疼痛治疗研究进展,首都医科大学麻醉学系,北京三博脑科医院,王保国,控制疼痛 医生的职责，患者的权利！,疼痛的定义,Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage , or described in terms of such damage. The international Association for the study of pain (IASP) 疼痛是一种与真正的或潜在的组织损伤有关的令人不愉快的感觉和情绪方面的经历。 国际疼痛研究协会(IASP),（APS , 1999）,这项调查包括了805名患有关节炎、背部疾病或其它疾病的慢性疼痛患者， 疼痛持续时间超过6个月，VAS评分为：5-10分 56患者的慢性疼痛病程超过5年 22患者被建议接受疼痛专家的治疗 47患者因为以下原因中的一种或几种屡次更换医生： 患者感觉“特别疼”（42） 医生缺乏疼痛治疗知识（31） 医生不重视患者感受到的疼痛（29） 疼痛未被积极治疗（27） 14患者每年ER大于1次 29患者更换医生大于3次,（APS , 1999）,美国的慢性疼痛调查,29%的加拿大人患有慢性疼痛(n=2012) 病人患有慢性疼痛的平均年数是10.7年 80%的病人报告曾经有中到重度疼痛的经历 各种疼痛都没有得到充分的治疗,IPSOS REID MARCH 2001 CANADIAN NATIONAL PAIN STUDY,慢性疼痛：加拿大的流行病学数字,多种痛机制,伤害感受 外周致敏 中枢致敏 异位兴奋 抑制降低/结构重组,周围神经系统可塑性的生理学机制,痛感受器的分布,膝关节的神经分布 带游离神经末梢的小的有髓和无髓纤维大部分都有疼痛的功能 带有感觉小体末梢的大的有髓纤维具有对本体感受有用的机械敏感功能,急性疼痛的病理生理学,Brookoff D. Hosp Pract (Off Ed) 2000;35:45,13,伤害性神经末梢处感受神经调质，细胞因子和神经营养因子的药理学感受器,Na+, Ca+,VR 1: Capsaicin Eicosanoids, H+,BK 1,2: Bradykinin, 1,2: Adrenergic,5-HTx,NK1:,Signal cascade: Ca+, cAMP, Kinases, Phosphorylation, .,Receptors mediate: - Excitation, Synergy - Potentiation - Sensitization, other Plasticity,Ion-channels: Na+, Ca+, K+,Receptor proteins are transported intra-axonally,Trk,Neurotrophins e.g. NGF control transcription,PgE: Prostaglandins,Hist,TNF- R1,Substance P,Sensitization through biochemical modifications of receptor proteins,Apologies to Ji & Stricharz 2004,风湿性关节炎 免疫系统激活导致的炎症,In inflammatory joint diseases cytokines such as TNF-* destroy cartilage and excite the nociceptors TNF- can be inhibited by specific antibody - interrupting immune system perpetuation of inflammation a basis for new antirheumatic drugs such as Adalimumab *TNF- = Tumor Necrosis Factor Alpha,双向的相互作用 神经系统 免疫系统: 炎症和疼痛的放大,Nerve Cells,Immune Cells,Cytokines, e.g. TNF-,Neuropeptides, NO,+,+,关节伤害性感受器的敏化 work by Schaible and Schmidt 1983-1998,Sensitization by 前列腺素 缓激肽 神经肽 细胞因子 .,炎症前的放电,炎症后的放电,Unphysiological range,Flexion,Extension,Joint capsule,Nociceptor,炎症激活的静息的伤害性感受器,Afferent fibers,Time,脊髓和神经受压迫的多个部位,Rckgrats,Vertebral disk and protrusion Nerve sensitization by nucleus pulposus material,Facet joint,Spinal nerve,Dura,一氧化氮合酶mRNA在轴突损伤部位蓄积,疼痛的中枢传递,外周神经纤维,Brain,交感神经纤维,疼痛信息的中枢处理过程,神经系统的可塑性和中枢神经系统的敏化,坐骨神经痛的多样生理病理机制 Baron 2004,伤害性成份: 受到刺激的C类伤害性感受器,C-fiber A-fiber,神经病理性成份 1: 椎间盘突出导致的神经根受压,神经病理性成份 2: 炎性介质 TNF- 损坏神经根,Intervertebral disc,Central sensitization,C-fiber,“混合性疼痛”, 一个新的临床术语,虽然所有的伤害性感受器都是游离的神经末梢,但是依据轴突可以将它们分为两大类。 