokinessuchastumornecrosisfactor–a(TNF-a),IL-1b,andIL-6areamongthemostwell-studiedglialmediators.
Theyareupregulatedinspinalcordgliaafternervein-jury,inammation,bonecancer,andchronicopioidexposure,andtheycontributetothedevelopmentofandmaintenanceofinam-matory,neuropathic,andcanerpainandmorphinetolerance[52,213,230,273].
TNF-aisprimarilyproducedbymicrogliaandplaysanessentialroleinthegenerationofcentralsensitizationandpersistentpain[92,289,301,308],inadditiontoitswell-docu-mentedroleinmodulatingperipheralsensitization[119,207,216].
IL-1bisinducedinastrocytesafterbonecancer,inammation,andnerveinjury[83,274,279,303].
IL-1bcanalsobeproducedbymicrogliaandneuronsinthespinalcord[36,51,92].
InhibitionofspinalandbrainIL-1bsignalingreducesinammatory,neuro-pathic,andcancerpain[83,163,232,274,303]andenhancesmor-phineanalgesia[120,270].
IL-18ishighlyrelatedtoIL-1b,andbothrequirecaspase-1andinammasomesforactivecleavage[146].
NerveinjuryinducesIL-18expressioninspinalmicroglia[34,167].
Furthermore,painfulinjuriesinducecytokineexpressioninperipheralglia.
Forexample,nerveinjuryandCFAinammationincreaseIL-1bexpressioninSGCsofDRGsandTGs[127,234].
Ofnote,acutemorphineupregulatesIL-1bonlyinperipheralglia(SGCs)inDRGsbutnotincentralglia(microgliaandastrocytes)inthespinalcord[18].
Chemokinesareexpressedinglialcells,particularlyinastro-cytesintheCNS[68],aswellasinneurons[84].
Inprimarycul-turesofastrocytes,TNF-ainducedrapidexpressionofCCL2,CXCL10,andCXCL1[72].
SpinalinjectionofTNF-a-activatedastrocytesresultsinpersistentmechanicalallodyniaviareleasingCCL2[71].
SpinalnerveligationalsoinducesCCL2inspinalastro-cytes,andintrathecaladministrationofanMCP-1neutralizingantibodyreducesneuropathicpain[72].
CCL2expressionisfur-therincreasedinastrocytesofthemedullarydorsalhornandcon-tributestotrigeminalneuropathicpain[305].
Consistently,micewithCCL2overexpressioninastrocytesdisplaypainhypersensi-tivity[162].
Growthfactorsareknowntobeinducedinspinalgliabynerveinjury.
Inparticular,nerveligationupregulatesbrain-derivedneu-rotrophicfactor(BDNF)inspinalmicroglia,viaactivationofP2X4andp38[244,254].
SpinalinjectionofATP-activatedmicrogliaissufcienttoinducemechanicalallodyniaviareleasingBDNF,and,conversely,neuropathicpainissuppressedbyspinalblockadeoftheBDNFreceptorTrkB[43].
Furthermore,treatmentofmicroglialcultureswithmorphineincreasesBDNFrelease,whichdoesnotre-quirel-opioidreceptorandTLR[60].
BDNFisalsoinducedinDRGneuronsafternerveinjuryandcanbereleasedfromprimaryaffer-entsinthespinalcord[66,143].
UnlikeBDNF,basicbroblastgrowthfactor(bFGForFGF-2)isinducedinreactiveastrocytesofthespinalcordinthelatephase(3weeks)ofnerveinjury[110].
IntrathecalinfusionofbFGFproducespersistentactivationofspinalastrocytes(upregulationofP-JNKandGFAP)andsustainedmechanicalallodynia[110].
Bycontrast,intrathecaladministrationofabFGF-neutralizingantibodyattenuatesestablishedneuro-pathicpain[156].
Therefore,bFGFmaintainschronicpainviaacti-vationofastrocytes.
Proteasesarealsoupregulatedinspinalgliaafternerveinjury.
Notably,spinalnerveligationinducesmatrixmetalloprotease-2(MMP-2)inspinalcordastrocytesandDRGSGCsinthelatephaseofneuropathicpaintomaintainneuropathicpain,viaactivationofIL-1bandERK[127].
NerveinjuryfurtherinducescathepsinSinspinalmicroglia[37]andtissuetypeplasminogenactivator(tPA)inspinalastrocytes[138]toenhanceneuropathicpain.
Arecentstudyshowedthatnerveinjuryincreasestheexpressionofthrombospondin-4(TSP4),anextracellularmatrixglycoprotein,inspinalcordastrocytes.
Thisincreaseisnotonlycorrelatedbutalsorequiredforthedevelopmentneuropathicpain[132].
TSP4releasefromastrocytescanpromotesynaptogenesis.
Ofgreatinterest,thea2d-1calciumchannelsubunit,apossibletargetofgabapentin,wasshowntobeaneuronalreceptorofTSP4.
Thus,gabapentinmayinhibitneuropathicpainviamodulatingsynaptogenesis[58].
AstrocytesalsoproducesmallmoleculemediatorssuchasD-serine,ATP,andglutamatetoenhancepainstates[69].
