1、***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“******”新事物 周***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？ ***真的镇痛吗？ 到 “为什么” Why？ ***为什么会镇痛/Acupucture-induced analgesia Human Observation/7/足三里/合谷***/对照组/合谷 优于 足三里/合谷 - 足三里/合谷***/对照组/合谷-足三里 双*** 优于 单***/对照组/合谷***

2、/非经***/***非经***也有镇痛效果/合谷***/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/12/14/留针/留针/捻针/捻针/耳

3、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***镇痛效果/合谷***内注射局***procaine阻断***镇痛/***合谷***/***/***位注射局*** 加 ***/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 at Heku point/Pain threshold change (

4、/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/9/Rabbit experiment/ cross infusion of CSF/Evidence showing a neuro

5、chemical basis for AA/TFL/ % change/Time/ min/AA + CSF perfusion/200/100/150/aCSF/Doner rabbit/Lat ventricle/III ventricle/perfusate/Infusion of CSF/Acupuncture/Control/50/0/10/Recipient rabbit/从 “是什么” What？ ***真的镇痛吗？是的！ 到 “为什么” Why？ ***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/

6、***镇痛的神经化学机制/小分子神经递质 5-羟色胺（5-HT）/ 去甲***上腺素（NA)/ 乙酰胆碱（ACh）/ etc 神经肽 ***肽，非***肽/Tail flick latency/ % change/The role of CNS 5-HT in EA analgesia/ICV inj/ITH inj/The role of CNS NA in EA analgesia/The role of CNS NA in EA analgesia/Tail flick latency/ % change/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/2Hz

7、 EA increases Enk release 100Hz EA increases Dyn release/12/0/500/1000/1500/2000/10/15/0/5/0/500/1000/1500/2000/0/5/10/15/2Hz 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 Tereniu

8、s/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/电针不同频率 发挥不同作用/放电频率/Response / Release/神经递质/神经肽/Thomas Hokfelt/ 1991/ Neuron 7/867-879/4/低频***释放神经递质/高频释放神经肽/2 Hz/100 Hz/1997/EA accelerates the release of endogenous opioids/Synergistic Interaction between neuropeptides/19/The optimal cycle of DD wave/The optima

9、l 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/***位接受什么***/机悈***/ 机悈***(砭）/*** 温度***：温针(经针)，灸(经皮) 电*** ：经针(电针)，经皮(TENS/电******位：两种方式/经针 (电针， EA) 0/5 - 3/0 mA 经皮 (经皮电***，TENS) 5 - 15 mA/15/必须应用恒流(constant current)电***仪/Equal potency of the analgesic

10、 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/电针和TENS的比较/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 HAN

11、S unit/18/ShenZhen 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***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/27/Rat experiment/Brain imaging and functional correlates

12、/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/Responders and non-responders in acupuncture analgesia/30/Zhang WT/ et al/ Bra

13、in Res 2003/ 982/168-178/Positive correlation/31/Zhang WT/ et al/ Brain Res 2003/ 982/168-178/从原理研究 返回临***实际/Hans Acupoint Nerve Stimulator (HANS) 韩 氏 *** 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/

14、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 (/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

15、 the skull Open the dura Remove tumor Suturing dura Suturing skin/Enflurene HANS + Enf/HANS produces a 45% - 50% reduction of anesthetic use/33/31/HANS/HANS/***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/37/35/0/2/8/16/2

16、4/48/5d/0/10/20/30/hr/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 0/01/100Hz (n=6/2Hz (n=3/Ashworth Score/1/2/3/4/5/P 0/01/0/

17、Clonus Score/38/36/100 Hz 2 Hz/Multiple acupuncture treatments can produce marked cumulative effect/2 Hz may serve as a control for 100 Hz/***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/37/Naive/100 Hz/2 Hz/PPE/PPD/mRNA levels/2Hz EA increas

18、ed the level of PPE mRNA in nucleus accumbens of CPP rats/GAPDH（532 bp/56/2 Hz PPE mRNA/PPD (250 bp/100Hz EA increased the level of PPD mRNA in nucleus accumbens of CPP rats/57/100 Hz PPD mRNA/Dr/ Paul White/ University of Texas/ South Western Medical Center and his group Wang/ B/G/ et al/ (1997) Ef

19、fect of the intensity of transcutaneous acupoint electrical stimulation on the postoperative analgesic requirement/ Anesth/ Analg/ 85/ 406-13 Hamza/ M/A/ et al/ (1999) Effect of the frequency of transcutaneous electrical nerve stimulation on the postoperative opioid analgesic requirement and recover

20、y profile/ Anesthesiology 91/ 1232-8 El-sayed/ A/ et al/ (1999) Percutaneous electrical nerve stimulation for low back pain/ A randomized crossover study/ JAMA 281/ 818-823 Hamza/ M/A/ et al/ (1999) Effect of the duration of electrical stimulation on the analgesic response in patients with low back

21、pain/ Anesthesiology 91/ 1622-7 Hamza/ M/A// et al/ (2000) Percutaneous electrical nerve stimulation/ a novel analgesic therapy for diabetic neuropathic pain/ Diabetic Care 23/ 365-370/Clinical verification of basic research findings/28/Acute pain/Chronic pain/由基础向临***反馈（翻译/中国研究者30年基础研究的精华 被美国医师在3年内作出

22、临***验证 喜乎？ 忧乎/韩济生1979第一次出国 在旧金山为华侨做针灸原理报告，讲英语，译成广东话/Plenary lecture at the Consensus Conference on Acupuncture/ NIH/ USA/ 1997/***镇痛成果 继续延伸 1990 用于“戒***/Drug addicts in China (million/80% - 85% heroin addicts/0/0/2/0/4/0/6/0/8/1/0/1990/1993/1997/2000/2002/2003/An increase of 14 folds in 14 years/1/05/Reg

23、istered drug addicts in China ( million/0/07/脑内一闪念/如果***引起脑内释放***样物质/ 为何不利用这类物质 减轻戒断症状（身体依赖） 压制强烈心瘾（精神依赖/药物成瘾/身体依赖：戒断症状， 来势凶猛 精神依赖：渴求，心瘾，极难解决/Effect of HANS on heart rate of heroin addicts/Day of treatment/1/2/3/4/5/6/7/8/9/10/100 Hz 2 Hz/Can HANS suppress heroin withdrawal syndrome? To reduce the dos

24、e of BPN needed for heroin detoxification/药物成瘾/身体依赖：戒断症状， 较易解决 精神依赖：渴求，心瘾，极难解决/The computer- controlled conditioned place preference (CPP) experimental system/52/条件性位置偏爱 实验装置 Conditioned place preference (CPP/21/2 Hz 100 Hz/脱*** （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***成瘾/HANS 抑制心瘾的最优

25、频率/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/2 Hz 100 Hz/No relapse over 1 year/Keeping drug free over 1 year/Aim/ HANS for

26、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 Ch

27、apter 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/***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 specif

28、ic 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 m

29、orphine 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

30、 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 deto

31、xification/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/6/6/0/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 (/Prior t

32、o 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 detoxific

33、ation 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/33/Prolonged EA increased the production and release of CCK-8-ir in brain/EA (15 Hz/ 3 mA) / hr/0/1/2/3/4/5/6/0/1/2/3/4/CCK-8-ir/fmol/mg/n=9-10/p0/05/0/1/2/3/4/5/6/0/10/20/30/40/50/CCK-8-ir/ fmol / 100 m l/n=6-8/p0/001/p0/01/p0/05/34/CCK-8 as Feedback Control of Opio