疼痛機理與臨床學習班

1、從臨床角度透視疼痛機理,貴陽醫(yī)學院附院麻醉科曾慶繁,,,疼痛機理離我們遠嗎?,麻醉: 抑制/對抗手術(shù)傷害性刺激 疼痛診療:針灸鎮(zhèn)痛 脊髓電刺激 椎間盤突出的臭氧治療 交感神經(jīng)阻滯治療疼痛 藥物: TCA 加巴噴丁卡馬西平辣椒素,,什么是疼痛？,分類(原因),生理性(創(chuàng)傷性)疼痛

2、 ↓病理性疼痛: 炎性痛 病理性神經(jīng)痛 癌痛心理性疼痛,←急性疼痛:手術(shù)后疼痛 創(chuàng)傷 急性病←慢性疼痛months or years,Acute pain is a normal and predictable physiologic respon

3、se to an adverse chemical, thermal, or mechanical stimulus; it is associated with surgery, trauma, or acute illness and is usually experienced for a limited and defined period of time,,,a few days or a few weeks,,急性疼痛總是涉

4、及到組織損傷周圍神經(jīng)和中樞神經(jīng)系統(tǒng)是動態(tài)的不是靜止的可塑性,,,手術(shù)后慢性疼痛,截肢amputation 100%→慢性疼痛或不適開胸手術(shù)thoracotomy 50-60% 疼痛持續(xù)6月 甚至 出現(xiàn)病理性神經(jīng)痛-燒灼樣 痛/麻刺感burning and tingling. 乳房切除術(shù)mastectomy 50-

5、60%疼痛持續(xù)6月開腹膽囊切除術(shù)open cholecystectomy 19%腹腔鏡膽囊切除術(shù)laparoscopic cholecystectomy 9%,病理性疼痛三大表現(xiàn),,定義,疼痛 ：組織損傷 ↓信息傳遞 脊髓 ↓ 腦 不愉快的感覺 情緒上的感受,疼痛信息傳遞,,

6、Transduction轉(zhuǎn)導（換能transducer換能器）,不同的傷害性刺激→非電刺激1.熱t(yī)hermal2.機械mechanical3.化學chemical stimuli ↓傷害性感受器NociceptorsAδ C纖維游離神經(jīng)末梢 ↓能量轉(zhuǎn)換converted to 電信號electrical signals,,,Nerve growth factor↗,,sufficient s

7、trength noxious stimulus depolarizes the nociceptor membrane. ↓expression of transducing ion-channel receptors. nonselective potassium or sodium channels gated by temperature, chemical stimuli, or mechanical sh

8、earing forces rather than by voltage,Transmission傳遞,Aß fibers: large myelinated傳遞非傷害性信息本體感覺 輕觸覺不傳導疼痛 傷害性感覺神經(jīng)元NociceptorsAδ fibers： 薄髓鞘 傳導快 高閾值機械感受 受體 機械熱受體 傳導快痛 針刺樣疼痛2. C-fibers (70%) 傳遞各種模式

9、的傷害信息 機械 熱 化學刺激 Mechanical thermal chemical stimuli C-多型傷害感受器C-polymodal nociceptors 傳導慢 燒灼樣痛,第一痛由有髓鞘的Aδ纖維傳導，而第二痛則由無髓鞘的C纖維傳導。選擇性阻斷Aδ纖維的傳導可使第一痛消失（中間），而選擇性阻斷C纖維的傳導可使第二痛消失（底部）。,,“Lissauer’s tract ↓脊髓背角 dorsal

10、 horn 二級投射神經(jīng)元“second-order” pain transmission cell projection neurons,,1.疼痛傳導特定神經(jīng)元(NS) 位于板層ⅠⅡ← Aδ C 接受傷害性刺激傳入 ↓,,2.廣動力范圍神經(jīng)元(WDR) ↗ large “receptive fields”位于板層lamina V 接受傷害性和非傷害性刺

11、激,→,,投射神經(jīng)元Projection neurons,Pain input to the spinal cord:lamina I ← A-delta and C fibers lamina II ← C fibers and relay it to other laminae.lamina V (wide-dynamic range neurons) ← A-delta, C and A-beta (low thr

