中腦導(dǎo)水管周圍灰質(zhì)在針刺效應(yīng)中的作用

宋敏,趙慶逸,蔣廣威,尹磊淼,2,徐玉東,2,劉艷艷,2,楊永清,2,王宇,2

中腦導(dǎo)水管周圍灰質(zhì)在針刺效應(yīng)中的作用

宋敏1,趙慶逸1,蔣廣威1,尹磊淼1,2,徐玉東1,2,劉艷艷1,2,楊永清1,2,王宇1,2

(1.上海中醫(yī)藥大學(xué),上海 201203;2.上海市針灸經(jīng)絡(luò)研究所,上海 200030)

神經(jīng)系統(tǒng)中樞整合是針刺效應(yīng)產(chǎn)生的基礎(chǔ)。穴位局部的針刺刺激是一種創(chuàng)傷性刺激。中腦導(dǎo)水管周圍灰質(zhì)(periaqueductal gray, PAG)是傷害性刺激的中繼站,其解剖結(jié)構(gòu)和生理功能復(fù)雜。該文基于PAG解剖結(jié)構(gòu)與神經(jīng)投射,總結(jié)PAG在針刺效應(yīng)中的鎮(zhèn)痛作用、心血管調(diào)節(jié)作用、內(nèi)分泌調(diào)控等作用。

中腦導(dǎo)水管周圍灰質(zhì);針刺療法;神經(jīng)遞質(zhì);綜述

針刺效應(yīng)是通過調(diào)控神經(jīng)-內(nèi)分泌-免疫網(wǎng)絡(luò)途徑實(shí)現(xiàn)的,具有多環(huán)節(jié)、多靶點(diǎn)特性[1]。其效應(yīng)主要取決于穴位、腦、效應(yīng)器官之間針刺信息的產(chǎn)生、傳導(dǎo)、整合和輸出。神經(jīng)系統(tǒng)中樞整合是針刺效應(yīng)產(chǎn)生的基礎(chǔ)[2]。穴位是針刺信息產(chǎn)生的起始部位,局部針刺刺激是一種創(chuàng)傷性刺激,多種感受器與外周神經(jīng)末梢的激活形成傳入沖動(dòng),并迅速地通過神經(jīng)反射發(fā)揮效應(yīng)[3]。

中腦導(dǎo)水管周圍灰質(zhì)(periaqueductal gray, PAG)也稱中央灰質(zhì),是中樞神經(jīng)系統(tǒng)傳導(dǎo)與整合傷害性刺激信息的中繼站,其解剖結(jié)構(gòu)和生理功能復(fù)雜。PAG是中腦極其重要的部分[4],位于中腦導(dǎo)水管(aqueductal, Aq)周圍[5],在第三腦室(third ventricle, 3V)和第四腦室(fourth ventricle, 4V)之間,其頭端在后聯(lián)合與第三腦室的室周灰質(zhì)銜接,尾部到達(dá)藍(lán)斑核(locus goeruleus, LC)上部,與第四腦室的底室灰質(zhì)相延續(xù)[6-7]。根據(jù)細(xì)胞學(xué)構(gòu)筑,PAG可分為4個(gè)區(qū)[8],即背內(nèi)側(cè)區(qū)(dorsomedial periaqueductal gray, dmPAG)、外側(cè)區(qū)(lateral periaqueductal gray, lPAG)、背外側(cè)區(qū)(dorsolateral periaqueductal gray, dlPAG)和腹外側(cè)區(qū)(ventrolateral periaqueductal gray, vlPAG)。PAG可釋放阿片肽、5-羥色胺、g-氨基丁酸、D-絲氨酸、P物質(zhì)等多種神經(jīng)遞質(zhì)[9]參與疼痛、恐懼、焦慮、呼吸、發(fā)聲等多種生理功能調(diào)控[10-11]。

