基礎(chǔ)醫(yī)學(xué)神經(jīng)生物學(xué)課件針刺鎮(zhèn)痛作用原理

1、針刺鎮(zhèn)痛研究40年回憶北京大學(xué) 神經(jīng)科學(xué)研究所韓濟(jì)生歷史回憶1958年出現(xiàn)了“針刺麻醉新事物周總理通過衛(wèi)生部指示：研究針麻原理全國(guó)100余座醫(yī)學(xué)院校參與研究1965年9月我接受國(guó)家任務(wù)主持此工程，至今40年回憶40年歷程，從科研方向、方法、結(jié)果進(jìn)行總結(jié)，可能有一定意義從 “是什么 What？針刺真的鎮(zhèn)痛嗎？到 “為什么 Why？針刺為什么會(huì)鎮(zhèn)痛？Acupucture-induced analgesiaHuman Observation:020406080-20020406080100120*Acupuncture at Heku pointPain threshold change (%)Ti

2、me in minutesneedlemanipulation(n=66)control group(n=22)7足三里合谷穴對(duì)照組合谷 優(yōu)于 足三里合谷 - 足三里合谷穴對(duì)照組合谷-足三里 雙穴 優(yōu)于 單穴對(duì)照組合谷穴非經(jīng)穴針刺非經(jīng)穴也有鎮(zhèn)痛效果合谷穴Site specificityMeridine/channel (morphological evidence?)Acupoints (precise to mm level?)Body points (Chinese original) or Ear points (French scholars) Bio-electrically sen

3、sitive sites, or densely innervated sitesrelative rather than absolute specificity12痛閾變化百分?jǐn)?shù)14留針留針捻針捻針耳針鎮(zhèn)痛：規(guī)律相似捻針有效，留針效差同一天 重復(fù)電針不同天 重復(fù)電針電針鎮(zhèn)痛有個(gè)體差異，具有可重復(fù)性大 鼠 實(shí) 驗(yàn)測(cè)痛是否能預(yù)測(cè)針麻效果？外科手術(shù)時(shí) 針麻效果術(shù)前測(cè)定針刺鎮(zhèn)痛效果合谷穴內(nèi)注射局麻藥procaine阻斷針刺鎮(zhèn)痛 針刺合谷穴針刺 穴位注射局麻藥 加 針刺Procaine infiltration in the acupointabolishes the effect of AA020

4、406080-20020406080100120(n=10) AcupunctureAcupuncture at Heku pointPain threshold change (%)Time in minutesProcaine infiltration + Acupuncture Analgesic effect produced by peripheral nerve Stimulation8Decay of the Effect of Acupuncture AnalgesiaAfter the termination of acupuncture stimulationHalf li

5、fe (T1/2) = 16 minPain threshold, % changeTime: 20 min / unit101002030405060809070Hegu 17.6 NMP 15.0 Zusanli 15.5 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 ve

6、ntricleperfusate 0 2040 60 0 2040 60Infusion of CSFAcupunctureControl50010Recipient rabbit從 “是什么 What？針刺真的鎮(zhèn)痛嗎？是的！到 “為什么 Why？針刺為什么會(huì)鎮(zhèn)痛？機(jī)制研究從何入手？從神經(jīng)生理電生理入手？從神經(jīng)化學(xué)物質(zhì)根底入手？神經(jīng)沖動(dòng)是電活動(dòng)到突觸末端是化學(xué)活動(dòng)針刺鎮(zhèn)痛的神經(jīng)化學(xué)機(jī)制 小分子神經(jīng)遞質(zhì)5-羥色胺5-HT, 去甲腎上腺素NA), 乙酰膽堿ACh, etc 神經(jīng)肽鴉片肽，非鴉片肽Tail flick latency, % change The role of CNS 5-HT in

7、 EA analgesiaICV injITH injBrain and spinal cord 5-HT mediate EA analgesia5-HTP5-HTPCinanCinan受體拮抗劑前體物質(zhì)對(duì)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 EAAD

8、OPS 前體物質(zhì)Phentol受體阻斷中樞神經(jīng)遞質(zhì)在腦的不同部位 發(fā)揮不同作用遞質(zhì)腦脊髓5-HT加強(qiáng)加強(qiáng)NA對(duì)抗加強(qiáng)阿片肽 年份 阿片受體 電 針 Hz 51975 + + 2內(nèi)啡肽 311976 + + 2強(qiáng)啡肽 171979 +100孤啡肽 171995100內(nèi)嗎啡肽 41997+2腦能產(chǎn)生自己的“嗎啡”內(nèi)源性阿片肽氨基酸 腦啡肽 2Hz EA increases Enk release 100Hz EA increases Dyn release120.000.501.001.502.002.50beforeAfter EAResponder0.000.100.200.30beforeA

9、fter EAResponder0.000.100.200.30Non-responder0.000.501.001.502.002.50Non-responder2Hz100HzEA15HzControlEnkephalin-ir in spinal perfusateDynorphin-ir in spinal perfusate *2Hz100HzEA15HzControl05001000150020001015050500100015002000051015*2Hz Enk100Hz Dynfmol / ml CSFFrequency dependence of peptide rel