Interestingly,inhibi-tionofglycinergictransmission,whichisknowntooccurinchronicpain,resultsinD-serinereleasefromastrocytestogeneratetactileallodynia[166].
D-serineisknownasanagonistofglycinesiteofN-methyl-D-aspartate(NMDA)receptors[176].
Inadditiontothepro-inammatoryandpronociceptivemedia-tors,glialcellsmayalsoproduceanti-inammatoryandantinoci-ceptivemediators,suchasIL-4,IL-10,andTGF-b[92]fortherecoveryandresolutionofpain[41,92,94,114,164].
Enhancementofendogenousproductionofinterleukin-10viagenetherapyhasbeenshowntoproducelong-termreliefinneuropathicpain[212].
Ofinterest,apossibleoff-targeteffectofhighdosesofsiR-NAsistoinduceIFN-ainspinalastrocytesforelicitingantinocicep-tiveeffects[237].
3.
Neuronal–glialandglial–glialinteractionsinpersistentpainBecausepainisconveyedonlybyneurotransmissionintheneu-ralcircuits,gliamustinteractwithneuronstomodulatepainsen-sitivity.
Herewefocusonneuronal–glial(neuronal–glial)(Section3.
1)andglial–glial(Section3.
2)interactionsintheCNSunderpersistentpainconditions(Fig.
3).
Wealsodiscussneuro–glialinteractionsinthePNSafterpainfulinjuriesandacutemor-phinetreatment(Section3.
3)(Fig.
4).
3.
1.
Neuronal–glialinteractions:SignalsfromneuronstogliaItisgenerallybelievedthatinjury-inducedspontaneousdis-chargefromprimaryafferentsdrivesneuropathicpain[149,155,286].
Severallinesofevidencesuggestthatnervein-jury-releasedsignalingmoleculesfromprimaryafferentcentralterminalstriggermicroglialactivation(Fig.
3).
Abrief,low-frequencyelectricalstimulationoftheperipheralC-berswasshowntoinducespinalmicroglialreactionwithoutcausingnotice-ablenerveinjury[97].
Sustainednerveblockadeviabupivacainemicrospherespreventednerveinjury-inducedmicroglialresponses(CD11bexpressionandP-p38induction)[276,287].
However,inhi-bitionofC-beractivityaloneinthesciaticnervewithresininfera-toxinmaynotbesufcienttopreventsparednerveinjury-inducedmicroglialactivation[226],suggestingpossiblecontributionoflargeA-bers.
Consistently,deletionofvesicularglutamatetrans-porter-2(vGluT2)inNav1.
8-expressingnociceptorsdidnotpre-ventnerveinjury-inducedspinalmicroglialreaction,suggestingthatglutamatereleasefromnociceptorsmaynotbesufcienttoR.
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022drivemicroglialreaction[208].
Althoughspontaneousactivityisimportantfortheinitiationofmicroglialactivation,itisnotsocrit-icalforthemaintenanceofmicroglialactivation[276].
Chemokines,suchasCCL2,CCL21,andCX3CL1,areidealformediatingneuronal–microglialinteractions,giventhedistinctexpressionoftheirligandsandreceptors.
NerveinjuryinducesCCL2andCCL21expressioninDRGneurons[19,281,298].
Stimula-tionofthedorsalrootresultsinactivity-dependentCCL2releaseinthespinalcord[239,255].
ChemokinesmayactivatemicrogliaviaP2X4signaling:CCL2inducesthesurfacetrafckingofP2X4[242],andCCL21increasestheexpressionofP2X4[19].
ActivationofP2X4resultedinBDNFexpressionandreleasefrommicrogliaviap38activation[245].
Proteaseshavealsobeenimplicatedinmicroglialactivation.
NerveinjuryinducesrapidandtransientupregulationofMMP-9inDRGneurons,whichisessentialfortheearly-phasedevelopmentofneuropathicpain[115].
Activity-dependentre-leaseofMMP-9fromprimarysensoryneuronswasimplicatedinmicroglialactivation,inpartthroughIL-1bcleavage[127].
Cathep-sinSisalsoinvolvedinmicroglial–neuronal–microglialsignaling.
Nerveinjury-evokedreleaseofcathepsinSfrommicrogliaresultsinfurtheractivationofmicroglia,throughthecleavageandreleaseofCX3CL1fromprimarysensoryneurons[35,37].
Thegrowthfactorneuregulin-1(NRG1)playsanactiveroleinmicroglialactivation.
AlthoughNRG1isexpressedinDRGneurons,itsreceptor,erbB2,isexpressedinmicroglia.
NRG1wasshowntoFig.
3.
Schematicofneuronal–glialandglial–glialinteractionsinthespinalcordinpersistentpain.
Spontaneousdischargeafterapainfulinjury(eg,nerveinjury)resultsinthereleaseofATP,chemokines(CCL2,CCL21,CX3CL1),MMP-9,NRG1,andCRGPfromprimaryafferentcentralterminals,leadingtoactivationofmicrogliainthedorsalhorn.
SpinalmicrogliaexpressthereceptorsforATP(P2X4,P2X7,P2Y6,P2Y12),andchemokines(CX3CR1,CCR2),andNRG1(ErB2).
