医学ppt课件大全针刺镇痛研究

针刺镇痛研究 40年回顾 北京大学 神经科学研究所 韩济生 历史回顾 1958年出现了 “ 针刺麻醉 ” 新事物 周总理通过卫生部指示：研究针麻原理 全国 100余座医学院校参与研究 1965年 9月我接受国家任务主持此项目， 至今 40年 回顾 40年历程，从科研方向、方法、结果 进行总结，可能有一定意义 从 “ 是什么 ” What？ 针刺真的镇痛吗？ 到 “ 为什么 ” Why？ 针刺为什么会镇痛？ Acupucture-induced analgesia Human Observation: 0 20 40 60 80-20 0 20 40 60 80 100 120 *Acupuncture at Heku point Pain threshold change (%) Time in minutes needle manipulation (n=66) control group (n=22) 7 足三里 合谷穴 对照组 合谷 优于 足三里 合谷 - 足三里 合谷穴 对照组 合谷 -足三里 双穴 优于 单穴 对照组 合谷穴 非经穴 针刺非经穴也有镇痛效果 合谷穴 Site specificity Meridine/channel (morphological evidence?) Acupoints (precise to mm level?) Body points (Chinese original) or Ear points (French scholars) Bio-electrically sensitive sites, or densely innervated sites relative rather than absolute specificity 12 痛阈变化百分数 14 留针 留针捻针 捻针 耳针镇痛：规律相似 捻针有效，留针效差 同一天 重复电针 不同天 重复电针 电针镇痛有个体差异，具有可重复性 大 鼠 实 验 测痛是否能预测针麻效果？ 外科手术时 针麻效果 术前测定针刺镇痛效果 合谷穴内注射局麻药 procaine阻断针刺镇痛 针刺合谷穴 针刺 穴位注射局麻药 加 针刺 Procaine infiltration in the acupoint abolishes the effect of AA 0 20 40 60 80-20 0 20 40 60 80 100 120 (n=10) Acupuncture Acupuncture at Heku point Pain threshold change (%) Time in minutes Procaine infiltration + Acupuncture Analgesic effect produced by peripheral nerve Stimulation 8 Decay of the Effect of Acupuncture Analgesia After the termination of acupuncture stimulation Half life (T1/2) = 16 min Pain threshold, % change Time: 20 min / unit 10 100 20 30 40 50 60 80 90 7 0 Hegu 17.6 NMP 15.0 Zusanli 15.5 HG+ZSL 15.5 9 Rabbit experiment: cross infusion of CSF Evidence showing a neurochemical basis for AA TFL, % change Time, min AA + CSF perfusion 200 100 150 aCSF Doner rabbit Lat ventricle III ventricle perfusate 0 20 40 60 0 20 40 60 Infusion of CSF Acupuncture Control 50 0 10 Recipient rabbit 从 “ 是什么 ” What？ 针刺真的镇痛吗？ 是的！ 到 “ 为什么 ” Why？ 针刺为什么会镇痛？ 机制研究从何入手？ 从神经生理（电生理）入手？ 从神经化学 （物质基础）入手？ 神经冲动是电活动 到突触末端是化学活动 针刺镇痛的神经化学机制 小分子神经递质 5-羟色胺（ 5-HT） , 去甲肾上腺素（ NA), 乙酰胆碱（ ACh） , etc 神经肽 鸦片肽，非鸦片肽 Tail flick latency, % change The role of CNS 5-HT in EA analgesia ICV inj ITH inj Brain and spinal cord 5-HT mediate EA analgesia 5-HTP 5-HTP Cinan Cinan 受体拮抗剂 前体物质 对照 ICV inj ITH inj The role of CNS NA in EA analgesia The role of CNS NA in EA analgesia Tail flick latency, % change ICV inj ITH inj Phentol Phentol DOPS DOPS Brain NA antagonizes EAA Spinal NA mediates EAA DOPS 前体物质 Phentol受体阻断 中枢神经递质在脑的不同部位 发挥不同作用 递质 脑 脊髓 5-HT 加强 加强 NA 对抗 加强 阿片 肽 年份 阿片受体 电 针 Hz 5 1975 + + 2 内啡 肽 31 1976 + + 2 强 啡 肽 17 1979 + 100 孤啡 肽 17 1995 100 内 吗 啡 肽 4 1997 + 2 脑能产生自己的脑能产生自己的 “吗啡吗啡 ” 内源性阿片肽内源性阿片肽 氨基酸 脑啡肽 2Hz EA increases Enk release 100Hz EA increases Dyn release 12 0.00 0.50 1.00 1.50 2.00 2.50 before After EA Responder 0.00 0.10 0.20 0.30 before After EA Responder 0.00 0.10 0.20 0.30 Non-responder 0.00 0.50 1.00 1.50 2.00 2.50 Non-responder 2Hz 100Hz EA 15HzControl Enkephalin-ir in spinal perfusate Dynorphin-ir in spinal perfusate * * * * 2Hz 100Hz EA 15HzControl 0 500 1000 1500 2000 10 15 0 5 0 500 1000 1500 2000 0 5 10 15 * * 2Hz Enk 100Hz Dyn fmol / ml CSF Frequency dependence of peptide release Human Study Mek-Arg-Phe Dynorphin A MEK-Arg-Phe Dynorphin A A study in collaboration with Dr. Lars Terenius 13 15 大鼠脊髓中脑啡肽和强啡肽的作用： 