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1、针刺镇痛研究针刺镇痛研究40年回顾年回顾北京大学北京大学 神经科学研究所神经科学研究所韩济生历史回顾历史回顾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 “是什么是什么” ” What？针刺真的镇痛吗？到 “为什么为什么” ” Why？针刺为什么会镇痛？Acupucture-induced analgesiaHuman Observation:020406080-20020406080100120*Acupuncture at
2、Heku pointPain threshold change (%)Time in minutesneedlemanipulation(n=66)control group(n=22)7足三里合谷穴对照组合谷合谷 优于优于 足三里足三里合谷 - 足三里合谷穴对照组合谷合谷- -足三里足三里 双穴双穴 优于优于 单穴单穴对照组合谷穴非经穴针刺非经穴也有镇痛效果针刺非经穴也有镇痛效果合谷穴Site specificityMeridine/channel (morphological evidence?)Acupoints (precise to mm level?)Body points (Ch
3、inese original) or Ear points (French scholars) Bio-electrically sensitive sites, or densely innervated sitesrelative rather than absolute specificity12痛阈变化百分数痛阈变化百分数14留针留针捻针捻针捻针捻针耳针镇痛：规律相似耳针镇痛：规律相似捻针有效，留针效差捻针有效，留针效差同一天同一天 重复电针重复电针不同天不同天 重复电针重复电针电针镇痛有个体差异，具有可重复性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？测痛是
4、否能预测针麻效果？外外科科手手术术时时 针针麻麻效效果果术术前前测测定定针针刺刺镇镇痛痛效效果果合谷穴内注射局麻药合谷穴内注射局麻药procaine阻断针刺镇痛阻断针刺镇痛 针刺合谷穴针刺合谷穴针刺针刺 穴位注射局麻药穴位注射局麻药 加加 针刺针刺Procaine infiltration in the acupointabolishes the effect of AA020406080-20020406080100120(n=10) AcupunctureAcupuncture at Heku pointPain threshold change (%)Time in minutesPro
5、caine infiltration + Acupuncture Analgesic effect produced by peripheral nerve Stimulation8Decay of the Effect of Acupuncture AnalgesiaAfter the termination of acupuncture stimulationHalf life (T1/2) = 16 minPain threshold, % changeTime: 20 min / unit101002030405060809070Hegu 17.6 NMP 15.0 Zusanli 1
6、5.5 HG+ZSL 15.5 9Rabbit experiment: cross infusion of CSFEvidence showing a neurochemical basis for AATFL, % changeTime, minAA + CSF perfusion 200 100 150 aCSFDoner rabbitLat ventricleIII ventricleperfusate 0 2040 60 0 2040 60Infusion of CSFAcupunctureControl50010Recipient rabbit从 “是什么是什么” ” What？针刺
7、真的镇痛吗？是的！是的！到 “为什么为什么” ” Why？针刺为什么会镇痛？机制研究从何入手？机制研究从何入手？从神经生理（电生理）入手？从神经生理（电生理）入手？从神经化学（物质基础）入手？从神经化学（物质基础）入手？神经冲动是电活动神经冲动是电活动到突触末端是化学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 analgesiaICV injITH injBrain
8、 and spinal cord 5-HT mediate EA analgesia5-HTP5-HTPCinanCinan受体拮抗剂受体拮抗剂前体物质前体物质对照对照ICV injITH inj The role of CNS NA in EA analgesia The role of CNS NA in EA analgesiaTail flick latency, % changeICV injITH injPhentolPhentolDOPSDOPSBrain NA antagonizes EAASpinal NA mediates EAADOPS 前体物质前体物质Phentol受体
9、阻断受体阻断中枢神经递质在脑的不同部位中枢神经递质在脑的不同部位 发挥不同作用发挥不同作用递质脑脊髓5-HT加强加强NA对抗加强阿片肽阿片肽 年份年份 阿片受体阿片受体 电电 针针 Hz 51975 + + 2内啡肽内啡肽 311976 + + 2强啡肽强啡肽 171979 +100孤啡肽孤啡肽 171995100内吗啡肽内吗啡肽 41997+2脑能产生自己的脑能产生自己的脑能产生自己的脑能产生自己的“ “吗啡吗啡吗啡吗啡” ”内源性阿片肽氨基酸氨基酸 脑啡肽脑啡肽 2Hz EA increases Enk release 100Hz EA increases Dyn release120.0
10、00.501.001.502.002.50beforebeforeAfter EAAfter EAResponderResponder0.000.100.200.30beforebeforeAfter EAAfter EAResponderResponder0.000.100.200.30Non-responderNon-responder0.000.501.001.502.002.50Non-responderNon-responder2Hz100HzEA15HzControlEnkephalin-ir in spinal perfusateDynorphin-ir in spinal pe
11、rfusate *2Hz100HzEA15HzControl05001000150020001015050500100015002000051015*2Hz Enk100Hz Dynfmol / ml CSFFrequency dependence of peptide release Human StudyMek-Arg-PheDynorphin AMEK-Arg-PheDynorphin AA study in collaboration with Dr. Lars Terenius 1315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