Activationofthesereceptorsinducesphosphorylationofp38andERK(earlyphase)inmicroglia,leadingtotheproductionandreleaseoftheproinammatorycytokines(TNF-a,IL-1b,IL-18)andthegrowthfactorBDNF,andtheconsequentsensitizationofdorsalhornneurons.
Astrocytescanbeactivatedbymicroglialmediators(TNF-aandIL-18),aswellasastrocyticmediators(matrixmetalloprotein-2(MMP-2)andbFGF).
SubsequentphosphorylationofJNKandP-ERKinastrocytesresultsintheproductionandreleaseofchemokines(eg,CCL2)andcytokines(eg,interleukin-1b[IL-1b]).
Astrocytesalsoproduceadenosinetriphosphate(ATP)andglutamateaftertheactivationofthehemichannels(Cx43andPNX1).
Afternerveinjury,downregulationofastrocyticGLT1resultsindecreaseinastrocyticuptakeofglutamate.
Releaseofastrocyticmediators(CCL2,interleukin-1b[IL-1b],glutamate)canelicitNMDAR-mediatedcentralsensitization.
Releaseofadenosinetriphosphate(ATP)andCCL2fromastrocytescanfurthermaintainmicroglialactivation.
8R.
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Jietal.
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Gliaandpain:IschronicpainagliopathyPAIN(2013),http://dx.
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org/10.
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022stimulatemicroglialproliferation,chemotaxis,andIL-1breleaseviaerbB2[26].
BlockadeoftheerbB2receptororsequestrationofendogenousNRG1reducesnerveinjury-inducedmicroglialproliferation,p38activation,andneuropathicpain[26].
NRG1alsoinducesmicroglialproliferationviaphosphorylationofERKandAKT[23].
Inaddition,releaseoftheneuropeptideCGRPfrompri-marysensoryneuronsisnotonlyinvolvedinneurotransmissionbutalsocontributestomicroglialactivationafterchronicmor-phineexposure[269].
p38MAPKservesasakeysignalingmoleculeinmicrogliabyintegratingvariousinputtomicroglia[112].
Microgliap38isacti-vatedbyATP[79],TNF-a[230],andIL-1b[225].
Afternerveinjury,p38isphosphorylatedfollowingtheactivationofmultiplerecep-tors,suchasATPreceptors(P2X4andP2Y12)[136,245]andchemo-kinereceptors(CCR2andCX3CR1)[2,315].
Microglialp38isalsoactivatedbyCGRPinchronicmorphine-inducedtolerance[269].
Notably,minocyclineinhibitsmicroglialactivationbyinhibitingspinalmicroglialp38activationafterinammationandchronicmorphinetreatment[48,100].
Uponactivation,p38inducesthesynthesisandreleaseofmicroglialmediatorsTNF-a,IL-1b,andBDNF[277].
Althoughp38iscriticalforthesynthesisandreleaseofinammatorymediators,ithasalimitedroleinmorphologicalchanges(microgliosis)andproliferationofmicroglia,whichcouldbemediatedbyanotherMAPKfamilymember,ERK[25].
Neuronalsignalsarealsoimportantfortheactivationofastro-cytes.
Forexample,neuronalactivityappearstodriveastrocyteactivationafternerveinjury[287]andinammation[264].
Basicbroblastgrowthfactor(bFGForFGF-2)isinducedinprimarysen-soryneuronsafternerveinjuryandhasanactiveroleinneuron–astrocytesignaling.
Asawell-knownactivatorofastrocytes,bFGFelicitsmitosis,growth,differentiation,andgliosisofastrocytes[110].
NerveinjurynotonlyinducesbFGFinDRGneurons[116]butalsoproducesadelayedbFGFupregulationinastrocytesformaintainingneuropathicpain[110].
3.
2.
Glial–glialinteractionsAstrocyticreactionisoftenprecededbymicroglialreaction,andmicroglialactivationisknowntodriveastrocyteactivation[197].
TNF-a,akeysignalmoleculeproducedbymicroglia,causesrapidJNKactivationinastrocytes[72].
Ofinterest,nerveinjuryelicitsIL-18andIL-18Rexpressioninspinalmicrogliaandastrocytes,respectively,andIL-18releasedfrommicrogliawasshowntoactivateIL-18RinastrocytestoupregulateNF-jBandfacilitateneuropathicpain[167].
Ontheotherhand,astrocytescanalsoreleasesignalingmole-culestoactivatemicroglia.
Afterspinalcordinjury,Cx43isupreg-ulatedandgainsanewfunctionofparacrinesignaling,leadingtothereleaseofATPandglutamate[123,148,240,262].
IncreasesinFig.
4.
Glialmediatorsmodulateexcitatoryandinhibitorysynaptictransmissioninthespinalcord.
(A)Modulationofexcitatorysynaptictransmissionatpresynaptic,postsynaptic,andextrasynapticsitesbyglialmediators.
Presynaptically,tumornecrosisfactor-a(TNF-a),interleukin-1b(IL-1b),CCL2,interferon-c(IFN-c),andTSP4increaseglutamatereleasetoenhanceEPSCfrequency.
Postsynaptically,IL-1bTNF-a,andCCL2increaseAMPARactivity.
Extrasynaptically,TNF-a,IL-1b,CCL2,andD-serineincreaseNMDAR-NR2BactivityandenhanceNMDA-inducedcurrents.