低频：脑啡肽 高频：强啡肽 Analgesic effect of electro-acupuncture DYN AB MEK AB n = 13 14 rats 100 50 0 2 4 8 16 32 64 128 Frequency of EA (Hz) 脑啡肽抗体 阻断 低频电针镇痛 强啡肽抗体 阻断 高频电针镇痛 电针镇痛效应 电针频率 Hz 脊髓鞘内注射 正常兔血清 电针不同频率 发挥不同作用 电针频率（ Hz ） 在 CNS释放的 神经肽 发挥镇痛作用 部位 低频 （ 2 4） 脑啡肽 内啡肽 脑和脊髓 高频 （ 80 120） 强啡肽 脊髓 放电频率 Response / Release神经递质 神经肽 Thomas Hokfelt, 1991, Neuron 7:867-879 4 低频刺激释放神经递质 高频释放神经肽 2 Hz 100 Hz 1997 EM -EP ENK DYN ANTIBODY NALOXONE 1976 1975 1979 Opioid Receptors EA accelerates the release of endogenous opioids Synergistic Interaction between neuropeptides Peptide released in CNS Enk Dyn Enk + Dyn A B 2Hz2Hz 100Hz100Hz 30 6 9 12 15 S 2Hz 100Hz 19 The optimal cycle of DD wave The optimal cycle seems to be 6 second (3 low, 3 high) 1 mA 2 mA 3 mA Trends in Neuroscience, 2003; 26: 17-22 电针方法 是否有改进余地？ 穴位接受什么刺激？ 机悈刺激 : 机悈压迫 (砭） ,针刺 温度刺激：温针 (经针 )，灸 (经皮 ) 电刺激 ：经针 (电针 )，经皮 (TENS) 电刺激穴位：两种方式 经针 (电针， EA) 0.5 - 3.0 mA 经皮 (经皮电刺激 ， TENS) 5 - 15 mA 15 电针 via needles TENS via skin electrodes 必须应用恒流 (constant current)电刺激仪 Equal potency of the analgesic effects produced by EA and TENS in rats EA TENS EA TENS 2 Hz 15 Hz 100 Hz Placebo TFL, % change 16 Cross tolerance between EA and TENS EA TENS N = 10 - 14 2 Hz 15 Hz 100 Hz TFL, % change 电针和 TENS的比较 刺激方式 电流到达深 部组织途径 刺激范围 操作条件 EA 经过针 精确 必须针灸医师 操作 TENS 经过皮肤 电极覆盖面 较大 可在医师指导 下自行操作 相同点：镇痛效果相似，镇痛机制相同， TENS使用方便。 HANS for the treatment of autism自闭症、孤独症 The HANS unit and the skin electrodes An autism patient is treating himself with a HANS unit. 18ShenZhen Hospital 电针镇痛的神经通路 经典神经生物学方法 脑影像方法 必须与针刺治疗效果相关者才有意义 Nerve pathways for low and high frequency EA analgesia 100 Hz 2 Hz -end Enk Dyn PBN Arcuate N. Hypoth. PAG Medulla DHN Nerve pathways for low and high frequency EA analgesia 100 Hz 2 Hz -end Enk Dyn PBN Arcuate N. Hypoth. PAG Medulla DHN 27Rat experiment Brain imaging and functional correlates Acupuncture may activate many brain areas. But which is related with the given functional change? It is advisable to find the correlation between the BOLD signals and the therapeutic effects produced by acupuncture 28 29 100Hz EA increases Dyn release 0.00 0.10 0.20 0.30 before After EA Responder 0.00 0.10 0.20 0.30 Non-responder 2Hz 100Hz EA 15HzControl Dynorphin-ir in spinal perfusate * * Responders and non-responders in acupuncture analgesia 0.00 0.50 1.00 1.50 2.00 2.50 before After EA Responder 0.00 0.50 1.00 1.50 2.00 2.50 Non-responder Enkephalin-ir in spinal perfusate * * 2Hz 100Hz EA 15HzControl 2Hz EA increases Enk release R. Primary Motor Area (R-MI) R. Supplementary Motor Area (R-SMA) 30Zhang WT, et al: Brain Res 2003; 982:168-178 Positive correlation Brain areas involved in AA: fMRI studies in humans 31 Right Primary Motor Area Right Supplementary Motor Area Left Secondary Somatosensory Area Left Insula Right Secondary Somatosensory Area Left Superior Temporal Gyrus Right Thalamus Right Anterior Cingulate Cortex Right Hippocampus Left Hippocampus Right Primary Somatosensory Area Right Insula Positive correlation Negative correlation Zhang WT, et al: Brain Res 2003; 982:168-178 Correlated brain areas involved in 2 Hz AA 从原理研究 返回临床实际 Hans Acupoint Nerve Stimulator (HANS) 韩 氏 穴 位 神 经 刺 激 仪 NeiGuan (Pe6) Heku (LI 4) 21 HANS Electrical stimulation parameters Frequency (Hz, 1-100) Intensity (mA, 0.5-3.0) Pulse width (ms, 0.1-0.6) 20 急性痛 （创伤，手术，术后，生育 ) 慢性痛 (神经损伤，炎症，肿瘤， ) 0 A B C D E F G 0 1 2 0 A B C D E F G 0 1 2 3 4 5 6 Fi-enf (%) Enflurene conc (%) Fex-enf (%) Enflurene conc (%) 0 A B C D E F G 0 1 2 3 MAC How effective is HANS for reducing Acute (surgical) pain? To reduce the dose of Enflurene used in Cranial Operations Prior to Incision After Incision Drilling the skull Open the dura Remove tumor Suturing dura Suturing skin Enflurene HANS + Enf HANS produces a 45% - 50% reduction of anesthetic use 3331 - HANS + HANS 针刺镇痛的积累效应 疗效增强，作用时间延长。 慢性痛需要多次治疗 多次治疗疗效是 渐增？ 还是渐减？ The Longlasting Effect of Electroacupuncture on Cold-induced Neuropathic Pain 3735 0 2 8 16 24 48 5d 0 10 20 30 hr control needling 2 Hz 100 Hz n=11-12 * * * * * * * Time after EA Number of Paw Lifts from cold plate / 5 min 2 Hz 100 Hz The Effect of one Rx of acupuncture can last as long as 2 days Cumulative effect of EA on spinal spasticity Session of EA 0 5 10 15 20 0 1 2 3 4 5 P 2 Hz Multiple acupuncture treatments can produce marked cumulative effect 2 Hz may serve as a control for 100 Hz 针刺积累效应的可能机制 促进有关基因的表达 Electroacupuncture accelerates the gene expression (prepro-enkephalin) in rat brain 1 100 100 200 300 400 500 600 700 800 900 mRNA Level ( % of Control ) Time after Electroacupuncture (hr) 0.5 2 4 24 72 PPE c-fos n=3 EA: 2/15 Hz, 30min, 3mA * * * * * * * 48 h 37 Naive 100 Hz 2 Hz PPE PPD mRNA levels 2Hz EA increased the level of PPE mRNA in nucleus accumbens of CPP rats GAPDH（ 532 bp） 2000 bp 1000 bp 750 bp 500 bp 250 bp 100 bp DL2000 CPP 2 Hz 100 Hz Restrain PPE（ 402 bp） NS Grey scale ratios ( PPE /GAPDH) 0.00 0.25 0.50 0.75 1.00 NS CPP 2 Hz 100 HzRestrain n=4 Treatment P 2 Hz Body Weight (kg) 0 1 2 3 4 5 6 7 8 9 10 11 Days of Treatment 45 50 55 60 Control 2Hz 2/100Hz100Hz (n=26-32) Effect of HANS on Body Weight during Opiate Withdrawal * * * * * * * * * Can HANS suppress heroin withdrawal syndrome? To reduce the dose of BPN needed for heroin detoxification BPN Dose ( mg/d ) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days of Treatment 0.0 0.5 1.0 1.5 2.0 2.5 * * * * * Buprenorphine HANS + BPN * P 100 Hz EA suppression of morphine CPP 212 Hz 100 Hz 脱毒 （抑制戒断症状） 防复吸 (抑制心瘾 ) 100 Hz 2 Hz 2 Hz 100 Hz 22 电针或 HANS 治疗海洛因成瘾 HANS 抑制心瘾的最优频率 Days of observation Drug use over 1 year (aver 4.6 y); Detoxification over 1 month; Male, Aver 25 y; n=29-30 Craving score (VAS) 30 min per day Pre-HANS HANS-treating Post-HANS 10 20 30 100 Hz 2 Hz Mock 2/100 Hz 0 0 1 2 3 4 5 2 Hz 100 Hz Effect of EA of different frequencies on heroine cue-induced changes in BOLD signals Abolished by 2 Hz EA Not affected by 100 Hz EA Strengthened by second cue exposure 2 Hz 100 Hz 0 Hz (mock) HANS 抑制心瘾的最优频率 Days of observation Drug use over 1 year (aver 4.6 y); Detoxification over 1 month; Male, Aver 25 y; n=29-30 Craving score (VAS) 30 min per day Pre-HANS HANS-treating Post-HANS 10 20 30 100 Hz 2 Hz Mock 2/100 Hz 0 0 1 2 3 4 5 2 Hz 100 Hz No relapse over 1 year Clinical Base Method of Detox : HANS Portable HANS available on discharge Success over 1 year Success