宋學軍Xue-Jun

Song,

MD,

PhD癌性神經病理性疼痛治療的新靶點2癌性和神經病理性疼痛的臨床治療候選方案★藥物治療:

1.非甾體類消炎鎮痛藥； 2.阿片類鎮痛藥

3.抗驚厥類藥；

4.抗抑郁藥★外周/中樞神經阻滯、刺激、毀損:★

外科性治療：各種微創、介入和常規手術

1.神經阻滯（局麻藥,阻斷Na+通道，神經沖動傳導阻滯)

2.外周/中樞神經電刺激(周圍神經PNS、脊髓SCS、深部腦DBS、運動皮層MCS)3.穴位電針(HANS)和經皮電刺激(TENS))(內啡肽腦啡肽強啡肽）4.射頻熱凝

(破壞熱耐受性差的C類和Aδ類纖維，60-75oC)★

麻醉技術方法的應用★

中醫中藥的應用以阿片類藥物為主的靶向性、綜合性、個性化治療Lancet

2011★

姑息治療??兩個新分子靶點：藥物治療癌性神經病理性疼痛的分子靶點（機制研究）對靶向性治療癌性神經病理性疼痛的最新探索●EphrinB-EphB

signaling

●

WNT

signalingPeripheralnervesandtheDRGPeripheralnociceptorsModified

from

McMahonandBennett:PainmechanismsNatRevNeurosci2007BrainPainmechanismsSpinalcordNeuron/glia/others5Neuropathicpain-inducingstimulie.g.,Proinflammatorycytokines(IL-1β,TNF-α)NeuropathicpaincancerpainNeuralpathwayNon-neural

(glialcells)pathway★Ourhypothesise.g.,NMDARsSpinal

centralsensitization我們首先提出并論證了這樣一個嶄新概念:

神經損傷或癌性刺激等強烈應激反應激活在神經元軸突－突觸的發育形成和可塑性調節以及神經再生過程中發揮重要作用的一類分子信號，它們因此在有關疼痛的發生發展過程中發揮關鍵作用。這些分子信號并不參與正常生理性疼痛的過程。揭示了神經病理性疼痛/癌性疼痛的嶄新概念和研究思路。e.g.,

nervedamage,

bonecancer,

etc.●EphrinB-EphB

signaling

●

WNT

signaling6EphrinB-EphBReceptorSignalingEphreceptor:namedforitsexpressioninanerythropoietin(紅細胞生成素)-producinghumanhepatocellularcarcinomacellline,consistofthelargestfamilyofreceptortyrosinekinases,whichplayvitalrolesintransmittingexternalsignalstotheinteriorofmanytypesofcells.EphBEphrinBNMDAReceptorAlphaScreenanalysisshowinginteractionofEphB1:NR17StructureofEphrinB-EphBreceptorsignalinganditsmutationmodels

A，SchematicofstructureofEphBandephrinB;B，KOmodelofEphB1(intracellularregion);C,KOmodelsofEphB1andEphrinB2WeCollaboratedwithDr.M.HenkemeyeratUTSouthwesternMedicalCenteratDallasWherethegeneticmiceweregenerated.

B

CAAAAWeinvestigatedrolesofephrinB-EphBreceptorsignalinginneuropathiccancerpainbymeansofpharmacologicalandgeneticapproaches8cbdaefGlialcellactivationBonecancerpainNeuropathicpainProinflammatorycytokines(IL-1β,TNF-α)TLRs/TLR4Neuronalhyperexcitability&enhancedsynapticplasticityNMDARs/NR1,NR2BCa2+-dependentsignalsEphrinB-EphBsignalingactivationBonecancerorNerveinjuryRolesofephrinB-EphBreceptorsignalinginneuropathicandbonecancerpainCentralSensitizationCancerResearch2011Pain

2008,2013CaMKIIGeneexpressionPhysicaldependenceonmorphineCREBNONOSNMDARs/NR1,NR2BGlutamateProlongedMORactivationEphrinB-EphBsignalingPKAPKGERKMMP-9activationIntegrinsJNeurosci2010FASEBJ

2009CancerResearch2011RolesofephrinB-EphBreceptorsignalinginmorphineaction10抑制脊髓EphB受體活性可以對抗嗎啡治療癌性疼痛的耐受作用SpinalinhibitionofEphBreceptorrescuesanalgesiceffectofmorphineintreatingTCI-inducedthermalhyperalgesiainratsanddefensivepaininmiceA,Mor:10mg/kg,s.c.,twiceaday.EphB2-Fc:2mg,i.t.,onceaday.B,EphB2-Fcinhibitsmorphine-inducedexpressionofEphB1.CancerResearch201111——

OneStone,TwoBirds

——2011;71(13):4392-402HighlightedbyNaturePublishingGroupAACR,etc.CancerResearch2011??兩個新分子靶點：藥物治療癌性神經病理性疼痛的分子靶點（機制研究）對靶向性治療癌性神經病理性疼痛的最新探索●EphrinB-EphB

signaling

●

WNT

signaling13CanonicalWNT/β-cateninpathwaysNoncanonicalβ-catenin-independentpathways?WNTsareafamilyofsecretedlipid-modifiedsignalingproteinsactingasshort-orlong-rangesignalingmoleculesintheregulationofcellularprocessesduringthedevelopmentofnervoussystems

and

others.?WNTligandsbindtothecysteine-richdomainfrizzled(FZ)receptorsandFZco-receptorstoactivateintracellularsignalingcascades.?TypicalWNTsignalingpathwaysincludecanonicalWNT/β-cateninpathwaysandnoncanonicalβ-catenin–independentpathways.●WNT