Astrocyte-releasedglutamatecanfurtherinduceNR2B-mediatedinwardcurrentsinsurroundingneurons.
(B)Modulationofinhibitorysynaptictransmissionatpresynaptic,postsynaptic,andextrasynapticsites.
Presynaptically,IL-1bandIL-6decreaseGABAandglycinereleasetodecreaseIPSCfrequency.
Postsynaptically,IL-1bdecreasesGABA/GlyRactivityandIPSCamplitude.
ProstaglandinE2(PGE2)inhibitsevokedglycinecurrent.
Extrasynaptically,IL-1b,CCL2,andIFN-csuppressGABA-and/orglycine-inducedcurrents.
TNF-ainhibitsactionpotentialsininhibitoryneurons.
InlaminaIneurons,BDNFproducesdisinhibitionbyalteringchloridereversepotential.
R.
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Jietal.
/PAINxxx(2013)xxx–xxx9Pleasecitethisarticleinpressas:JiR-Retal.
Gliaandpain:IschronicpainagliopathyPAIN(2013),http://dx.
doi.
org/10.
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2013.
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022extracellularATPhavebeendocumentedinawiderangeofperiph-eralandcentralnervoussysteminjuries,suchassciaticnerveentrapment[159],traumaticbraininjury[50,64],andspinalcordinjury[191,265].
ATPiscriticalfornerveinjury-evokedmicroglialactivationviaactivationofP2X4,P2X7,P2Y6,andP2Y12receptors[244,253].
Ofnote,CCL2isinducednotonlyinprimarysensoryneuronsbutalsoinastrocytes[72,281].
AlthoughDRG-CCL2inducesmicroglialactivation,astrocytic-CCL2maymaintainmicroglialactivation.
IFN-c,astrongmicroglialactivatorandneu-ropathicpaininducer[250],isalsoproducedbyastrocytes[196].
Finally,microgliaandastrocytescouldbeself-activatedviaautocrineorparacrinesignals.
Forexample,bFGFisupregulatedinspinalastrocytesafternerveinjurytomaintainastrocyteactiva-tion[110].
Nerveinjury-inducedastrocyticMMP-2upregulationinthelatephasecanmaintainastrocyticactivationandneuropathicpainthroughIL-1bcleavage(activation)andphosphorylationofERKinastrocytes[127].
3.
3.
Neuronal–glialinteractionsindorsalrootandtrigeminalgangliainthePNSSGCsinDRGsandTGsaretightlyassociatedwithsensoryneu-ronsviagapjunction;andgapjunctioncommunicationbetweenSGCsandSGCandneuronsisgreatlyenhancedinpersistentpainconditions[54,90,91].
Nerveinjury-inducedSGCactivationre-quiresneuronalactivityandlocalinammation[144,287].
Puriner-gicsignalingiscriticallyinvolvedinneuronal–glialcommunicationinDRGs[29,304].
Forexample,activity-dependentATPreleasefromneuronalsomaactivatesP2X7inSGCs[304],leadingtoTNF-areleasefromSGCs,whichcaninturnactonsurroundingneuronstoincreasetheirexcitability[119,216](Fig.
4).
ATPcanalsobereleasedfromSGCstoactivateP2X3receptor,whichisex-pressedinprimarysensoryneuronsandplaysanimportantroleinperipheralsensitization[40,217].
Ofnote,MMP-9mediatesneuron–SGCinteractioninDRGsafteracutemorphinetreatment,whichcanmaskmorphineanalgesia[153](Fig.
5).
Systemicmorphineadministrationwasshowntoeli-citrapidMMP-9upregulationinDRGneuronsintherecoveryphaseofmorphineanalgesia(2hours),whichrequiresactivationofl-opioidreceptors[153].
Notably,morphineanalgesiaisen-hancedandprolongedinMmp9knockoutmice[153].
Acutemor-phinealsoupregulatesGFAPandIL-1binSGCsofDRGs,andbothrequireMMP-9[18].
MMP-9releasefromneuronsresultsinIL-1bcleavageandrelease,whichinturnactivatesIL-1breceptorsinsensoryneuronstoelicitactionpotentials[20].
IL-1bisknowntoincreasetheexcitabilityofsensoryneuronsviaenhancingso-diumcurrentsandsuppressingpotassiumcurrents[20,233,236].
Ofinterest,IL-1bhasalsobeenshowntomaskmorphine-inducedanalgesia[103,120].
Thus,targetingperipheralneuronal–glialinteractions,inadditiontopreviouslyrecognizedcentralneuro-nal–glialinteractions,canalsoenhanceopioidanalgesia.
4.
GlialmediatorsmodulateexcitatoryandinhibitorysynaptictransmissionAkeyissueregardingglialcontrolofpainishowglialmedia-torsregulatesynaptictransmission.
Strikingly,glialmediatorscanmodulatespinalcordsynaptictransmissionatverylowconcen-trations.
Althoughneurotransmitters(eg,glutamate,GABA,gly-cine,andsubstanceP)normallyregulateneuronalandsynapticactivityatmicromolarconcentrations,glialmediators(cytokines,chemokines,andgrowthfactors)canchangesynapticactivityatnanomolarconcentrationsinvitro[43,72,128].
