神經(jīng)病理性痛的發(fā)病機(jī)制及治療研究*

江　茜，歐陽娟，黃　誠

(贛南醫(yī)學(xué)院　1.2014級碩士研究生;2.基礎(chǔ)醫(yī)學(xué)院，江西　贛州　341000)

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神經(jīng)病理性痛的發(fā)病機(jī)制及治療研究*

江茜1，歐陽娟2，黃誠2

(贛南醫(yī)學(xué)院1.2014級碩士研究生;2.基礎(chǔ)醫(yī)學(xué)院，江西贛州341000)

神經(jīng)病理性痛是由于軀體感覺系統(tǒng)的損傷或疾病所引起的疼痛，是臨床上的常見病和慢性病，嚴(yán)重影響患者的生活質(zhì)量。作為一種全球負(fù)擔(dān)性疾病，神經(jīng)病理性痛的高發(fā)病率和低治愈率受到國內(nèi)外研究學(xué)者的密切關(guān)注。有研究證實外周和中樞機(jī)制共同參與了神經(jīng)病理性痛的發(fā)生發(fā)展過程。目前針對神經(jīng)病理性痛的治療主要有藥物治療、電針治療、微創(chuàng)技術(shù)治療等。傳統(tǒng)中草藥因其不良反應(yīng)小的優(yōu)點成為近年來研究熱點?，F(xiàn)對近年來該病的發(fā)病機(jī)制及治療進(jìn)展作一綜述。

神經(jīng)病理性痛；發(fā)病機(jī)制；治療

神經(jīng)病理性痛是世界公認(rèn)的難題，它由一系列不同疾病或損傷所引起，臨床表現(xiàn)各異，直接或間接造成神經(jīng)系統(tǒng)損害[1-3]。2011年國際疼痛研究學(xué)會(IASP)對神經(jīng)病理性痛(neuropathic pain,NP)提出新定義：神經(jīng)病理性痛是由于軀體感覺系統(tǒng)的損傷或疾病所引起的疼痛[4]。NP的特點是傷害性刺激消失后仍出現(xiàn)疼痛，主要表現(xiàn)為痛覺過敏(hyperalgesia)、痛覺超敏(allodynia)、炎癥區(qū)域持續(xù)性的自發(fā)痛(spontaneous pain)[5]。

據(jù)調(diào)查顯示，NP的發(fā)病率世界各異，英國約1%[6]，美國約1.5%[7]，加拿大17.9%[8]，在我國發(fā)生率約為7%，有超過2/3的患者治療不能有效的緩解疼痛[9]，這不僅嚴(yán)重影響患者的生活質(zhì)量[10]，還增加了社會負(fù)擔(dān)[10-11]。近年來，研究人員根據(jù)該病不同的疼痛特點建立起多種NP動物模型，對NP的認(rèn)識和理解有了進(jìn)一步發(fā)展。本文就近年NP發(fā)病機(jī)制及治療方面研究進(jìn)展進(jìn)行綜述。

1　神經(jīng)病理性痛的發(fā)病機(jī)制

NP發(fā)病機(jī)制極其復(fù)雜，盡管有些進(jìn)展，但仍有許多目前還不甚清楚。而且有多種模型來研究NP發(fā)病機(jī)制，其結(jié)果也不一致。越來越多的學(xué)者認(rèn)為外周和中樞機(jī)制共同參與了NP的發(fā)生發(fā)展過程[12-17]。下面就NP的外周及中樞機(jī)制作一闡述。