Signaling14Themostimportantregionsfornociceptivetransmission&integrationDRGneurons:ReceiveandtransmitnociceptiveinformationThesuperficial

layers

of

spinaldorsalhorn:GateControlTheoryofPainWeinvestigatedrolesofWNTsignalinginDRGand

spinaldorsalhorninneuropathicandbonecancerpainAnimal

Models:Peripheral

nerve

injury?CCI

modelBone

cancer

pain

model

-tumorcellimplantation(TCI,tibia):2×105;NCTC2472.15ABCDFigure1Zhangetal.,JCI2013Liuetal.,Pain2015ExpressionofWNTgenesandprotein

inDRGandthespinalcord

is

greatly

increased

after

nerve

injury16DistributionofWnt3ainDRGsensoryneuronsafternerveinjuryABCZhangetal.,J

Clin

Invest2103TheincreasedWnt3a

isseeninall

DRGcells,butmostinthenociceptivesmallandmedium-sizedcells.

Inthesmallcells,

Wnt3amostintheCGRP-positiveones.Figure217ExpressionanddistributionofWnt3ainthespinalcord

after

CCIFigure3ABCThe

increasedWnt3aisalsoseeninthesuperficiallayersofspinaldorsalhornipsilateraltothenerveinjury;

Wnt3aiscolocalizedwithneuronalsomaanddendritesand

astrocytes.18Nucleartransportation(activation)ofβ-catenininthespinalcord,butnotinDRGafternerveinjuryABCDZhangetal.,JCI2013Figure419Figure5.Increased

expressionofWnt3a,Fz1,Fz8,andβ-cateninproteinandthe

cellulardistributionofWnt3ainmousespinalcordinamodelofbonecancer.ACBDTCIactivatesWNT/β-cateninpathwayinthespinalcordZhangetal.,J

Clin

Invest2103Activation

of

theWNT/β-cateninpathwayinthespinalcord

is

matching

the

time

course

of

pain

development

after

CCI

and

TCI,

respectively.20A-D.SpinalblockingWntsignalinginhibitsproductionandpersistenceofneuropathicpaininCCIrats.E,F.Wntagonistevokespaininna?verats.ACBDEFFigure6抑制脊髓WNT信號活動可以抑制神經病理性疼痛21SpinalblockingWntsignalinginhibitsproductionandpersistenceofbonecancerpain

in

TCI

miceCADBEFGHFigure7抑制脊髓WNT信號活動可以抑制癌性疼痛22E

Figure9Zhangetal.,JCI2013FChIPassay:

ananti–β-cateninantibodyprecipitatedchromatinDNAcontainingIL-18promotersequences.23SpinalcentralsensitizationNeuropathicpainGlialactivationProinflammatorycytokines,IL-18,TNF-αinspinalcordWNT/β-cateninpathwayNerveinjuryorbonecancerEnhancingneuralsynapticplasticityNR2BandCa2+-dependentsignalsZhang

et

al.,

JCI

201324

Azzolin

et

al.,

Cell

2014

Wnt信號通路激活的核心環節是細胞漿破壞復合體對β-catenin的調控那么,是什么通過怎樣的機制調控β-catenin？25Nerve

injuryWehave

foundthatneuropathic-pain-inducingnerveinjurycan

activate

Wnt

signaling

and

causenucleartranslocationofYAP/TAZ.

YAP/TAZactivityplaysacriticalroleinthepathogenesisofneuropathicpain.

Xu,

Wu,

et

al.,

J

Neurosci

2016.926

YAP/TAZ轉核門控機制“ON-OFF

Switch”27我們新合成抑制小分子dCTB可以抑制脊髓YAP/TAZ從細胞漿轉移到細胞核，能夠非常好的抑制神經病理性疼痛Xu,Wuetal.,JNeurosci201628SpinalcentralsensitizationNeuropathicor

cancer

painNerveinjuryorbonecancerXu

et

al.,

J

Neurosci

2016Zhang

et

al.,

JCI

2013Nucleartransportation(activation)ofβ-cateninnotseeninDRGCCItreatmentcausedneitheralterationofβ-cateninexpressionnorβ-cateninnucleartransport,indicatingthatWNTsignalingactivitydoesnotresultintheactivationofβ-catenin.Theseresultssuggestthat,afternerveinjury,WNTsignalingmayfunctioninaβ-catenin–independentpathwayinpresynapticDRGneurons,unlikeinthespinalcord.

Zhangetal.,JCI2013脊髓:

WNT/β-cateninYAP/TAZ

轉核門控機制“ON-OFF

Switch”InDRG

?Inspinalcord&DRGRykreceptorpathwayLiuetal.,Pain201529ExpressionofmRNAandproteinofRykreceptorinDRGandthespinalcordafternerveinjury----------Ryk-FL:FulllengthRyk-CTF:C-terminalfractionRyk-ICD:intracellulardomain30Nerve

injury

increases

expression

of

Ryk

and

greatnucleus-transportationofRykinDRG

cells31ActivationofWnt/Rykreceptorsignalingcontributestoincreasedactivityof[Ca2+]iandneuralhyperexcitabilityininjured-DRGs32ExpressionandcellulardistributionofRykreceptorinthespinaldorsalhorninshamandnerveinjuredrats33ActivationofWnt/Rykreceptorsignaling