12、 electro-acupunctureDYN ABMEK ABn = 13 14 rats100500248163264128Frequency of EA (Hz)脑啡肽抗体脑啡肽抗体阻断阻断低频电针镇痛低频电针镇痛强啡肽抗体强啡肽抗体阻断阻断高频电针镇痛高频电针镇痛电针镇痛效应电针镇痛效应电针频率电针频率 Hz脊髓鞘内注射脊髓鞘内注射正常兔血清正常兔血清电针不同频率电针不同频率 发挥不同作用发挥不同作用电针频率电针频率（HzHz）在在CNSCNS释放的释放的 神经肽神经肽发挥镇痛作用发挥镇痛作用部位部位低频低频（2 24 4）脑啡肽脑啡肽内啡肽内啡肽脑和脊髓脑和脊髓高频高频（808012
13、0120）强啡肽强啡肽脊髓脊髓放电频率放电频率Response / Release神经递质神经递质神经肽神经肽Thomas Hokfelt, 1991, Neuron 7:867-8794低频刺激释放神经递质低频刺激释放神经递质高频释放神经肽高频释放神经肽2 Hz100 Hz1997 EMEM -EPENKDYNANTIBODYNALOXONE197619751979Opioid ReceptorsEA accelerates the release of endogenous opioidsSynergistic Interaction between neuropeptidesPeptid
14、e released in CNSEnkDynEnk + DynAB2Hz2Hz100Hz100Hz30691215 S2Hz100Hz19 The optimal cycle of DD waveThe optimal cycle seems to be 6 second (3 low, 3 high)1 mA2 mA3 mATrends 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？穴位接受什么刺激？机悈刺激机悈刺激: : 机悈压迫机悈压迫( (砭）砭）, ,针刺针刺温度刺激：温针温度刺激：温针( (经针经针) )，灸，灸( (
15、经皮经皮) )电刺激电刺激 ：经针：经针( (电针电针) )，经皮，经皮(TENS)(TENS)电刺激穴位：两种方式经针经针 (电针， EA)0.5 - 3.0 mA经皮经皮 (经皮电刺激，TENS)5 - 15 mA15电针电针via needlesTENSvia skin electrodes必须应用恒流必须应用恒流( (constant current) )电刺激仪电刺激仪Equal potency of the analgesic effects produced by EA and TENS in ratsEATENSEATENS2 Hz15 Hz100 HzPlaceboTFL,
16、% change16Cross tolerance between EA and TENSEATENSN = 10 - 142 Hz15 Hz100 HzTFL, % change电针和电针和TENSTENS的比较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、孤独症自闭症、孤独症The HANS unit and the skin electrodesAn autism patient
17、 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 -endEnkDynPBNArcuate N.Hypoth.PAGMedullaDHNNerve pathways for low and high frequency EA analgesia 100 Hz 2 Hz -endEnkDynPBNArcuate N.H
18、ypoth.PAGMedullaDHN27Rat experimentBrain imaging and functional correlatesAcupuncture 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 acupuncture2829100Hz EA
19、increases Dyn release0.000.100.200.30beforebeforeAfter EAAfter EAResponderResponder0.000.100.200.30Non-responderNon-responder2Hz100HzEA15HzControlDynorphin-ir in spinal perfusate *Responders and non-responders in acupuncture analgesia0.000.501.001.502.002.50beforebeforeAfter EAAfter EAResponderRespo
20、nder0.000.501.001.502.002.50Non-responderNon-responderEnkephalin-ir in spinal perfusate*2Hz100HzEA15HzControl 2Hz EA increases Enk release R. Primary Motor Area (R-MI)R. Supplementary Motor Area (R-SMA)30Zhang WT, et al: Brain Res 2003; 982:168-178Positive correlationBrain areas involved in AA: fMRI
21、 studies in humans31Right Primary Motor AreaRight Supplementary Motor AreaLeft Secondary Somatosensory AreaLeft InsulaRight Secondary Somatosensory AreaLeft Superior Temporal GyrusRight ThalamusRight Anterior Cingulate CortexRight HippocampusLeft HippocampusRight Primary Somatosensory AreaRight Insu
22、laPositive correlationNegative correlationZhang WT, et al: Brain Res 2003; 982:168-178Correlated brain areas involved in 2 Hz AA从原理研究返回临床实际返回临床实际Hans Acupoint Nerve Stimulator (HANS)韩韩 氏氏 穴穴 位位 神神 经经 刺刺 激激 仪仪NeiGuan (Pe6) Heku (LI 4) 21HANSElectrical stimulation parametersFrequency (Hz, 1-100)Intens
23、ity (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，)0ABCDEFG0120ABCDEFG0123456Fi-enf (%)Enflurene conc (%)Fex-enf (%)Enflurene conc (%)0ABCDEFG0123MACHow effective is HANS for reducing Acute (surgical) pain?To reduce the dose of Enflurene used in Cranial OperationsPrior to In