基于PAG解剖結(jié)構(gòu)與神經(jīng)投射,本文總結(jié)PAG在針刺效應(yīng)中的作用,現(xiàn)報(bào)道如下。

1 PAG參與的經(jīng)典神經(jīng)環(huán)路

1.1 參與調(diào)節(jié)鎮(zhèn)痛神經(jīng)環(huán)路

PAG在疼痛信息傳遞中處于承上啟下的作用,是調(diào)節(jié)疼痛信息的關(guān)鍵腦區(qū)。其疼痛信息向上傳遞可被來自脊髓和延髓的感受傷害性刺激的第二級神經(jīng)元激活,上傳至丘腦核進(jìn)行傷害性信息處理[12-13];同時(shí)PAG也是下行抑制疼痛的關(guān)鍵腦區(qū)[13]。在功能上,PAG與前扣帶回(anterior cingulate cortex, ACC)和延髓頭端腹側(cè)內(nèi)側(cè)核群(rostral ventromedial medulla, RVM)形成鎮(zhèn)痛神經(jīng)網(wǎng)絡(luò)結(jié)構(gòu)[14-18],即ACC-PAG-RVM。根據(jù)不同的疼痛性質(zhì)PAG釋放不用的神經(jīng)遞質(zhì),如GABA、D-ser、c-Fos蛋白等,再以RVM為接替站傳至延/脊髓背角,抑制/易化傷害性信息的傳入,參與體內(nèi)和體外的各種疼痛調(diào)控[19]。詳見圖1。

注:尾狀核(caudate nucleus, CN)、基底外側(cè)杏仁核(basolateral amygdala, BLA),經(jīng)典抑制疼痛神經(jīng)傳導(dǎo)通路和針刺鎮(zhèn)痛神經(jīng)傳導(dǎo)通路共同的神經(jīng)通路是ACC將疼痛信號傳至PAG,激活PAG釋放不同的生物活性物質(zhì)調(diào)節(jié)疼痛

1.2 參與調(diào)節(jié)心血管功能神經(jīng)環(huán)路

延髓頭端腹外側(cè)區(qū)(rostral ventrolateral medulla, rVLM)是心血管交感活動(dòng)的基礎(chǔ)中樞,其傳入投射經(jīng)過孤束核(nucleus tractus solitaries, NTS)接受來自外周多種感受刺激,其下行投射經(jīng)延髓和脊髓中間外側(cè)柱交感節(jié)前神經(jīng)元調(diào)控心血管功能平衡,在生理功能上rVLM與下丘腦室旁核(para- ventricular nucleus, PVN)有聯(lián)系[20-22]。研究顯示PAG參與心血管疾病的神經(jīng)調(diào)控,在PAG中微量注射去甲腎上腺素可引起PVN激活非NMDA谷氨酸受體加壓素介導(dǎo)升壓反應(yīng)[23],通過引起交感神經(jīng)活動(dòng)和壓力反射敏感性增加,升高患者體位性低血壓的嚴(yán)重程度[24]。研究顯示基底外側(cè)杏仁核(basolateral amygdala, BLA)與PAG之間也存在調(diào)節(jié)平均動(dòng)脈壓和心率的神經(jīng)投射[25]。詳見圖2。

注:下丘腦室旁核(paraventricular nucleus, PVN)、交感神經(jīng)(sympathetic nerve, SN),經(jīng)典調(diào)控心血管功能神經(jīng)網(wǎng)絡(luò)和針刺調(diào)節(jié)心血管疾病神經(jīng)傳導(dǎo)通路調(diào)控心血管疾病的共同腦核團(tuán)是PAG和rVLM