Inparticular,glialmediatorscanmodulatebothexcitatoryandinhibitorysynaptictransmission(Fig.
5).
Althoughmoststudiesusedyoung(3-to5-week-old)andadultanimals(ratsandmice)forrecordingspinalneuronalactivities[43,72,128,189,296],somestudiesusedneonatalanimals[73,81,259].
Itiswellknownthatthegeneexpressionprolesofprimarysensoryandspinalcordneurons,glialresponses,aswellasspinalcordpaincircuitsundergodra-maticchangesintherst2weeksafterbirth[16,61,172].
Thus,cautionmustbetakentointerpretthedatafromneonatalanimals.
4.
1.
ModulationofexcitatorysynaptictransmissionGlialmediatorscanmodulateexcitatorysynaptictransmissionviapre-,post-,andextrasynapticmechanisms(Fig.
5).
Theeffectsofproinammatorycytokinesandchemokinesonexcitatorypost-synapticcurrents(EPSCs)havebeenexaminedinlaminaIIneuronsusingexvivospinalcordslicepreparations[293].
AlthoughtheEPSCfrequencychangemayresultfrompresynapticmechanisms(duetoglutamatereleasefrompresynapticterminals),theEPSCamplitudeincreaseiscausedbyenhancedsignalingofglutamatereceptors(AMPAsubtype)inpost-synapticsites.
IncubationofspinalcordsliceswithTNF-a,IL-1b,andCCL2veryrapidly(withinminutes)increasedspontaneousEPSC(sEPSC)fre-quency[72,128,296].
ChronicexposureofcultureddorsalhornneuronstoIFN-calsoincreasedsEPSCfrequency[260](Fig.
5A),supportingapossiblepresynapticmodulation.
TNF-aincreasessEPSCfrequencyviaactivationofTRPV1inpresynapticterminals,asthissEPSCincreaseisabolishedinTrpv1knockoutmice.
Sin-gle-cellPCRanalysisindicatesthatTNF-a-respondinglaminaIIinterneuronsareexclusivelyexcitatoryones,becausetheyallex-pressvesicularglutamatetransporter-2(vGluT2).
TheselaminaIIneuronsalsoreceiveinputfromTRPV1-expressingC-bersandmakesynapsestolamina-Iprojectionneurons[241],formingaFig.
5.
Schematicrepresentationofneuronal–glialinteractionsindorsalrootandtrigeminalgangliaoftheperipheralnervoussystem(PNS).
Spontaneousneuronaldischargeafterpainfulinjuryresultsinadenosinetriphosphate(ATP)releaseinneuronalsomata,leadingtotheactivationofP2X7andsubsequentreleaseoftumornecrosisfactor-a(TNF-a)insatelliteglialcells(SGCs).
Persistentnociceptiveactivityoractivationofopioidreceptorsbymorphinealsoresultsinmatrixmetalloproteinase-9(MMP-9)releasefromprimarysensoryneurons,causingthecleavage(activation)andreleaseofinterleukin-1b(IL-1b)inSGCs.
TNF-aandIL-1bbindrespectiveTNFRandIL-1Ronsensoryneuronstoelicithyperexcitability.
SGCscanalsoreleaseATPviahemichannels(Cx43andPNX1)orgapjunctioncommu-nicationtoactivateP2X3inneuronsfortriggeringperipheralsensitization.
Inaddition,SGCsexpressKir4.
1tomaintainhomeostasisofextracellularK+levelsofsensoryneurons,andinjury-induceddownregulationofKir4.
1inSGCswilldisruptthisK+homeostasisandgenerateneuronalhyperexcitability.
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022spinalcircuittomediateTNF-a-inducedpain.
ArecentstudyalsodemonstratedthatTSP4,producedbyastrocytes,increasedsEPSCfrequency[132].
GlialmediatorssuchasIL-1bandCCL2alsoincreasetheampli-tudesofsEPSCs,viaAMPA-mediatedpostsynapticmechanisms(Fig.
5A).
TNF-aisknowntoinducethetrafckingandsurfaceexpressionofAMPAreceptorsinhippocampalneurons[12,220].
Afterspinalcordinjury,TNF-ainducesrapidtrafckingofGluR2-lackingAMPARstotheplasmamembraneinspinalcordmotorneurons[59].
Ofnote,inammationinducesaTNF-a–dependentsurfacetrafckingofGluR1-AMPARsinthedorsalhorn[32].
AlthoughTNFR1isthepredominantreceptormediatingtheeffectsofTNF-a,bothTNFR1andTNFR2arerequiredfortheinductionofcentralsensitization[301,309].
Pro-inammatorycytokinesandchemokinesfurtherinducecentralsensitizationviaextrasynapticmechanisms(Fig.
5A).
NMDAcurrentsinlaminaIIneurons,inducedbybathapplicationofNMDAtospinalcordslices,areenhancedbyIL-1b,TNF-a,orCCL2[72,128].
TNF-aincreasesNMDAreceptor(NMDAR)activitythroughphosphorylationofERKindorsalhornneurons[292].
IL-1binducesphosphorylationoftheNR1subunitinspinalcordneurons[302].
AstrocyticD-serineenhancesNMDAcurrentsviabindingtheglycinesiteofNMDAreceptors[201].