12、eshold mechanoceptors),,1.疼痛傳導特定神經(jīng)元(NS) 傳導疼痛2.廣動力范圍神經(jīng)元(WDR) 傳導刺激的類型和位置,GluSP,Aδ C,Projection neurons,-A-delta and Cfibers co-release1.Glu→NMDA/ nonNMDA-R ↑+

13、 2.SP→NK-1 R 電壓依賴性離子通道開放Ca+ Na+ 興奮性觸突后電位高速路 小路 “freeway “ local streets’ ↓ ↓ 外側(cè)丘腦 內(nèi)側(cè)丘腦,疼痛神經(jīng)遞質(zhì),freeway,local streets,,疼痛的脊髓調(diào)控,,中樞下行調(diào)控,中樞下行調(diào)控,腦內(nèi)痛調(diào)制部位及其下行傳導通路

14、1、中腦導水管周圍灰質(zhì)（PAG）→、2、中縫大核及鄰近的網(wǎng)狀神經(jīng)核（5-羥色胺能）3、藍斑核群（去甲腎上腺素能神經(jīng)元）→后側(cè)索→脊髓后角。這些下行纖維直接、或通過脊髓內(nèi)抑制性中間神經(jīng)元，對脊髓后角投射神經(jīng)元發(fā)揮抑制性調(diào)制作用，從而抑制傷害性信息向腦內(nèi)的傳遞。,,,,,PAG腦啡肽enk,藍班NE,中縫大核5-HT,脊髓背角膠質(zhì)區(qū)抑制性中間神經(jīng)元,5-HT藍班↓NE,,腦啡肽 強啡肽,抑制性中間神經(jīng)元,觸突前抑制 觸突后抑制

15、,Inhibitory Neurotransmission1. Inhibitory interneurons or descendingprojections release various NTs: GABA, NE, or endogenous opioids2. Bind receptors on presynapse ofafferent pain fiber, inhibit Ca2+ channels,le

16、ading to reduced vesicle release3. Also bind post-synaptically: can signalvia G-proteins to cause K+ efflux orCl- influx (both are hyperpolarizing),,GluSP,,nociceptors do not adapt,連續(xù)刺激continued stimulation ↓1.感受器

17、反復放電→自發(fā)性疼痛continuous or repetitive firing of the nociceptor 2.感受器反應(yīng)域值下降 a decrease in the threshold ↓外周(感受器)敏化sensitization of nociceptors,傳入纖維持續(xù)放電可引起投射神經(jīng)元的反應(yīng)發(fā)生改變,中樞敏化“central sensitization” ↓痛覺過敏 hyperalgesia痛覺

18、倒錯 allodynia.,,,Mechanisms of peripheral and central sensitization in neuropathic pain.,Primary Afferentpathways,←descending modulatory Systems（NE/5-HT）opioid,,noxiousstimulus, such as an injury or disease,持續(xù)傷害性刺激

19、手術(shù)炎癥神經(jīng)損傷,外周敏化Peripheral sensitization to pain:,1.感受器反復放電continuous or repetitive firing of the nociceptor 2.異位從動 背根神經(jīng)節(jié)的電位震蕩 →自發(fā)性疼痛3.感受器反應(yīng)域值下降a decrease in the threshold →對熱 冷 靜態(tài)機械刺激 交感神經(jīng)釋放的NE敏感,一炎癥湯“

20、inflammatory soup”,nociceptor function is altered by the “inflammatory soup” that characterises a region oftissue injury.,CGRP,CGRP,Peripheral sensitization to pain:,neurogenicinflammation,degranulation,→nitric oxide,P

21、lasmae xtravasation,phospholipaseA2,,1.Bradykinin:powerful algogenic substance, from kininogens in the circulation, activates nociceptors in a way that is dependent on protein kinase C and calcium,,2.cytokines(interleuk

22、ins interferon tumour necrosis factor)↓Spontaneous pain(ongoing)瘙癢 走蟻感TNF-α 拮抗劑阿達木單抗（Adalimumab） 依那西普(Etanercept) 因福利美InfliximabNSAIDS?治療,P

