宋學(xué)軍Xue-Jun

Song,

MD,

PhD癌性神經(jīng)病理性疼痛治療的新靶點(diǎn)2癌性和神經(jīng)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(zhèn)痛藥； 2.阿片類鎮(zhèn)痛藥

3.抗驚厥類藥；

4.抗抑郁藥★外周/中樞神經(jīng)阻滯、刺激、毀損:★

外科性治療：各種微創(chuàng)、介入和常規(guī)手術(shù)

1.神經(jīng)阻滯（局麻藥,阻斷Na+通道，神經(jīng)沖動(dòng)傳導(dǎo)阻滯)

2.外周/中樞神經(jīng)電刺激(周圍神經(jīng)PNS、脊髓SCS、深部腦DBS、運(yùn)動(dòng)皮層MCS)3.穴位電針(HANS)和經(jīng)皮電刺激(TENS))(內(nèi)啡肽腦啡肽強(qiáng)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(shù)方法的應(yīng)用★

中醫(yī)中藥的應(yīng)用以阿片類藥物為主的靶向性、綜合性、個(gè)性化治療Lancet

2011★

姑息治療??兩個(gè)新分子靶點(diǎn)：藥物治療癌性神經(jīng)病理性疼痛的分子靶點(diǎn)（機(jī)制研究）對(duì)靶向性治療癌性神經(jīng)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(gè)嶄新概念:

神經(jīng)損傷或癌性刺激等強(qiáng)烈應(yīng)激反應(yīng)激活在神經(jīng)元軸突－突觸的發(fā)育形成和可塑性調(diào)節(jié)以及神經(jīng)再生過(guò)程中發(fā)揮重要作用的一類分子信號(hào)，它們因此在有關(guān)疼痛的發(fā)生發(fā)展過(guò)程中發(fā)揮關(guān)鍵作用。這些分子信號(hào)并不參與正常生理性疼痛的過(guò)程。揭示了神經(jīng)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(xì)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(duì)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(gè)新分子靶點(diǎn)：藥物治療癌性神經(jīng)病理性疼痛的分子靶點(diǎn)（機(jī)制研究）對(duì)靶向性治療癌性神經(jīng)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(hào)活動(dòng)可以抑制神經(jīng)病理性疼痛21SpinalblockingWntsignalinginhibitsproductionandpersistenceofbonecancerpain

in

TCI

miceCADBEFGHFigure7抑制脊髓WNT信號(hào)活動(dòng)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(hào)通路激活的核心環(huán)節(jié)是細(xì)胞漿破壞復(fù)合體對(duì)β-catenin的調(diào)控那么,是什么通過(guò)怎樣的機(jī)制調(diào)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(zhuǎn)核門控機(jī)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(xì)胞漿轉(zhuǎn)移到細(xì)胞核，能夠非常好的抑制神經(jīng)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(zhuǎn)核門控機(jī)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