Interestingly,astrocyticglutamatereleasecanbedetectedasslowinwardcur-rents,viapatch-clamprecordingsinnearbyneurons.
SlowinwardcurrentsaremediatedbyextrasynapticNR2Breceptorsandin-ducedinspinaldorsalhornneuronsafterinammation[10].
4.
2.
ModulationofinhibitorysynaptictransmissionReductionorlossofinhibitorysynaptictransmission(disinhibi-tion)inthespinalcordpaincircuithasbeenstronglyimplicatedinthegenesisofcentralsensitizationandchronicpain[8,44,169,294].
Disinhibitionafterperipheralnerveinjuryinvolvesatrans-synapticreductionintheexpressionofthepotassium-chlo-rideco-transporterKCC2andsubsequentdisruptionofanionhomeostasis(chloridehomeostasis)inspinallaminaIneurons.
Insomecases,theshiftinthetransmembraneaniongradientcanconvertnormallyinhibitoryanionicsynapticcurrentstobeexcit-atory[44].
GlialmediatorssuchasBDNF,cytokines,chemokines,andPGE2canalsomodulateinhibitorysynaptictransmissionviapre-,post-,andextrasynapticmechanisms(Fig.
5B).
Presynaptically,IL-1bandIL-6wereshowntoinhibitthefrequencyofspontaneouspostsyn-apticcurrents(sIPSCs)inspinallaminaIIneurons[128].
Postsyn-aptically,IL-1breducesthesIPSCamplitude[128].
PGE2inhibitsglycinergicneurotransmissioninthedorsalhornviapost-synapticGlyR3andthecAMP/PKApathway[5,96].
Atextrasynapticsites,GABAandglycinecurrents,inducedbybathapplicationofGABAandglycine,canbesuppressedbyIL-1bandIL-6[128].
BDNFactsonspinallaminaIneuronstoreverseGABAinhibitionbyalteringchloridereversepotential[43].
Fur-thermore,ATPormorphine-stimulatedmicrogliaresultinadepo-larizingshiftintheanionreversalpotentialbyreleasingBDNF[43,60].
Likenerveinjury,administrationofATP-stimulatedmicrogliaorpharmacologicaldisruptionofchloridetransportinvivoalterthephenotypeofspinallaminaIoutputneurons,lead-ingtoneuropathicpainphenotypes[129].
TNF-awasalsoshowntosuppressactionpotentialsinGAD67+inhibitoryneuronsinspinalcordslices[296].
Moreover,CCL2andIFN-cinhibitGABA-inducedresponsesinspinalcordneurons[81,259].
Itremainstobeinvestigatedhowanti-inammatorycytokines(eg,IL-4,IL-10,TGF-b)regulatesynapticplasticity.
ItappearsthatIL-10cansuppressTNF-a-inducedsynapticplasticity(unpublishedobservations).
Inparticular,theanti-inammatorylipidmediatorssuchasresolvinE1(RvE1)andneuroprotectin(NPD1)blockedTNF-a-inducedsynapticplasticity(sEPSCfrequencyincrease)[292].
NPD1andRvD2furtherreversedinammation-inducedsynapticplasticityandtetanicstimulation-inducedspinallong-termpotentiation(LTP)[189].
Finally,theproinammatorycytokinesTNF-a,IL-1b,andIL-6alsoelicitlong-termneuronalplasticityinthepaincircuitbyinducingthephosphorylationofthetranscriptionfactorcAMPre-sponseelement-bindingprotein(CREB),leadingtothetranscrip-tionofCREB-mediatedpronociceptivegenes(eg,cyclooxygenase-2[COX-2],neurokinin-1[NK-1])inspinalcordneurons[111,128,206].
Ofnote,TNF-aissufcienttoinducespinalLTPafternerveinjury[154],andtetanicstimulation-inducedspinalLTPisabolishedinTNFR1orTNFR2knockoutmice[188].
4.
3.
ConcludingremarksInthepastdecadegreatprogresshasbeenmadetodemon-stratecriticalrolesofglialcells,suchasmicroglia,astrocytes,andSGCsinthegenesisofpersistentpain.
Asevidenceemerges,thelistofglial-derivedsignalingmoleculesandmediatorscontin-uestogrow(Tables1–4).
Gliacancommunicatewithneuronsby''listening''and''talking''toneurons.
Itisincreasinglyappreciatedthatchronicpaincanmanifestnotonlybyneuralplasticitybutalsobydysfunctionofglialcells.
Underthenormalphysiologicalconditions,astrocytesandSGCsprovidetrophicsupporttoneuronsandmaintainthehomeostasisofK+,glutamate,andH2OinCNSandPNS[258].
AstrocytesandSGCscouldalso''insulate''theneuralcircuitofpainbyformingastructuralbarrierandkeepthecircuitsilentbyreleasinginhibitorymediators[172].
Nervein-jury-inducedchronicpainisassociatednotonlywithneuropathybutalsowith''gliopathy.
''AstrocyteslosetheirabilitytomaintainthehomeostasisofK+andglutamate,leadingtoneuronalheperex-citability,asaresultofhigherextracellularlevelsofglutamateandK+.
Dysfunctionofastrocyticwaterchannel(AQP4)willalsoresultinedemaintheCNSandPNS[258].
