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1、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 analgesiaHuman Observation:,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
2、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 sitesrelative rather than absolute specificity,12,14,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
3、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 acupointabolishes 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(%),Time in minutes,Pr
4、ocaine infiltration+Acupuncture,Analgesic effect produced by peripheral nerve Stimulation,8,Decay of the Effect of Acupuncture AnalgesiaAfter the termination of acupuncture stimulationHalf life(T1/2)=16 min,9,Rabbit experiment:cross infusion of CSF,Evidence showing a neurochemical basis for AA,TFL,%
5、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？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
6、),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,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 EA increases Enk release 100Hz EA increases Dyn r
7、elease,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 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,电针不同频率 发挥不同作用,放
8、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,EA accelerates the release of endogenous opioids,Synergistic Interaction between neuropeptides,19,The optimal cycle of DD wave,The optimal cycle seems to be 6 second(3 low,3 high),1 mA2 mA3 mA,Tr
9、ends 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,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,EATENS,EATENS,2 Hz,15 Hz,100 Hz,Pla
10、cebo,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 HANS unit.,18,ShenZhen Hospital,电针镇痛的神经通路,经典神经生物学方法 脑影像方法必须与针刺治疗效果相关者才有意义,Nerve pa
11、thways 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,Acupuncture may activate many brain areas.But which is related with the given
12、 functional change?It is advisable to find the correlation between the BOLD signals and the therapeutic effects produced by acupuncture,28,http:/,29,Responders and non-responders in acupuncture analgesia,30,Zhang WT,et al:Brain Res 2003;982:168-178,Positive correlation,31,Zhang WT,et al:Brain Res 20
13、03;982:168-178,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,
14、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 the skull Open the dura Remove tumor Suturing dura Suturing skin,EnflureneHANS+Enf,HANS
15、 produces a 45%-50%reduction of anesthetic use,33,31,-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,37,35,0,2,8,16,24,48,5d,0,10,20,30,hr,Time after EA,Number of Paw Lifts from cold plate/5 min,2 Hz 100 Hz,The
16、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,*,Clonus Score,38,36,100 Hz 2 Hz,Multiple acupuncture treatments can produce marked cumulative e
17、ffect,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,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）,56,2 Hz PPE mRNA,PPD(250
18、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 groupWang,B.G.et al.(1997)Effect of the intensity of transcutaneous acupoint electrical stimulation on the postoperative analgesic r
19、equirement.Anesth.Analg.85,406-13Hamza,M.A.et al.(1999)Effect of the frequency of transcutaneous electrical nerve stimulation on the postoperative opioid analgesic requirement and recovery profile.Anesthesiology 91,1232-8El-sayed,A.et al.(1999)Percutaneous electrical nerve stimulation for low back p
20、ain.A randomized crossover study.JAMA 281,818-823Hamza,M.A.et al.(1999)Effect of the duration of electrical stimulation on the analgesic response in patients with low back pain.Anesthesiology 91,1622-7Hamza,M.A.,et al.(2000)Percutaneous electrical nerve stimulation:a novel analgesic therapy for diab
21、etic neuropathic pain.Diabetic Care 23,365-370,Clinical verification of basic research findings,28,Acute pain,Chronic pain,http:/,由基础向临床反馈（翻译）,中国研究者30年基础研究的精华被美国医师在3年内作出临床验证喜乎？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,针刺镇痛成果继续延伸
22、1990 用于“戒毒”,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,Registered drug addicts in China(million),0.07,脑内一闪念,如果针刺引起脑内释放吗啡样物质,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）,http:/,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
23、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 dose 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)exp
24、erimental system,52,条件性位置偏爱 实验装置Conditioned place preference(CPP),21,2 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,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
25、 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 detox.+HANS ready in the pocket 30%success over 1 year,Previous drug addicts keeping drug free for one year after discharging from the detoxific
26、ation center were awarded with a prize.Guangdong province,Jan 2002,Substance AbuseA complehensive textbookEds.J Lowinson,et al 3rd Edition,1997Chapter 51 Acupuncturewritten by M Smith,et al.,59,物 质 依 赖第4版2005第49章AcupunctureHan et al.,The essence of acupuncture treatment:-Consolidation of Homeostasis
27、,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 effectstrengthening negative feedback mechanismActivating specific circuitry or Producing specific neurotransmitters site specific(acupoint)manipulationparameter(frequency)specific stimulation,1,Acupuncture can resume the home
28、ostasis,2,Gentle and mildUnlike morphine which produces analgesia,acupuncture induces hypo-algesiaLittle aversive effectsUnlike morphine which produces severe aversive side effects,acupuncture produces little or no aversive side effects.,Characteristics of acupuncture effects,3,Normal subject is in
29、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 i
30、n surgeryreduction of the need for analgesicsTreatment of drug addictionreduction 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
31、,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 to Incision After Incision Drilling the skull Open the dura Remove tumor Suturing dura Suturing skin,EnflureneHANS+Enf,-HANS,+HANS,100:8,100:25,Adopted from:substance abuse Lowinso
32、n 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,t
33、here 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
34、,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 Opioid Effect,Exogenousopiates,Endogenousopioids,CCK-8,ReleaseSynthesis,Opioidtolerance,Opioidanalgesia,Opiates,Acupuncture,OR,CCKR,G,G,IP3,Ca2+i,Inhibitingcalcium influx,Mobilizingcalcium storage
35、,Dorsal Horn Neuron,35,Interaction between opioids and antiopioidsdetermines the effectiveness ofAcupuncture-induced Analgesia,Nonresponder,Responder,CCK antisense,CCK sense,37,Days after icv injection,CCK antisense icv injection decreases brain CCK content increases opioid analgesia,ChangingPoor re
36、spondersintoGood responders,Rats show a poor response to morphine and EAhave a high content of brain CCK,38,P77PMC rats having a low brain CCK content show ahigh vulnerability to audiogenic seizureandhigh response to acupuncture analgesia,Over expression of brain CCK by icv CCK vector Decreases seiz
37、ure Decreases EA analg.(Changing good responders into poor responders),39,Effect of AA Depends on a Balance between EOP and CCK,36,针刺研究永无止境,扩大战果，向临床其他疾病延伸：镇痛，戒毒，神经系统难治疾病（如儿童自闭症、多动症，脑瘫，抑郁躁狂），减肥 等等。深入机理研究：分子，基因组学，蛋白质组学，网络，认知水平,Thank you!,Peking University Health Science Center,11th,3rd,10th,Neuroscience Research Institute,
