疼痛机理与临床(学习班)课件

从临床角度透视疼痛机理疼痛机理离我们远吗?麻醉:抑制/对抗手术伤害性刺激

疼痛诊疗:针灸镇痛脊髓电刺激椎间盘突出的臭氧治疗交感神经阻滞治疗疼痛药物:TCA加巴喷丁卡马西平辣椒素分类(原因)生理性(创伤性)疼痛↓病理性疼痛:炎性痛病理性神经痛癌痛心理性疼痛

←急性疼痛:手术后疼痛创伤急性病←慢性疼痛monthsoryearsAcutepainisanormalandpredictablephysiologicresponsetoanadversechemical,thermal,ormechanicalstimulus;itisassociatedwithsurgery,trauma,oracuteillnessandisusuallyexperiencedforalimitedanddefinedperiodoftimeafewdaysorafewweeks急性疼痛总是涉及到组织损伤周围神经和中枢神经系统是动态的不是静止的可塑性手术后慢性疼痛截肢amputation100%→慢性疼痛或不适开胸手术thoracotomy50-60%疼痛持续6月甚至出现病理性神经痛-烧灼样痛/麻刺感burningandtingling.乳房切除术mastectomy50-60%疼痛持续6月开腹胆囊切除术opencholecystectomy19%腹腔镜胆囊切除术laparoscopiccholecystectomy9%疼痛信息传递Nervegrowthfactor↗sufficientstrengthnoxiousstimulusdepolarizesthenociceptormembrane.↓expressionoftransducingion-channelreceptors.nonselectivepotassiumorsodiumchannelsgatedbytemperature,chemicalstimuli,ormechanicalshearingforcesratherthanbyvoltageTransmission传递Aßfibers:largemyelinated传递非伤害性信息本体感觉轻触觉不传导疼痛

伤害性感觉神经元NociceptorsAδfibers：薄髓鞘传导快高阈值机械感受受体机械热受体传导快痛针刺样疼痛2.C-fibers(70%)

传递各种模式的伤害信息机械热化学刺激

MechanicalthermalchemicalstimuliC-多型伤害感受器C-polymodalnociceptors传导慢烧灼样痛第一痛由有髓鞘的Aδ纤维传导，而第二痛则由无髓鞘的C纤维传导。选择性阻断Aδ纤维的传导可使第一痛消失（中间），而选择性阻断C纤维的传导可使第二痛消失（底部）。“Lissauer’stract↓脊髓背角dorsalhorn二级投射神经元“second-order”paintransmissioncellprojectionneuronsPaininputtothespinalcord:laminaI

←A-deltaandCfiberslaminaII

←Cfibersandrelayittootherlaminae.laminaV(wide-dynamicrangeneurons)←A-delta,CandA-beta(lowthresholdmechanoceptors)1.疼痛传导特定神经元(NS)传导疼痛2.广动力范围神经元(WDR)传导刺激的类型和位置GluSPAδCProjectionneurons

-A-deltaandCfibersco-release1.Glu→NMDA/nonNMDA-R↑+2.SP→NK-1R电压依赖性离子通道开放Ca+Na+兴奋性触突后电位高速路小路“freeway“localstreets’↓↓外侧丘脑内侧丘脑疼痛神经递质疼痛的脊髓调控中枢下行调控脑内痛调制部位及其下行传导通路1、中脑导水管周围灰质（PAG）→、2、中缝大核及邻近的网状神经核（5-羟色胺能）3、蓝斑核群（去甲肾上腺素能神经元）→后侧索→脊髓后角。这些下行纤维直接、或通过脊髓内抑制性中间神经元，对脊髓后角投射神经元发挥抑制性调制作用，从而抑制伤害性信息向脑内的传递。PAG脑啡肽enk蓝班NE中缝大核5-HT脊髓背角胶质区抑制性中间神经元InhibitoryNeurotransmission1.InhibitoryinterneuronsordescendingprojectionsreleasevariousNTs:GABA,NE,orendogenousopioids2.Bindreceptorsonpresynapseofafferentpainfiber,inhibitCa2+channels,leadingtoreducedvesiclerelease3.Alsobindpost-synaptically:cansignalviaG-proteinstocauseK+effluxorCl-influx(botharehyperpolarizing)GluSPnociceptorsdonotadapt连续刺激continuedstimulation↓1.感受器反复放电→自发性疼痛continuousorrepetitivefiringofthenociceptor2.感受器反应域值下降adecreaseinthethreshold↓外周(感受器)敏化sensitizationofnociceptors传入纤维持续放电可引起投射神经元的反应发生改变中枢敏化“centralsensitization”