10、ease Human StudyMek-Arg-PheDynorphin AMEK-Arg-PheDynorphin AA study in collaboration with Dr. Lars Terenius 1315大鼠脊髓中腦啡肽和強(qiáng)啡肽的作用： 低頻：腦啡肽 高頻：強(qiáng)啡肽Analgesic effect of electro-acupunctureDYN ABMEK ABn = 13 14 rats100500248163264128Frequency of EA (Hz)腦啡肽抗體阻斷低頻電針鎮(zhèn)痛強(qiáng)啡肽抗體阻斷高頻電針鎮(zhèn)痛電針鎮(zhèn)痛效應(yīng)電針頻率 Hz脊髓鞘內(nèi)注射正常兔血清電針不同頻

11、率 發(fā)揮不同作用電針頻率（Hz）在CNS釋放的 神經(jīng)肽發(fā)揮鎮(zhèn)痛作用部位低頻（24）腦啡肽內(nèi)啡肽腦和脊髓高頻（80120）強(qiáng)啡肽脊髓放電頻率Response / Release神經(jīng)遞質(zhì)神經(jīng)肽Thomas Hokfelt, 1991, Neuron 7:867-8794低頻刺激釋放神經(jīng)遞質(zhì)高頻釋放神經(jīng)肽2 Hz100 Hz1997EM-EPENKDYNANTIBODYNALOXONE197619751979Opioid ReceptorsEA accelerates the release of endogenous opioidsSynergistic Interaction between n

12、europeptidesPeptide 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 電針方法是否有改進(jìn)余地？穴位接受什么刺激？機(jī)悈刺激: 機(jī)悈壓迫(砭,針刺溫度刺激：溫針(經(jīng)針)，灸(經(jīng)皮)電刺激 ：經(jīng)針(電針)，經(jīng)皮(TENS)電刺激穴

13、位：兩種方式經(jīng)針 (電針， EA)0.5 - 3.0 mA經(jīng)皮 (經(jīng)皮電刺激，TENS)5 - 15 mA15電針via needlesTENSvia skin electrodes必須應(yīng)用恒流(constant current)電刺激儀Equal potency of the analgesic effects produced by EA and TENS in ratsEATENSEATENS2 Hz15 Hz100 HzPlaceboTFL, % change16Cross tolerance between EA and TENSEATENSN = 10 - 142 Hz15 Hz1

14、00 HzTFL, % change電針和TENS的比較刺激方式電流到達(dá)深部組織途徑刺激范圍操作條件EA經(jīng)過針精確必須針灸醫(yī)師操作TENS經(jīng)過皮膚電極覆蓋面較大可在醫(yī)師指導(dǎo)下自行操作相同點(diǎn)：鎮(zhèn)痛效果相似，鎮(zhèn)痛機(jī)制相同，TENS使用方便。HANS for the treatment of autism自閉癥、孤獨(dú)癥The HANS unit and the skin electrodesAn autism patient is treating himself with a HANS unit.18ShenZhen Hospital電針鎮(zhèn)痛的神經(jīng)通路 經(jīng)典神經(jīng)生物學(xué)方法 腦影像方法必須與針刺治療

15、效果相關(guān)者才有意義 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.Hypoth.PAGMedullaDHN27Rat experimentBrain imaging and functional correlatesAcupuncture may a

16、ctivate 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 increases Dyn release0.000.100.200.30beforeAfter EAResponder0.000.100.200.30Non-responder2H

17、z100HzEA15HzControlDynorphin-ir in spinal perfusate *Responders and non-responders in acupuncture analgesia0.000.501.001.502.002.50beforeAfter EAResponder0.000.501.001.502.002.50Non-responderEnkephalin-ir in spinal perfusate*2Hz100HzEA15HzControl 2Hz EA increases Enk release R. Primary Motor Area (R

18、-MI)R. Supplementary Motor Area (R-SMA)30Zhang WT, et al: Brain Res 2003; 982:168-178Positive correlationBrain areas involved in AA: fMRI studies in humans31Right Primary Motor AreaRight Supplementary Motor AreaLeft Secondary Somatosensory AreaLeft InsulaRight Secondary Somatosensory AreaLeft Superi

19、or Temporal GyrusRight ThalamusRight Anterior Cingulate CortexRight HippocampusLeft HippocampusRight Primary Somatosensory AreaRight InsulaPositive correlationNegative correlationZhang WT, et al: Brain Res 2003; 982:168-178Correlated brain areas involved in 2 Hz AA從原理研究返回臨床實(shí)際Hans Acupoint Nerve Stim

20、ulator (HANS)韓 氏 穴 位 神 經(jīng) 刺 激 儀NeiGuan (Pe6) Heku (LI 4) 21HANSElectrical stimulation parametersFrequency (Hz, 1-100)Intensity (mA, 0.5-3.0)Pulse width (ms, 0.1-0.6)20急性痛創(chuàng)傷，手術(shù)，術(shù)后，生育)慢性痛(神經(jīng)損傷，炎癥，腫瘤，)0ABCDEFG0120ABCDEFG0123456Fi-enf (%)Enflurene conc (%)Fex-enf (%)Enflurene conc (%)0ABCDEFG0123MACHow e