C纤维:小的无髓鞘轴突， 伤害性的机械，热和化学刺激可以激活C-纤维的伤害性感受器。感觉到的疼痛是一种很难定位的钝痛。 A-纤维: 小的有髓鞘轴突，伤害性的机械和/或热刺激可以激活它，疼痛是一种定位准确的锐痛。,痛觉的传递,Central sensitization-LTP,Peripheral injury triggers a change in the excitability of the CNS so that normal inputs evoked exaggerated responses leading to pain hypersensitivity (Sturge, 1883). Woolf et al (1983) provided the first evidence demonstrating that strong noxious stimulation to peripheral nerve or tissue leads to a lasting increase in excitability of spinal neurons.,正常的初级传入纤维末梢终止于脊髓背角较深的位置,神经损伤后，C-纤维末梢萎缩，A-纤维末梢芽生进入脊髓背角的较浅部位,Neuronal circuits established in the rat spinal superficial dorsal horn,Lu Y 2 J. Neurosci. 25: 3900 2005.,大鼠纤维诱导的脊髓场电位 Liu and Sandkhler 1995,Potentiated synaptic transmission,Amplitude,LTP,C-fiber evoked spinal field potential,LTP, a model for long term sensitization in the central nervous system,Tetanic C-fiber stimulation 100 Hz, 5 sec,. any prolonged nociceptive input may induce spinal LTP!,轴突信号将损伤信息传递到细胞核,痛导致神经塑性,导致神经元的基因转录 类鸦片系统的弱化 中枢神经系统运动控制系统的失调 皮层拓扑的重组 痛相关认知和行为可以持久化和放大痛 多种社会效应,伤害性刺激的跨膜基因诱导导致复杂的神经塑形响应,NMDA-receptors,* IEGs = Immediate Early Genes,Transcriptional regulation of: - Neurotransmitters - Synaptic receptor proteins - Trophic substances Adverse functional modifications in the pain system, e.g.: - Neuronal Sensitization Attenuation of inhibitory cells - Neuronal cell death,*,Induction of such as 重复伤害性刺激后在大鼠脊髓神经元出现 “Immediate Early Genes”如c-fos转录标志着痛通路中长时程可塑性 Herdegen, Zimmermann et al. 1993,Dorsal horn,Laminae 1 - 3,Laminae 4 - 7,Afferent C-fibers,to brain,Attenuation of c-Fos, LTP, sensitization, apoptosis by - Oligo-Desoxynucleotides against c-fos - Block of either NMDA, NK1, NOS, TNF .,参与神经损伤后多处痛发生的细胞机制 Zimmermann et al., 1989 - 2004,Transynaptic gene induction,Deficiency of neurotrophic factors from target,Abnormal excitability, Stump pain,Sensitization, Impaired inhibition, Apoptosis, Phantom pain,c-Fos c-Jun,LTP, Long term potentiation,c-Jun Bcl-2,Regeneration, Apoptosis,DR ganglion,Nerve sprouts,Spinal cord,Axonal transport,Brookoff D. Hosp Pract (Off Ed) 2000;35:45,慢性疼痛是一种疾病,慢性疼痛的病理生理学,外周冲动产生,. 参与: 残肢痛 感觉异常和多神经病痛 感觉异常和椎间盘突出引起的痛,Ectopic excitation at site of axonal injury IIIIIII I II IIII,外周神经损伤后中枢延迟痛产生,. 参与: 幻觉痛 疱疹痛 三叉神经痛,Transient injury-discharge following nerve trauma,Spinal Sensitization,IIIIIIIIII,Hyperactivity,II III IIIII,Delayed apoptosis,Inhibitory Neuron,损