疼痛机理与临床学习班

从临床角度透视疼痛机理,贵阳医学院附院麻醉科曾庆繁,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,什么是疼痛？,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months or years,Acute pain is a normal and predictable physiologic response to an adverse chemical, thermal, or mechanical stimulus; it is associated with surgery, trauma, or acute illness and is usually experienced for a limited and defined period of time,a few days or a few weeks,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amputation 100%慢性疼痛或不适开胸手术thoracotomy 50-60% 疼痛持续6月 甚至 出现病理性神经痛-烧灼样 痛/麻刺感burning and tingling. 乳房切除术mastectomy 50-60%疼痛持续6月开腹胆囊切除术open cholecystectomy 19%腹腔镜胆囊切除术laparoscopic cholecystectomy 9%,病理性疼痛三大表现,定义,疼痛 ：组织损伤 信息传递 脊髓 脑 不愉快的感觉 情绪上的感受,疼痛信息传递,Transduction转导（换能transducer换能器）,不同的伤害性刺激非电刺激1.热thermal2.机械mechanical3.化学chemical stimuli 伤害性感受器NociceptorsA C纤维游离神经末梢 能量转换converted to 电信号electrical signals,Nerve growth factor,sufficient strength noxious stimulus depolarizes the nociceptor membrane. expression of transducing ion-channel receptors. nonselective potassium or sodium channels gated by temperature, chemical stimuli, or mechanical shearing forces rather than by voltage,Transmission传递,A fibers: large myelinated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NociceptorsA fibers： 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 Mechanical thermal chemical stimuli C-多型伤害感受器C-polymodal nociceptors 传导慢 烧灼样痛,第一痛由有髓鞘的A纤维传导，而第二痛则由无髓鞘的C纤维传导。选择性阻断A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）。,“Lissauers tract 脊髓背角 dorsal horn 二级投射神经元“second-order” pain transmission cell projection neurons,1.疼痛传导特定神经元(NS) 位于板层 A C 接受伤害性刺激传入 ,2.广动力范围神经元(WDR) large “receptive fields”位于板层lamina V 接受伤害性和非伤害性刺激,投射神经元Projection neurons,Pain input to the spinal cord:lamina I A-delta and C fibers lamina II C fibers and relay it to other laminae.lamina V (wide-dynamic range neurons) A-delta, C and A-beta (low threshold mechanoceptors),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,GluSP,A C,Projection neurons,-A-delta and Cfibers co-release1.GluNMDA/ nonNMDA-R + 2.SPNK-1 R 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 “ local streets 外侧丘脑 内侧丘脑,疼痛神经递质,freeway,local streets,疼痛的脊髓调控,中枢下行调控,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,5-HT蓝班NE,脑啡肽 强啡肽,抑制性中间神经元,触突前抑制 触突后抑制,Inhibitory Neurotransmission1. Inhibitory interneurons or descendingprojections release various NTs: GABA, NE, or endogenous opioids2. Bind receptors on presynapse ofafferent pain fiber, inhibit Ca2+ channels,leading to reduced vesicle release3. Also bind post-synaptically: can signalvia G-proteins to cause K+ efflux orCl- influx (both are hyperpolarizing),GluSP,nociceptors do not adapt,连续刺激continued stimulation 1.感受器反复放电自发性疼痛continuous or repetitive firing of the nociceptor 2.感受器反应域值下降 a decrease in the threshold 外周(感受器)敏化sensitization of nociceptors,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“central sensitization” 痛觉过敏 hyperalgesia痛觉倒错 allodynia.,Mechanisms of peripheral and central sensitization in neuropathic pain.,Primary Afferentpathways,descending modulatory Systems（NE/5-HT）opioid,noxiousstimulus, such as an injury or disease,持续伤害性刺激手术炎症神经损伤,外周敏化Peripheral sensitization to pain:,1.感受器反复放电continuous or repetitive firing of the nociceptor 2.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a decrease in the threshold 对热 冷 静态机械刺激 交感神经释放的NE敏感,一炎症汤“inflammatory soup”,nociceptor function is altered by the “inflammatory soup” that characterises a region oftissue injury.,CGRP,CGRP,Peripheral sensitization to pain:,neurogenicinflammation,degranulation,nitric oxide,Plasmae xtravasation,phospholipaseA2,1.Bradykinin:powerful algogenic substance, from kininogens in the circulation, activates nociceptors in a way that is dependent on protein kinase C and calcium,2.cytokines(interleukins interferon tumour necrosis factor)Spontaneous pain(ongoing)瘙痒 走蚁感TNF- 拮抗剂阿达木单抗（Adalimumab） 依那西普(Etanercept) 因福利美InfliximabNSAIDS?治疗,PKA phosphorylates Nav1.8/1.9; PKC phosphorylates noxious stimuli receptors (TRPV, ASIC)4. Result: increased ion influx per depolarization; lowered activation threshold,Upregulated 3.Nerve growth factor(fibroblastsandSchwannCells)tyrosine kinase receptorsincreases the excitability of nociceptors which leads to hyperalgesia,Capsaicin receptor4.purines receptorP2X3 (a ligand-gated ion channel triggered by ATP) which is selectively expressed by small-diameter sensory neurons5.acid-sensing ion channelis rapidly activated by conditions of acidity below pH 静态不痛的机械压力刺激:用手轻压皮肤钝痛,6. prostaglandin E2 adenosine Serotonin 改变离子通道的电压阈值易化动作电位传递7.TRPM8 receptor冷痛域下降 冷刺激:20 C物体接触皮肤烧灼样痛治疗:TRPM8受体拮抗剂 薄荷Menthol?,Damaged nerves,Sodium channel,NGF,-R,TRPV1-R,1.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-R TRPV-1 R 表达(在未损伤纤维),1.TRPV1 receptor热痛域下降热刺激:40 C 物体接触皮肤烧灼样痛辣椒素治疗2.1 2 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:Paroxysmal pain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,Central sensitization,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),Central sensitization (WDR),AMPA-R,NE/5-HT, R,Ca+ 通道,Glu,GABA,Na通道,触突后:1.AMPA表 A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 Glu sp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 R4.下行易化系统,Mitogenactivated protein kinase system (MAPK).,触突前治疗:1.-receptor agonists Opioids2.Cal