2 PAG參與針刺鎮(zhèn)痛作用

經(jīng)脊髓初步整合后,針刺鎮(zhèn)痛信號上傳至延髓中縫背核經(jīng)PAG激活杏仁核,釋放阿片類受體至大腦皮層進(jìn)行綜合整合,尾狀核接受來自大腦皮層大量下行纖維傳導(dǎo)束,由來自皮質(zhì)谷氨酸能神經(jīng)元投射末端突觸前膜大麻素受體1(CB1)激活PAG[26],釋放g-氨基丁酸(GABA)、D-絲氨酸(D-Ser)、c-Fos蛋白、內(nèi)啡肽等生物活性物質(zhì)[27-29],有效地抑制體內(nèi)和體表疼痛[30]。經(jīng)對針刺鎮(zhèn)痛治療前后靜息狀態(tài)下fMRI數(shù)據(jù)對比,顯示針刺后PAG與ACC之間的靜息態(tài)功能連接度顯著增加[31]。詳見圖1。根據(jù)疼痛部位的劃分,PAG參與頭痛、頜面痛、上肢和下肢痛、腹痛等針刺鎮(zhèn)痛過程。

2.1 頭痛

電針風(fēng)池穴能下調(diào)PAG區(qū)5-羥色胺受體5-HT7表達(dá),繼而降低外周血降鈣素基因相關(guān)肽(calcitonin gene related peptide, CGRP)含量,減少偏頭痛大鼠的頭痛行為[15]。

2.2 頜面痛

針刺牙髓疼痛模型大鼠內(nèi)庭穴,可誘發(fā)PAG中Fos免疫反應(yīng)性(Fos-ir)細(xì)胞數(shù)量增加,激活下行抑制纖維向脊髓傷害感受神經(jīng)元的釋放,抑制牙髓疼痛[32]。

2.3 上肢和下肢痛

電針刺激坐骨神經(jīng)痛大鼠足三里和三陰交穴,可緩解慢性結(jié)扎性損傷大鼠的神經(jīng)痛癥狀,免疫組織化學(xué)方法檢測顯示lPAG區(qū)P2X3受體表達(dá)上調(diào),提示lPAG中P2X3受體在疼痛調(diào)節(jié)中起抑制作用[33]。電針爪子急性疼痛模型大鼠足三里和上巨虛穴,微透析檢測顯示PAG中組胺、多巴胺和去甲腎上腺釋放增加,疼痛緩解[34]。

2.4 腹痛

電針刺激痛經(jīng)模型大鼠三陰交穴可明顯緩解痛經(jīng)大鼠的疼痛反應(yīng),ELISA法檢測顯示PAG中腦啡肽和b-內(nèi)啡肽含量升高[35]。Zyloney CE等[36]提前給予患者熱源產(chǎn)生痛覺,持續(xù)電針刺激患者的三間和合谷穴,可減弱疼痛,發(fā)現(xiàn)PAG可以協(xié)調(diào)多個(gè)腦區(qū)對疼痛感覺進(jìn)行自發(fā)活動(dòng)的連接,降低熱痛覺。