1.1神經(jīng)病理性痛的外周機(jī)制神經(jīng)病理性痛外周機(jī)制主要包括：

1.1.1受損神經(jīng)產(chǎn)生的異位放電(Ectopic discharges) 異位放電是指在一些本不該產(chǎn)生自發(fā)電活動的部位產(chǎn)生的自發(fā)放電，比如背根神經(jīng)節(jié)、外周神經(jīng)的軸突等[18]。最早證明異位放電參與NP的證據(jù)來自于Chung的研究[19-20]，在造模前或造模后，他們把受損神經(jīng)的背根剪斷，動物的自發(fā)痛以及觸誘發(fā)痛和痛超敏均明顯減輕，這說明異位放電在NP的發(fā)生和發(fā)展過程中起著重要作用；Ossipov M. H.等[21]用辣椒素破壞細(xì)纖維之后不能消除SNL模型大鼠的觸誘發(fā)痛行為，這提示觸誘發(fā)痛主要由粗纖維介導(dǎo)，因異位放電主要來自于大中神經(jīng)元，因此，人們推測異位放電可能是觸誘發(fā)痛的兇手。此外，有研究[22-24]發(fā)現(xiàn)神經(jīng)損傷后異位放電出現(xiàn)的時間與機(jī)械痛敏出現(xiàn)的時間相當(dāng)，且神經(jīng)損傷后異位放電的頻率以及放電纖維的比例均隨著時間的延長逐漸降低，這與動物痛行為的變化相一致；同時還發(fā)現(xiàn)越痛敏的大鼠異位放電越強。以上研究均表明異位放電與神經(jīng)病理性痛的相關(guān)性。但是也有研究[25-26]認(rèn)為損傷神經(jīng)的異位放電不是脊神經(jīng)選擇結(jié)扎模型 (spinal nerve ligation,SNL)大鼠痛行為的必要條件。孫錢等認(rèn)為異位電活動確實參與慢性神經(jīng)病理性痛的產(chǎn)生、發(fā)展和維持，但對神經(jīng)病理痛的后期維持作用有限[18]。異位電活動參與形成NP主要與離子通道相關(guān)。有研究者認(rèn)為電壓依賴性鈉離子通道的Nav1.3通道在異位放電中起著主導(dǎo)作用[27]；抑制鉀通道可使異位放電頻率增加，提示鉀通道參與異位放電的形成[28]；背根神經(jīng)節(jié)(dorsal root ganglion,DRG)神經(jīng)元傳入末梢中樞端電壓門控Ca2+通道在神經(jīng)病理性痛狀態(tài)下表達(dá)上調(diào)，引起Ca2+依賴的興奮性神經(jīng)遞質(zhì)釋放增加[29]，從而參與NP的形成和發(fā)展。

1.1.2炎性細(xì)胞與細(xì)胞因子的作用炎性細(xì)胞在周圍神經(jīng)損傷引起的NP中起著重要的作用[30]?；瘜W(xué)介質(zhì)5-HT、緩激肽、SP、組胺等的釋放可致炎性細(xì)胞的激活、血管舒張以及血漿蛋白的滲出，最終使傷害性感受器敏感化，進(jìn)而傳導(dǎo)低強度的痛覺刺激，引起NP。有研究發(fā)現(xiàn)，細(xì)胞因子中IL-6、IL-1β、TNF-α可能是與疼痛作用關(guān)系最為密切的細(xì)胞因子[31]，其中TNF-α 起關(guān)鍵作用[32]。

Deleo等[33]在NP動物模型中發(fā)現(xiàn)大鼠脊髓腰段的IL-1β含量增高；Gao YJ 等[34]認(rèn)為IL-1β能增強興奮性突觸傳遞和減少異質(zhì)性突觸傳遞，產(chǎn)生神經(jīng)病理性疼痛；Laughlin等[35]研究發(fā)現(xiàn)鞘內(nèi)應(yīng)用IL-1β拮抗劑可有效緩解痛敏癥狀。有研究顯示硬膜外注射TNF-α可使正常大鼠產(chǎn)生急性機(jī)械性痛覺過敏[36]；劉先國等[37]結(jié)果表明神經(jīng)損傷可能通過上調(diào)TNF-α導(dǎo)致Nav1.3和Nav1.8過表達(dá)，從而引起NP。Arruda等[38]發(fā)現(xiàn)外周神經(jīng)損傷大鼠脊髓前后角的IL-6 mRNA升高，認(rèn)為細(xì)胞因子包括IL-6是向高級中樞提供傷害信息的神經(jīng)遞質(zhì)；Orellana DI等認(rèn)為IL-6通過JAKs/STATs信號通路調(diào)節(jié)(N-甲基-D-門冬氨酸，NMDA)受體的Ca2+內(nèi)流，從而引起神經(jīng)退行性病變[39]。鄒曉琴等[40]通過酶聯(lián)免疫吸附法對SNI模型大鼠研究發(fā)現(xiàn)TNF-α、 IL-1β、IL-6的表達(dá)均顯著上調(diào)，亦證實以上細(xì)胞因子參與NP的形成和維持。