Asaresultofgliopathy,gliacannolongerinsulatethepaincircuit;insteadtheyserveasanampli-erofpain,byproducingproinammatoryandpronociceptivemediators.
PainfulinjuriesevokerapidreactionofSGCsinthePNS,fol-lowedbymicroglialandastrocyticreactionintheCNS.
Moststud-iesongliaandpainfocusonmicrogliaandastrocytesinthespinalcord.
Uponactivation,presumablyinitiatedbyneuronalsignals,gliasynthesizeandreleaseproinammatoryandpronociceptivemediators(eg,proinammatorycytokinesandchemokinesandgrowthfactors)toenhancepainstates,viaactivationofkeysignal-ingpathways,suchastheMAPkinasepathways.
Activationofhemichannels(eg,Cx43andPNX1)andP2X7resultsinthereleaseofATPandglutamatefromastrocytes.
Importantly,glialmediators(eg,TNF-a,IL-1b,IL-6,CCL2,BDNF)canpowerfullymodulateexcit-atoryandinhibitorysynaptictransmissionatcomparablylowerconcentrations.
Glialmediators(ATP,CCL2,IFN-c,bFGF,MMP-2)alsoresultinfurtheractivationofglialcellsviaparacrineorauto-crineregulation.
Lastbutnottheleast,gliamayalsoproduceanti-inammatoryandantinociceptivemediatorsfortheresolutionofacutepain.
Furtherinquiryisneededtodeterminewhetherfailureintheproductionoftheseresolutionmediatorsleadstothetransi-tionfromacutepaintochronicpain.
5.
Remainingquestionsandfuturedirections5.
1.
IsglialactivationassociatedwithpainDespitethegrowingimportanceofglialcellsinpainregulation,''glialactivation''isnotwelldened.
Moststudiesintheelduseglialreaction(upregulationoftheglialmarkersIBA1,CD11b,andR.
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022GFAPtodenetheactivationofmicroglia(IBA1/CD11b),astrocytes(GFAP),andSGCs(GFAP)(Table1).
Althoughtheupregulationofthesemarkersisassociatedwithpainbehaviors,especiallyintheinductionphase,thereareseveralcaveatsrelatedtothesemarkers.
First,dissociationbetweenmicroglialmarkerexpressionandpainbehaviorshasbeenreportedbydifferentgroups[21,38,307].
Com-paredtomicroglialmarkers(IBA1andCD11b),theastrocyticmar-kerGFAPisbettercorrelatedwithpainbehaviors,especiallyafterinammation,bonecancer,chemotherapy,andHIVneuropathy[98,211,297,307].
Second,weshouldnotexcludemicroglialactiva-tionifthereisnochangeinIBA1expression.
Glialactivationcanalsomanifestasquickresponses,suchasCa2+changesandphos-phorylationofsignalingmolecules(eg,MAPKs)thatcouldoccurwithinminutesafterastimulationorinsult.
Indeed,sensorywhis-kerstimulationwasshowntoevokerapidincreases,withinseveralseconds,inastrocyticcytosolicCa2+inthebarrelcortexofadultmice[266].
Third,evenundertheactivationstateswithupregula-tionofglialmarkersandhypertrophy,microgliacouldstillhavedifferentfunctionalstatesbyexhibitingeitherpro-inammatory(neurotoxic,M1)andanti-inammatory(neuroprotective,M2)phenotypes[93,284].
Finally,andimportantly,glialreactivityandmorphologicalchangesdonotdirectlymodulatepain.
Neuronalactivityandpainsensitivityarecontrolledbytheglialmediators(cytokines,chemokines,ATP,BDNF,glutamate).
Thus,theregula-tionofglialsignalingmoleculesandglialmediatorsafterpainfulinjuries(Tables2–4)couldbebetterassociatedwithpainstatesthanglialreactivity.
5.
2.
CanwetargetgliaforpaintherapyHowcanwedesigndrugstotargetglialactivityforpaincon-trolDowereallyneedglia-selectivedrugsIndeed,itisextremelydifculttodesigndrugsthattargetonlyglialcellswithoutaffect-ingneurons.
Furthermore,eliminationofglialcellswithglia-selec-tivetoxinsmaycausedetrimentaleffects,giventhesupportiveandprotectiverolesofglia.
Instead,therearealternativestrategies:(1)totargettheMAPKsignalingpathways(ERK,p38,JNK),hemichan-nels(eg,Cx43andPNX1),orP2X7tosuppressthereleaseofglialmediators;(2)totargettheupstreamactivatorsofglia,suchasP2X4,P2Y6/12,MMP-9/2,andcathepsinS;and(3)totargetthedownstreammediatorsreleasedbyglia,suchasTNF-a,IL-1b,IL-6,orBDNF.
Weshouldlearnlessonsfromrecentfailuresin2clinicaltrials:1trialwithaglialmodulator,propentofylline,whichshowednoefcacyinreducingneuropathicpaininpatientswithpost-her-peticneuralgia[141];anothertrialwithaCCR2antagonistAZD2423,whichshowednosignicanteffects,comparedtopla-cebo,inpost-traumaticneuralgiapatients[122].
