疼痛的中枢机制

疼痛的中枢机制于布为教授上海第二医科大学附属瑞金医院DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.疼痛DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.“Wemustalldie.ButthatIcansavehimfromdaysoftorture,thatiswhatIfeelismygreatandevernewprivilege.Painisamoreterriblelordofmankindthanevendeathitself.”-AlbertSchweitzerDepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.国际疼痛研究会（IASP）对疼痛的定义（2001):ƒ疼痛是与实际或潜在的组织损伤相关联的不愉快的感觉和情绪体验，或用这类组织损伤的词汇来描述的主诉症状；ƒ无交流能力决不能否认一个个体正有着痛体验，需要适当缓解疼痛治疗的可能性；ƒ疼痛既是一种生理感觉，又是对这感觉的一种情感反应。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.疼痛的意义DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.„疼痛是一种警戒信号：表示机体已经发生组织损伤或预示即将遭受损伤，通过神经系统的调节，引起一系列防御反应，保护机体避免伤害。疼痛长期持续不止，便失去警戒意义，反而对机体构成难以忍受的精神折磨，严重影响学习、工作、饮食和睡眠，降低生活质量，产生一种不可忽视的经济和社会问题。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.疼痛的产生DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.„由一定的刺激（伤害性刺激）作用于外周感受器（伤害性感受器），换能后转变成神经冲动（伤害性信息），循相应的感觉传入通路（伤害性传入通路）进人中枢神经系统，经脊髓、脑干、间脑中继后直到大脑边缘系统和大脑皮质，通过各级中枢整合后产生疼痛感觉和疼痛反应。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.伤害感受器•游离的神经末梢•广泛分布于机体的皮肤、肌肉、关节和内脏等不同组织DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.传入伤害信息ƒ主要是Aδ和C纤维ƒ沿背根进入脊髓背角ƒ再将伤害信息传向脊髓以上的结构DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.躯干、四肢的痛觉通路：新脊-丘束旧脊-丘束或脊-网-丘束脊-颈束后索-内侧丘系脊髓固有束头面部的痛觉通路：三叉神经三叉丘系内脏痛觉通路：交感神经副交感神经脊髓上行通路脊髓丘脑束DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.痛觉的整合中枢DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.疼痛的中枢机制DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.闸门控制学说-MelzackandWall„20世纪60年代„脊髓背角的第II层,被认为是“闸门”所在„当粗纤维（Aδ）传导时，形成闸门关闭效应，而细纤维（C）传达时，形成闸门开放效应DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.NNN+-PainfibreSensoryfibreAscendingpain‘C’DescendinginhibitionPainSensationDescendingfacilitation-NTouch‘Aβ’闸门控制学说DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.„根据这一理论,可利用特定的(高频、低强度)电刺激来兴奋粗的有髓纤维,通过抑制同一节段细纤维的传入而发挥镇痛作用,构成了“经皮电刺激镇痛”(TENS)的基本原理。„另外，SCS疗法、McGill疼痛问卷（MPQ）也是根据闸门控制理论推出的。闸门控制学说DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.内源性痛觉调制系统ƒ20世纪70年代ƒ发现“阿片肽”家族ƒ“下行抑制系统”的提出DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.阿片肽与阿片受体DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.下行抑制系统DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.内源性痛觉调制系统针刺镇痛DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.可塑性改变或者中枢敏感化„20世纪80年代„痛觉过敏„感觉异常„引发“超前镇痛”理论DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.痛觉过敏与感觉异常DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.神经重塑NNN+-PainfibreSensoryfibreAscendingpain‘C’DescendinginhibitionPainSensationDescendingfacilitation+NTouch‘Aβ’DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.中枢敏感化DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.20世纪90年代－„疼痛的分子生物学研究得到发展„寻找痛靶分子„进行靶向治疗DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.SP/NK-1,BDNF/TrkB,EAAs/NMDA,GABA,PKs,ATP/P2X3,COX-2,Ca2+,etc.DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.SP/NK-1受体DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.SP/NK-1受体‰ActivatephospholipaseC→→↑Ca++„PIP2-IP3-ligand-gatedERCa++channels„PIP2-Diaglyceride-PKC-voltage-sensCa++‰↑cAMP‰↑cGMP‰Slowdepolarization–excitatory‰EnhancedresponsivenessofNMDAreceptorDepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.BDNF/TrkB受体„神经营养因子家族中的一员，能够促进神经细胞生长、分化和再生；„在脊髓背角中作为神经递质和神经调质，参与对伤害性感受的调节。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.EAAs/NMDA受体„促进Ca2+离子内流，激活PKC蛋白；„诱导GABA受体磷酸化，使其兴奋抑制作用减弱；„在脊髓神经元敏化中具有关键作用，参与神经重塑。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.ATP/P2X3受体„ATP是伤害性传入纤维末梢释放的神经递质；„P2X3只在背根神经节中在与伤害性感受有关的小直径细胞表达。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.COX-2表达IL-1受体的神经细胞结合可以分泌COX-2，使得PGE2的水平增加，作用于突触前后，易化突触传递，提高神经兴奋性。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedicalUniversity.胶质细胞„神经调制、神经营养和神经免疫；„与痛觉过敏的产生和疼痛持续状态有关。神经损伤后，可以激活胶质细胞，释放神经活性因子，包括疼痛相关的活性物质，引起一系列的生化和病理反应，参与脊髓疼痛调制过程，从而导致痛觉改变或痛觉过敏。DepartmentofAnesthesiology,RuiJinHospital,ShanghaiSecondMedical