1.1.3交感神經(jīng)的參與眾所周知，在正常的DRG內(nèi)，沒有或僅有少量交感神經(jīng)節(jié)后纖維的出現(xiàn)。但在外周神經(jīng)損傷的腰部DRG內(nèi)，發(fā)現(xiàn)有交感神經(jīng)節(jié)后纖維芽生，出現(xiàn)交感-感覺耦聯(lián)現(xiàn)象，這被認(rèn)為是神經(jīng)病理性痛的特征之一[41]。動物模型證實這種病理交互作用是通過交感神經(jīng)末梢釋放的去甲腎上腺素選擇性作用于腎上腺素能α2受體實現(xiàn)的[42-44]。腎上腺素能受體拮抗劑以及化學(xué)交感神經(jīng)阻滯劑均能有效減輕外周神經(jīng)損傷后引起的異常疼痛，這說明交感神經(jīng)在外周痛覺敏化機(jī)制中發(fā)揮一定的作用。

1.2神經(jīng)病理性痛的中樞機(jī)制

1.2.1脊髓結(jié)構(gòu)重塑 有研究認(rèn)為，中樞突觸功能的重塑是引發(fā)慢性疼痛的重要機(jī)制[45]。正常情況下，低閾值的Aβ纖維存在于脊髓膠質(zhì)區(qū)的第Ⅲ和Ⅳ層，高閾值的C纖維存在于脊髓背角的Ⅱ板層，神經(jīng)損傷后，Aβ 纖維末梢異常芽生進(jìn)入脊髓背角的第Ⅱ板層[46-48]， 并且Aβ纖維的細(xì)胞表型發(fā)生改變，合成興奮性的神經(jīng)遞質(zhì)SP、VIP和EAAs[49]。因某些標(biāo)記技術(shù)缺乏特異性，這些發(fā)現(xiàn)尚未定論，且在某些物種中未損傷的Aβ 纖維也可在Ⅱ?qū)颖磉_(dá)[50]，但這些結(jié)構(gòu)的改變確實存在，提示外周神經(jīng)損傷后低閾值的Aβ纖維可能是NP發(fā)生的解剖學(xué)基礎(chǔ)之一。

1.2.2中樞敏化作用中樞敏化是指脊髓及脊髓以上痛覺相關(guān)神經(jīng)元興奮性異常升高或突觸傳遞增強，從而放大疼痛信號傳遞。LaMotte等[51]通過實驗發(fā)現(xiàn)皮內(nèi)注射TRPV1受體激動劑引起次級皮膚痛覺過敏，首次在人體上驗證了中樞敏化現(xiàn)象。Yan[52]和Ho等[53]證實脊髓背角NMDA受體的激活或磷酸化參與中樞敏化的發(fā)生和維持。有研究表明，外周神經(jīng)損傷后，突觸前神經(jīng)細(xì)胞釋放谷氨酸，作用于突觸后神經(jīng)細(xì)胞上NMDA受體，使細(xì)胞內(nèi)的Ca2+水平升高，促進(jìn)iNOS、nNOS、NO和COX-2的釋放，進(jìn)而作用于周圍細(xì)胞并激活第二信使系統(tǒng)，通過激活細(xì)胞內(nèi)不同信號分子來調(diào)節(jié)遞質(zhì)和炎癥介質(zhì)的表達(dá)，參與NP的形成和發(fā)展[54-59]。