Thefailuresmayresultfrommultiplereasons,includinglackoftranslationfromrodentstohumanbeings,differentwaysofpainmeasurementinrodentsandhumanbeings(evokedpainvsspontaneouspain),anddifferentpainconditionstestedinrodentsandhumanbeings(nervetrauma-inducedpainhypersensitivityinseveralweeksvspost-herpetic/traumaticneuralgiaaftermanyyears).
Ofnote,pro-pentofyllineisawell-knowninhibitorofphosphodiesterase,andthereforecouldaltercAMPlevelsinglialandnon-glialcells[63].
Propentofyllineisalsoanadenosineuptakeinhibitor[63].
Com-paredtothecompletelackofeffectofpropentofylline,AZD2423(150mg)showedsometrendstowardreductioninparoxysmalpainandparesthesia/dysesthesia,indicatingthataCCR2antago-nistmayhavesomepossibleeffectsforsomesensorycomponentsofpain[122].
Notably,thevariabilitybetweenandwithinindivid-ualswasveryhigh,inpartbecauseofthenatureofamulticentertrial.
ItisalsoaconcernthatinhibitionofglialresponsesintheCNScannotbevalidatedinthistrial,becauseofthelackofeffectiveimagingtechniquefordetectingglialresponses(seeSection6.
3).
Theoretically,itshouldbemoreeffectiveforadrugtotargetbothneuronsandgliaforpainrelief.
Forexample,p38isactivatedbothinspinalcordmicrogliaandDRGneurons,andsystemicp38inhibitorhasbeenshowntoalleviateneuropathicpaininaclinicaltrial[6].
Recentstudieshavedemonstratedthattheanti-inamma-toryandpro-resolutionlipidmediatorssuchasresolvins(RvD1,RvD2,RvE1),protectins/neuroprotectins(PD1/NPD1),andlipoxins(LXA4)couldpotentlyreduceinammatoryandpostoperativepain,atverylowdoses[101,114,231].
Peri-surgicalapplicationofPD1/NPD1effectivelyprotectsnervetrauma-inducedneuropathicpainandspinalcordglialactivationinmice[291].
RvE1andPD1furtherinhibitglialactivationincultures[290,291].
Thereceptorsofthesemediators,suchasChemR23(RvE1)andALX(RvD1andLXA4)arewidelyexpressedinneurons,glia,andimmunecells[39,114,210,231].
Thus,theselipidmediatorsnotonlyinhibitglialactivationandinammationbutalsoinhibitTRPchannels(eg,TRPA1/V1)andreversesynapticplasticityinneurons[114,188,189].
Giventhepotencyandsafety,theseendogenousli-pidmediators,ortheiranalogs,orsmall-moleculeagonistsoftheirFig.
6.
Glialbrillaryacidicprotein(GFAP)immunostainingofmouse,rhesusmonkey,andhumanastrocytesincortex.
Notestrikingdifferencesinthesizesofmouse,monkey,andhumanastrocytes.
Alsonotedifferencesinthenumberandlengthsofbranchesofastrocytesfrommouse,monkey,andhumanbeing.
Sizesofastrocytesincreasewithincreasingcomplexityofbrainfunction.
Scale,50lm.
ImagesarereproducedfromKimelbergandNedergaard[133],withpermission.
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022receptors,couldbedevelopedforpreventingandtreatingchronicpain,viatargetingbothneuronalandnon-neuronal(immuneandglial)mechanisms.
5.
3.
HowmuchdoweknowabouthumangliaLittleisknownabouttheroleofhumangliainpaincontrol.
In-deed,astrocytesfrommice,monkeys,andhumanbeingsarequitedifferentintheirsizes[180,182](Fig.
6).
ThehumanbrainappearstocontainsubtypesofGFAP-positiveastrocytesthatarenotrepre-sentedinrodents.
Inhumancortex,astrocytesaremorethan2-foldlargerindiameterandextend10-foldmoreGFAP-positiveprimaryprocessesthantheirrodentcounterparts(Fig.
6).
Thedomainofasinglehumanastrocytehasbeenestimatedtocontactupto2mil-lionsynapses[133,180].
Remarkably,humanglialprogenitorcells(GPCs),afterbeingimplantedintoneonatalimmunodecientmice,aregapjunction-coupledtohostastroglia,propagateCa2+signals3-foldfasterthantheirhosts,andexhibitenhancedLTPandlearn-ingcapability[88].
Hence,humanastrocytescouldplayamoresophisticatedroleinchronicpainthanrodentastrocytes.
Impor-tantly,astrocytereaction,butnotmicroglialreaction,isassociatedwithchronicpaininHIV-infectedpatients[211].
ActivationoftheMAPKpathwaysisalsocorrelatedwithneuropathicpaininthesepatients[211].
Futureresearchshouldfocusonthefollowing:studyingtheresponsesofhumangliainculturesandhumangliatransplantationinmice;investigatingthechangesinhumangliainpainfuldiseaseconditionsinpostmortemtissues;andimagingreal-timeglialactivationinpatientswithchronicpain.
ConictofintereststatementTheauthorsdeclarenoconictofinterestinregardtothiswork.
AcknowledgmentsThisworkwassupportedbyNationalInstitutesofHealthGrantsNS67686andDE17794(toR.
R.
J.
)andDE22743(toR.
R.
J.
andM.
N.
).
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