Rate Hainan Yes Yes 11/ 56 Ca 20 % Shanghai + / - Yes 57/227 Ca 25% Guangdong Yes + / - 9 / 500 Ca 2 % Keeping drug free over 1 year Aim: HANS for detox. + HANS ready in the pocket 30% success over 1 year Previous drug addicts keeping drug free for one year after discharging from the detoxification center were awarded with a prize. Guangdong province, Jan 2002 Substance Abuse A complehensive textbook Eds. J Lowinson, et al 3rd Edition, 1997 Chapter 51 Acupuncture written by M Smith, et al. 59 物 质 依 赖 第 4版 2005 第 49章 Acupuncture Han et al. The essence of acupuncture treatment: -Consolidation of Homeostasis 针刺治疗的实质 加强内环境稳定 试图总结提高到理论水平？ What does acupuncture do? General modulatory effect strengthening negative feedback mechanism Activating specific circuitry or Producing specific neurotransmitters site specific (acupoint) manipulation parameter (frequency) specific stimulation 1 Acupuncture can resume the homeostasis 2 Gentle and mild Unlike morphine which produces analgesia, acupuncture induces hypo-algesia Little aversive effects Unlike morphine which produces severe aversive side effects, acupuncture produces little or no aversive side effects. Characteristics of acupuncture effects 3 Normal subject is in a balanced status. Acupuncture produces only minor effect. In patients, homeostasis is damaged. Acupuncture can play a major role in bringing body function back to a physiological status. Models for the study of acupuncture effect 4 Quantification of acupuncture effects in the patient Analgesic effect in surgery reduction of the need for analgesics Treatment of drug addiction reduction of pharmacological agents needed for detoxification 5 How effective is HANS for reducing Acute (surgical) pain? To reduce the dose of Enflurene used in Cranial Operations HANS produces a 45% - 50% reduction of anesthetic use 66 0 A B C D E F G 0 1 2 0 A B C D E F G 0 1 2 3 4 5 6 Fi-enf (%) Enflurene conc (%) Fex-enf (%) Enflurene conc (%) 0 A B C D E F G 0 1 2 3 MAC Prior to Incision After Incision Drilling the skull Open the dura Remove tumor Suturing dura Suturing skin Enflurene HANS + Enf - HANS + HANS 100 : 8 100 : 25 Adopted from: substance abuse Lowinson et al. Eds, 4th edition, Chapter 49, 2005 Buprenorphin dose Methadone dose Reduction of opioids for the detoxification of heroine addicts 7 The ancient Chinese philosophy holds that every issue has its counterpart which plays opposite role (the Yin-Yang concept) By modulating the neurochemical balance, there is always a room for improving acupuncture effect The Yin and Yang concept 32 Development and Recovery of EA Tolerance 1 2 3 4 5 6 | 4 8 12 16 240 20 40 60 80 100 n=30 EA sessions Time of recovery Tail flick latency, % increase (Hr ) 33 Prolonged EA increased the production and release of CCK-8-ir in brain EA (15 Hz, 3 mA) , hr 0 1 2 3 4 5 60 1 2 3 4 CCK-8-ir,fmol/mg * * * * * n=9-10 p0.05* 0 1 2 3 4 5 60 10 20 30 40 50 CCK-8-ir, fmol / 100 m l * * *n=6-8 p0.001p0.01 p0.05 * * * 34 CCK-8 as Feedback Control of Opioid Effect Exogenous opiates Endogenous opioids CCK-8 ReleaseSynthesis Opioid tolerance Opioid analgesia Opiates Acupuncture OR CCKR G G IP3 Ca2+i Inhibiting calcium