21、ffective is HANS for reducing Acute (surgical) pain?To reduce the dose of Enflurene used in Cranial OperationsPrior to Incision 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+

22、 HANS針刺鎮(zhèn)痛的積累效應(yīng)療效增強(qiáng)，作用時(shí)間延長(zhǎng)。慢性痛需要屢次治療屢次治療療效是漸增？ 還是漸減？The Longlasting Effect of Electroacupuncture on Cold-induced Neuropathic 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 l

23、ong as 2 daysCumulative effect of EA on spinal spasticitySession of EA05101520012345P 0.01100Hz (n=6)2Hz (n=3)Ashworth Score12345P 2 HzMultiple acupuncture treatments can produce marked cumulative effect2 Hz may serve as a control for 100 Hz針刺積累效應(yīng)的可能機(jī)制促進(jìn)有關(guān)基因的表達(dá)Electroacupuncture accelerates the gene

24、 expression (prepro-enkephalin) in rat brain1100100200300400500600700800900mRNA Level ( % of Control )Time after Electroacupuncture (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 ratsGAPDH532 bp

25、2000 bp1000 bp750 bp500 bp250 bp100 bpDL2000CPP2 Hz100 HzRestrainPPE（402 bp）NSGrey scale ratios (PPE/GAPDH)0.000.250.500.751.00NSCPP2 Hz100 HzRestrainn=4TreatmentP0.05*#P0.05562 Hz PPE mRNA PPD (250 bp)1000 bp100 bp2000 bp750 bp500 bp250 bpDL 2000 NSCPP2 Hz100 HzRestrainGAPDH (532 bp)100Hz EA increa

26、sed the level of PPD mRNA in nucleus accumbens of CPP ratsTreatment0.00.51.01.5Grey scale ratios (PPD/GAPDH)n=4NSCPP2 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 sup

27、press heroin withdrawal syndrome?To reduce the dose of BPN needed for heroin detoxificationBPN Dose (mg/d)1234567891011121314Days of Treatment0.00.51.01.52.02.5*Buprenorphine HANS + BPN * P 100 HzEA suppression of morphine CPP212 Hz 100 Hz 脫毒 抑制戒斷病癥防復(fù)吸 (抑制心癮)100 Hz 2 Hz2 Hz 100 Hz22電針或HANS 治療海洛因成癮HA

28、NS 抑制心癮的最優(yōu)頻率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 HzEffect of EA of different frequencies on heroine cue-induced changes in

29、 BOLD signalsAbolished by 2 Hz EANot affected by 100 Hz EAStrengthened by second cue exposure2 Hz 100 Hz 0 Hz (mock)HANS 抑制心癮的最優(yōu)頻率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-HANS

30、102030100 Hz2 HzMock2/100 Hz 00123452 Hz 100 HzNo relapse over 1 yearClinical BaseMethod of Detox :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 deto

31、x. + HANS ready in the pocket 30% success over 1 yearPrevious drug addicts keeping drug free for one 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

32、 Acupuncturewritten by M Smith, et al.59物 質(zhì) 依 賴第4版2005第49章AcupunctureHan et al.The essence of acupuncture treatment: -Consolidation of Homeostasis針刺治療的實(shí)質(zhì)加強(qiáng)內(nèi)環(huán)境穩(wěn)定試圖總結(jié)提高到理論水平？What does acupuncture do?General modulatory effectstrengthening negative feedback mechanismActivating specific circuitry or Prod

33、ucing specific neurotransmitters site specific (acupoint) manipulationparameter (frequency) specific stimulation1Acupuncture can resume the homeostasis2Gentle and mildUnlike morphine which produces analgesia, acupuncture induces hypo-algesiaLittle aversive effectsUnlike morphine which produces sever

34、e aversive side effects, acupuncture produces little or no aversive side effects.Characteristics 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 bac

35、k to a physiological status. Models for the study of acupuncture effect4Quantification 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 fo

36、r reducing Acute (surgical) pain?To reduce the dose of Enflurene used in Cranial OperationsHANS produces a 45% - 50% reduction of anesthetic use660ABCDEFG0120ABCDEFG0123456Fi-enf (%)Enflurene conc (%)Fex-enf (%)Enflurene conc (%)0ABCDEFG0123MACPrior to Incision After Incision Drilling the skull Open

37、 the dura Remove tumor Suturing dura Suturing skin EnflureneHANS + Enf- HANS+ HANS100 : 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 philosoph

38、y 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 concept32Development and Recovery of EA Tolerance123456|48121624020406080100n=30EA sessionsTi

39、me of recoveryTail flick latency, % increase(Hr)33Prolonged EA increased the production 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-8ReleaseSynthesisOpioidtoleranceOpioidanalgesiaOpiatesAcupunctureORCCKRGGIP3Ca2+iInhibitingcalc