3 PAG參與針刺調(diào)節(jié)其他疾病

3.1 心血管系統(tǒng)疾病

高血壓、心律失常、心絞痛等心血管疾病屬于中醫(yī)學(xué)“心悸”“眩暈”“胸痹”“真心痛”等范疇[37]。激活PAG可引起血壓和心率變化[38]。針刺穴位能夠抑制心血管交感神經(jīng)興奮性神經(jīng)元,主要通過激活下丘腦弓狀核(arcuate hypothalamic nucleus, ARC)、中腦導(dǎo)水管周圍灰質(zhì)腹外側(cè)區(qū)(vlPAG)和髓質(zhì)核中縫蒼白球(globus pallidus, GP)中的神經(jīng)元,以及抑制延髓頭端腹外側(cè)區(qū)(rVLM)前運(yùn)動(dòng)交感神經(jīng)元的活動(dòng)[39-40]。電針刺激內(nèi)關(guān)和間使穴可減弱ARC和vlPAG激活的交感神經(jīng)興奮反應(yīng),激活谷氨酸能神經(jīng)元,延長電針刺激產(chǎn)生的作用[41]。電針高血壓模型貓的內(nèi)關(guān)穴和間使穴,發(fā)現(xiàn)ARC和vlPAG之間的興奮性谷氨酸含量升高,長時(shí)間的電針刺激抑制血壓升高,起到降血壓作用[42]。電針壓力性高血壓模型大鼠雙側(cè)足三里穴20 min,結(jié)果顯示壓力誘導(dǎo)的高血壓大鼠血壓降低,其抑制作用主要由PAG中的一氧化氮介導(dǎo),導(dǎo)致交感神經(jīng)抑制系統(tǒng)的激活和心臟活動(dòng)的減弱[43]。研究顯示[44]電針內(nèi)關(guān)和間使穴可以通過大麻素受體1(CB1受體)激活vlPAG中的內(nèi)源性大麻素-GABA系統(tǒng),抑制交感神經(jīng)興奮性心血管反射,減輕心絞痛。針刺治療心血管疾病的神經(jīng)通路。詳見圖2。

3.2 內(nèi)分泌系統(tǒng)疾病

機(jī)體激素分泌過多或過少造成內(nèi)分泌紊亂,會引起一系列疾病。針刺可治療內(nèi)分泌系統(tǒng)疾病[45]。有文獻(xiàn)研究[46]用鏈脲佐菌素(streptozotocin, STZ)建立糖尿病大鼠模型,在dlPAG中檢測到神經(jīng)元型一氧化氮合酶(neuronal nitric oxide synthase, nNOS)和一氧化氮合酶(nitric oxide synthase, NOS)的含量表達(dá)增加;針刺大鼠足三里穴后,dlPAG中nNOS和NOS降低,提示針刺抑制糖尿病引起dlPAG中nNOS和NOS的增加,降低血糖含量。

4 PAG參與針刺耐受

連續(xù)多次給予機(jī)體針刺,機(jī)體對刺激的反應(yīng)性降低,出現(xiàn)針刺耐受現(xiàn)象。孫夢婕等[28]通過多次電針刺激大鼠足三里、三陰交穴建立電針耐受模型,觀察大鼠機(jī)械痛閾(MWT)百分?jǐn)?shù)的變化,顯示MWT百分?jǐn)?shù)逐漸降低,通過ELISA法檢測到PAG中的D-ser水平升高;電針耐受的大鼠PAG內(nèi)微量注射星形膠質(zhì)細(xì)胞抑制劑氟代檸檬酸后,再電針刺激,結(jié)果顯示大鼠MWT百分?jǐn)?shù)增加, PAG中D-ser水平下降,電針耐受癥狀緩解,研究表明多次外周電針刺激機(jī)體出現(xiàn)耐受現(xiàn)象,其機(jī)制與PAG中星膠質(zhì)細(xì)胞活化引起D-ser釋放增加有關(guān)。還有文獻(xiàn)研究證實(shí)了多次給予大鼠足三里和三陰交穴電針刺激后,大鼠MWT百分?jǐn)?shù)逐漸減少,電針的鎮(zhèn)痛作用下降,電針耐受形成,實(shí)驗(yàn)結(jié)果發(fā)現(xiàn)耐受大鼠lPAG中的P2X7受體陽性表達(dá)細(xì)胞數(shù)增加,功能活化,表明P2X7受體激活參與了大鼠針刺耐受形成機(jī)制[47-48]。

5 討論

根據(jù)筆者以上對PAG在針刺效應(yīng)中的作用的總結(jié)(見表1),可見針刺效應(yīng)主要通過針刺穴位產(chǎn)生針刺信號,激活腦區(qū)核團(tuán)釋放生物活性物質(zhì),起到調(diào)節(jié)機(jī)制功能的作用。實(shí)驗(yàn)研究表明,針刺穴位可激活PAG釋放腦啡肽、b-內(nèi)啡肽、5-羥色胺、P2X7受體、g-氨基丁酸、谷氨酸等生物活性物質(zhì),參與調(diào)控鎮(zhèn)痛、心血管和內(nèi)分泌疾病[15,35,44,49],但PAG具體亞核釋放神經(jīng)遞質(zhì)參與針刺的神經(jīng)調(diào)控有待深入研究。