24、cision After Incision Drilling the skull Open the dura Remove tumor Suturing dura Suturing skin EnflureneHANS + EnfHANS produces a 45% - 50% reduction of anesthetic use3331- 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 Neuropath
25、ic Pain37350281624485d0102030hrcontrolneedling2 Hz100 Hzn=11-12*Time after EANumber of Paw Lifts from cold plate/ 5 min2 Hz 100 HzThe Effect of one Rx of acupuncture can last as long as 2 daysCumulative effect of EA on spinal spasticitySession of EA05101520012345P 0.01100Hz (n=6)2Hz (n=3)Ashworth Sc
26、ore12345P 2 HzMultiple acupuncture treatments can produce marked cumulative effect2 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 brain1100100200300400500600700800900mRNA Level ( % of Control )Time after Electroa
27、cupuncture (hr)0.5242472PPEc-fosn=3EA: 2/15 Hz, 30min, 3mA*48 h37Naive100 Hz2 HzPPEPPDmRNA levels2Hz EA increased the level of PPE mRNA in nucleus accumbens of CPP ratsGAPDH（532 bp）2000 bp1000 bp750 bp500 bp250 bp100 bpDL2000CPP2 Hz 100 Hz RestrainPPE（402 bp）NSGrey scale ratios (PPE/GAPDH)0.000.250.
28、500.751.00NSCPP2 Hz100 HzRestrainn=4TreatmentP0.05*#P0.05562 Hz PPE mRNA PPD (250 bp)1000 bp100 bp2000 bp750 bp500 bp250 bpDL 2000 NSCPP 2 Hz100 HzRestrainGAPDH (532 bp)100Hz EA increased the level of PPD mRNA in nucleus accumbens of CPP ratsTreatment0.00.51.01.5Grey scale ratios (PPD/GAPDH)n=4NSCPP
29、2 Hz100 HzRestrainP0.05*#P 2 HzBody Weight (kg)01234567891011Days of Treatment45505560Control2Hz2/100Hz100Hz(n=26-32)Effect of HANS on Body Weight during Opiate Withdrawal*Can HANS suppress heroin Can HANS suppress heroin withdrawal syndromewithdrawal syndrome? ?To reduce the dose of To reduce the d
30、ose of BPNBPN needed for heroin detoxification needed for heroin detoxificationBPN Dose (BPN Dose (mg/dmg/d) )1 12 23 34 45 56 67 78 89 91010 11111212 1313 1414Days of TreatmentDays of Treatment0.00.00.50.51.01.01.51.52.02.02.52.5*BuprenorphineBuprenorphine HANS + BPN HANS + BPN * P0.001, compared w
31、ith BPN group * P 100 Hz 100 HzEA suppression of morphine CPP212 Hz 100 Hz 脱毒脱毒 （抑制戒断症状）（抑制戒断症状）防复吸防复吸 ( (抑制心瘾抑制心瘾) )100 Hz 2 Hz2 Hz 100 Hz22电针或电针或HANS HANS 治疗海洛因成瘾治疗海洛因成瘾HANS HANS 抑制心瘾的最优频率抑制心瘾的最优频率Days of observationDrug use over 1 year (aver 4.6 y); Detoxification over 1 month; Male, Aver 25 y; n
32、=29-30Craving score (VAS)30 min per dayPre-HANSHANS-treatingPost-HANS102030100 Hz2 HzMock2/100 Hz 00123452 Hz 100 HzEffect of EA of different frequencies on heroine cue-induced changes in BOLD signalsAbolished by 2 Hz EANot affected by 100 Hz EAStrengthened by second cue exposure2 Hz 100 Hz 0 Hz (mo
33、ck)HANS HANS 抑制心瘾的最优频率抑制心瘾的最优频率Days of observationDrug use over 1 year (aver 4.6 y); Detoxification over 1 month; Male, Aver 25 y; n=29-30Craving score (VAS)30 min per dayPre-HANSHANS-treatingPost-HANS102030100 Hz2 HzMock2/100 Hz 00123452 Hz 100 HzNo relapse over 1 yearClinical BaseMethod of Detox :
34、HANSPortable HANS available on dischargeSuccess over 1 yearSuccess RateHainanYesYes11/ 56Ca 20 %Shanghai+ / -Yes57/227Ca 25%GuangdongYes+ / -9 / 500Ca 2 %Keeping drug free over 1 yearAim: HANS for detox. + HANS ready in the pocket 30% success over 1 yearPrevious drug addicts keeping drug free for on