↓痛觉过敏hyperalgesia痛觉倒错allodynia.Mechanismsofperipheralandcentralsensitizationinneuropathicpain.PrimaryAfferentpathways←descendingmodulatorySystems（NE/5-HT）opioidnoxious

stimulus,suchasaninjuryordisease持续伤害性刺激手术炎症神经损伤外周敏化

Peripheralsensitizationtopain:1.感受器反复放电continuousorrepetitivefiringofthenociceptor2.异位从动背根神经节的电位震荡→自发性疼痛3.感受器反应域值下降adecreaseinthethreshold→对热冷静态机械刺激交感神经释放的NE敏感

一炎症汤“inflammatorysoup”nociceptorfunctionisalteredbythe“inflammatorysoup”thatcharacterisesaregionoftissueinjury.CGRPCGRPPeripheralsensitizationtopain:neurogenicinflammationdegranulation→nitricoxidePlasmaextravasationphospholipaseA21.Bradykinin:powerfulalgogenicsubstance,fromkininogensinthecirculation,activatesnociceptorsinawaythatisdependentonproteinkinaseCandcalcium2.cytokines(interleukinsinterferontumournecrosisfactor)↓Spontaneouspain(ongoing)瘙痒走蚁感TNF-α拮抗剂阿达木单抗（Adalimumab）

依那西普(Etanercept)

因福利美InfliximabNSAIDS?治疗PKAphosphorylatesNav1.8/1.9;PKCphosphorylatesnoxiousstimulireceptors(TRPV,ASIC)

4.Result:increasedioninfluxperdepolarization;loweredactivationthreshold

Upregulated3.Nervegrowthfactor(fibroblastsandSchwannCells)→tyrosinekinasereceptorsincreasestheexcitabilityofnociceptorswhichleadstohyperalgesiaCapsaicinreceptor4.purinesreceptorP2X3

(aligand-gatedionchanneltriggeredbyATP)whichisselectivelyexpressedbysmall-diametersensoryneurons5.acid-sensingionchannelisrapidlyactivatedbyconditionsofaciditybelowpH→静态不痛的机械压力刺激:用手轻压皮肤→钝痛6.

prostaglandinE2adenosineSerotonin改变离子通道的电压阈值易化动作电位传递7.TRPM8receptor↑冷痛域下降冷刺激:20ºC物体接触皮肤→烧灼样痛治疗:TRPM8受体拮抗剂薄荷Menthol?DamagednervesSodiumchannelNGFα-RTRPV1-R1.神经损伤/退变(上2)2.完整神经(下2)3.损伤→钠通道表达(2)4.NGF产生5.钠通道NE-RTRPV-1R表达(在未损伤纤维)1.TRPV1receptor↑热痛域下降热刺激:40ºC物体接触皮肤→烧灼样痛辣椒素治疗2.α1α2受体↑对NE刺激域值下降→SMP酚拖拉明治疗3.钠通道↑→自发性疼痛Lidocaine,Carbamazepine治疗二神经损伤损伤神经自发冲动脊髓神经元自发冲动→自发性疼痛阵发性电击样疼痛:Paroxysmalpain机理:外周伤害性感受器兴奋性增加异位冲动产生背根节电位振荡利多卡因TCA卡马西平Centralsensitization脊髓背角广动力神经元(WDR)兴奋性增加广动力神经元(WDR):接受伤害性和非伤害性传入表现为1.对伤害性刺激的反应活性增加(痛觉倒错)2.感受野的扩大(痛觉过敏)Centralsensitization(WDR)AMPA-RNE/5-HTµR

Ca+通道GluGABANa通道触突后:1.AMPA表↑↓Aβ纤维(轻触觉)传导疼痛→动态机械感觉倒错2.WDR钠通道表达↑→兴奋性触突后电位↑3.+MAPK(细胞内级联反应)触突前:1.传入C纤维触突前Ca+通道表达↑→Glusp释放↑2.抑制性中间神经元(GABA能)调亡3.下行抑制系统功能降低↓µR↓4.下行易化系统↑Mitogenactivatedproteinkinasesystem(MAPK).触突前治疗:1.μ-receptoragonistsOpioids2.Calcium-channelblocker:Gabapentin加巴喷丁3.α2-receptoragonists:Clonidin