表1 針刺效應(yīng)與PAG中生物活性物質(zhì)濃度變化的關(guān)系

PAG參與了針刺鎮(zhèn)痛、調(diào)節(jié)心血管功能平衡的神經(jīng)網(wǎng)絡(luò)。對比兩類疾病的針刺療法與經(jīng)典神經(jīng)網(wǎng)絡(luò)發(fā)現(xiàn)有共同腦核團(tuán)和神經(jīng)通路,在針刺鎮(zhèn)痛和經(jīng)典鎮(zhèn)痛的神經(jīng)環(huán)路中,存在共同的神經(jīng)通路,即ACC將疼痛信號傳至PAG,激活PAG釋放不同的生物活性物質(zhì)調(diào)節(jié)疼痛;而針刺和經(jīng)典調(diào)節(jié)心血管功能平衡的神經(jīng)網(wǎng)絡(luò)中有共同的腦核團(tuán),即PAG和rVLM,心血管功能失衡信息激活心血管交感活動(dòng)的基礎(chǔ)中樞rVLM,上傳至PAG釋放不同的生物活性物質(zhì),下行至rVLM前運(yùn)動(dòng)交感神經(jīng)元的活動(dòng),抑制心血管交感神經(jīng)興奮性神經(jīng)元。

針刺麻醉是因針刺誘導(dǎo)內(nèi)源性阿片類物質(zhì)釋放,激活中樞神經(jīng)的阿片類受體,以及調(diào)控腦組織釋放出5-羥色胺、血管緊張素Ⅱ以及g-氨基丁酸等多種內(nèi)源性的神經(jīng)遞質(zhì),進(jìn)而產(chǎn)生中樞鎮(zhèn)痛作用[50-51]。目前尚無研究表明針刺麻醉釋放的神經(jīng)遞質(zhì)與PAG有關(guān)。

針刺的本質(zhì)是一種創(chuàng)傷性刺激,作為傷害刺激信息中繼站,PAG在針刺信號的產(chǎn)生、傳導(dǎo)與中樞整合過程中起重要作用。因此,PAG在針刺的非特異性效應(yīng)以及在針刺治療其他疾病中的作用,有待進(jìn)一步研究。

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Role of Periaqueductal Gray in Acupuncture Effects

1,1,1,1,2,1,2,1,2,1,2,1,2.

1.,201203,; 2.,200030,

Central integration of nervous system is the foundation of acupuncture effects. Local acupuncture stimulation is a traumatic stimulus. Periaqueductal Gray (PAG) is a relay station for noxious stimulation and its anatomical structure and physiological functions are rather complicated. Based on the anatomical structure and neural projection of PAG, this article was to summarize the role of PAG in acupuncture effects including analgesic effect, and regulatory effect on cardiovascular system and endocrine system.

Periaqueductal gray; Acupuncture therapy; Neurotransmitters; Review

R2-03

A

10.13460/j.issn.1005-0957.2019.07.0812

1005-0957(2019)07-0812-06

2019-01-17

國際重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃(2018YFC1704600);國家自然科學(xué)基金項(xiàng)目(81173332,81173341,81201753,81473760, 81574058);上海市衛(wèi)生和計(jì)劃生育委員會項(xiàng)目(ZJ2016029)

宋敏(1992—),女,2016級碩士生,Email:songminmin_nm33@163.com

王宇(1973—),男,副研究員,碩士生導(dǎo)師,Email:wy.sh.cn@163.com

楊永清(1964—),男,研究員,博士生導(dǎo)師,Email:yyq@shutcm.edu.cn