35、e year after discharging from the detoxification 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 acupu
36、ncture treatment: -Consolidation of Homeostasis针刺治疗的实质针刺治疗的实质加强内环境稳定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 (freq
37、uency) specific stimulation1Acupuncture can resume the homeostasis2Gentle 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.Char
38、acteristics of acupuncture effects3Normal 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 effect4Quantificatio
39、n of acupuncture effects in the patientAnalgesic effect in surgeryreduction of the need for analgesicsTreatment of drug addictionreduction of pharmacological agents needed for detoxification5How effective is HANS for reducing Acute (surgical) pain?To reduce the dose of Enflurene used in Cranial Oper
40、ationsHANS produces a 45% - 50% reduction of anesthetic use6 60ABCDEFG0120ABCDEFG0123456Fi-enf (%)Enflurene conc (%)Fex-enf (%)Enflurene conc (%)0ABCDEFG0123MACPrior to Incision After Incision Drilling the skull Open the dura Remove tumor Suturing dura Suturing skin EnflureneHANS + Enf- HANS+ HANS10
41、0 : 8100 : 25Adopted from: substance abuse Lowinson et al. Eds,4th edition, Chapter 49, 2005 Buprenorphin doseMethadone doseReduction of opioids for the detoxification of heroine addicts7The ancient Chinese philosophy holds that every issue has its counterpart which plays opposite role (the Yin-Yang
42、 concept)By modulating the neurochemical balance, there is always a room for improving acupuncture effect The Yin and Yang concept32Development and Recovery of EA Tolerance123456|4812 16 24020406080100n=30EA sessionsTime of recoveryTail flick latency, % increase(Hr)33Prolonged EA increased the produ
43、ction and release of CCK-8-ir in brainEA (15 Hz, 3 mA) , hr012345601234CCK-8-ir,fmol/mg*n=9-10p0.05*012345601020304050CCK-8-ir, fmol / 100 m l*n=6-8p0.001p0.01p0.05*34CCK-8 as Feedback Control of Opioid EffectExogenousopiatesEndogenousopioidsCCK-8ReleaseSynthesisOpioidtoleranceOpioidanalgesiaOpiates
44、AcupunctureORCCKRGGIP3Ca2+iInhibitingcalcium influxMobilizingcalcium storageDorsal Horn NeuronExcitationInhibition35Interaction between opioids and antiopioidsdetermines the effectiveness ofAcupuncture-induced AnalgesiaNonresponderResponderCCK antisenseCCK sense37Brain CCK contentMorphine analgesia0
45、2469Days after icv injectionCCK antisense icv injection decreases brain CCK content increases opioid analgesiaChangingPoor respondersintoGood respondersRats show a poor response to morphine and EAhave a high content of brain CCK38P77PMC rats having a low brain CCK content show ahigh vulnerability to
46、 audiogenic seizureandhigh response to acupuncture analgesiaOver expression of brain CCK by icv CCK vector Decreases seizure Decreases EA analg. (Changing good responders into poor responders)39051005100510 -EP antibodies, icvENK antibodies, icv, ith -receptor antagonist, icv, ithDyn antibodies, ith
47、 receptor antagonist, ithEnkephalin degrading enzymeinhibitor RB 101PreproCCK cDNA vector, icvCCK-8 (ng dose) icv, ithCCK antisense RNA, icvCCKB antagonist L-365,260CCK antibodies, icv, ith, PAGbkm/dEOPCCKCCKCCKEOPEOPEffect of AA Depends on a Balance between EOP and CCK36针刺研究永无止境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 Center11th3rd10thNeuroscience Research Institute