23、KA phosphorylates Nav1.8/1.9; PKC phosphorylates noxious stimuli receptors (TRPV, ASIC)4. Result: increased ion influx per depolarization; lowered activation threshold,Upregulated 3.Nerve growth factor(fibroblastsandSc

24、hwannCells)→tyrosine kinase receptorsincreases the excitability of nociceptors which leads to hyperalgesia,Capsaicin receptor4.purines receptorP2X3 (a ligand-gated ion channel triggered by ATP) which is selectively e

25、xpressed by small-diameter sensory neurons5.acid-sensing ion channelis rapidly activated by conditions of acidity below pH →靜態(tài)不痛的機械壓力刺激:用手輕壓皮膚→鈍痛,6. prostaglandin E2 adenosine Serotonin 改變離子通道的電壓閾值易化動作電位傳遞7.TRP

26、M8 receptor↑冷痛域下降 冷刺激:20 ºC物體接觸皮膚→燒灼樣痛治療:TRPM8受體拮抗劑 薄荷Menthol?,Damaged nerves,Sodium channel,NGF,α-R,TRPV1-R,1.神經(jīng)損傷/退變(上2)2.完整神經(jīng)(下2)3.損傷→鈉通道表達(2)4.NGF產(chǎn)生5.鈉通道 NE-R TRPV-1 R 表達(在未損傷纖維),1.TRPV1 recept

27、or↑熱痛域下降熱刺激:40 ºC 物體接觸皮膚→燒灼樣痛辣椒素治療2.α1 α2 受體↑對NE刺激域值下降→SMP酚拖拉明治療3.鈉通道 ↑→自發(fā)性疼痛Lidocaine,Carbamazepine治療,二 神經(jīng)損傷,,損傷神經(jīng)自發(fā)沖動,脊髓神經(jīng)元自發(fā)沖動,→自發(fā)性疼痛,陣發(fā)性電擊樣疼痛:Paroxysmal pain機理:外周傷害性感受器興奮性增 加 異位沖動產(chǎn)生 背根節(jié)電位振蕩利多卡因

28、TCA 卡馬西平,Central sensitization,脊髓背角廣動力神經(jīng)元(WDR)興奮性增加廣動力神經(jīng)元(WDR):接受傷害性和非傷害性傳入表現(xiàn)為 1.對傷害性刺激的反應(yīng)活性增加(痛覺倒錯)2.感受野的擴大(痛覺過敏),Central sensitization (WDR),AMPA-R,NE/5-HT,µ R,Ca+ 通道,Glu,GABA,Na通道,觸突后:1.AMPA表↑

29、 ↓ Aβ纖維(輕觸覺)傳導疼痛→動態(tài)機械感覺倒錯2. WDR鈉通道表達↑ →興奮性觸突后電位↑3.+ MAPK(細胞內(nèi)級聯(lián)反應(yīng)),,,觸突前: 1.傳入C纖維觸突前Ca+ 通道表達↑ → Glu sp釋放↑ 2.抑制性中間神經(jīng)元(GABA能)調(diào)亡3.下行抑制系統(tǒng)功能降低↓ µ R↓4.下行易化系統(tǒng)↑,Mitogenactivated protein kinase system (MAPK).,觸突前治療:

30、1.μ-receptor agonists Opioids2.Calcium-channel blocker: Gabapentin加巴噴丁 3.α2-receptor agonists: Clonidine4.NA/5-HT-reuptakeblocker: TCA:阿米替林 venlafaxine文拉發(fā)辛5. GABABagonists Baclofen巴氯

31、酚,,觸突后治療:NMDA-receptor antagonists: Ketamine, dextromethorphan?右美沙芬NK1-receptor antagonists:阿瑞吡坦Aprepitant(止吐藥)Selective sodium-channel blocker: Carbamazepine卡馬西平,WDR wind-up?上發(fā)條?上揚?,,glial cells (brown cell), which

32、further enhances excitability in WDR neurons by releasing cytokines and increasing glutamate levels.,CaMK:鈣調(diào)素依賴性蛋白激酶ERK:絲裂原活化蛋白激酶 BDNF:腦源性神經(jīng)生長因子,總之:如下原因?qū)е虏±硇蕴弁?炎癥湯→外周感受器活化初級傳入纖維自發(fā)放電 離子通道(Na)