盡管首次描述中樞敏化是發(fā)生在脊髓背角，但有研究發(fā)現(xiàn)杏仁核、前腦回和前額皮質(zhì)區(qū)等結(jié)構(gòu)同樣可發(fā)生類似的突觸改變[60-62]。這仍有待進(jìn)一步的研究。

1.2.3膠質(zhì)細(xì)胞的激活以往認(rèn)為膠質(zhì)細(xì)胞只具有支持、保護(hù)和營養(yǎng)功能，但近年來大量研究證明膠質(zhì)細(xì)胞(主要是星形膠質(zhì)細(xì)胞和小膠質(zhì)細(xì)胞)通過影響神經(jīng)遞質(zhì)、神經(jīng)調(diào)質(zhì)或細(xì)胞因子的釋放而誘發(fā)NP[63]。神經(jīng)損傷后可激活星形膠質(zhì)細(xì)胞，產(chǎn)生和釋放某些促炎細(xì)胞因子(如TNF-α、IL-1、IL-6等)、炎性介質(zhì)和神經(jīng)活性物質(zhì)參與NP的產(chǎn)生和維持，而這些物質(zhì)的過量表達(dá)又能誘導(dǎo)中樞敏化，使NP進(jìn)一步發(fā)展和持續(xù)[64]；此外，Marco等[65]發(fā)現(xiàn)膠質(zhì)細(xì)胞在慢性疼痛患者的丘腦部位亦有高表達(dá)。動物實驗研究證實鞘內(nèi)注射膠質(zhì)細(xì)胞激動劑可誘發(fā)觸誘發(fā)痛[66]；而注射膠質(zhì)細(xì)胞抑制劑卻能緩解疼痛[67-68]。星形膠質(zhì)細(xì)胞參與NP的另一種說法和谷氨酸轉(zhuǎn)運體-1(glutamate transporter-1,GLT-1)及谷氨酸/天冬氨酸轉(zhuǎn)運體(glutamate/aspanate transporter，GLAST)有關(guān)。星形膠質(zhì)細(xì)胞上大量表達(dá)GLT-1和GLAST，當(dāng)外周神經(jīng)炎癥或損傷時，先誘導(dǎo)GLT-1和GLAST短暫增多，隨后便持續(xù)性地抑制其表達(dá)，導(dǎo)致谷氨酸攝取減少，促進(jìn)谷氨酸能的突觸傳遞和谷氨酸濃度增加，進(jìn)而促進(jìn)NP的產(chǎn)生及發(fā)展[69-70]。

2　神經(jīng)病理性痛的治療

NP的病因、發(fā)病機(jī)制以及癥狀之間關(guān)系復(fù)雜，其治療效果不盡如人意，多數(shù)患者需長期用藥。這種不良的治療效果很可能與我們沒有找到針對每個患者具體的疼痛機(jī)制的靶點有關(guān)。但隨著近年來研究的進(jìn)一步深入，NP的治療取得了很大的進(jìn)展。

2.1藥物治療藥物療法仍是目前臨床上治療NP的主要方法，其目的是抑制痛覺傳導(dǎo)通路神經(jīng)元的異位放電和對傷害性刺激的超強反應(yīng)。用于治療NP的藥物主要有加巴噴丁、5%利多卡因貼劑、阿片類鎮(zhèn)痛劑、鹽酸曲馬多和三環(huán)類抗抑郁劑[71]、抗癲癇藥物[72]、NMDA受體阻斷劑等[73]。其中阿片類藥物、NMDA受體拮抗劑等還可通過鞘內(nèi)注射的方式進(jìn)行給藥[74-75]。盡管多項研究發(fā)現(xiàn)鞘內(nèi)使用藥物種類較多，但有關(guān)藥物療效、安全、穩(wěn)定性的數(shù)據(jù)有限，仍需進(jìn)一步研究證實。有證據(jù)表明，NMDA受體阻斷劑氯胺酮雖可有效地治療NP，但同時也會引起食欲減退和致幻[73，76]；阿片類鎮(zhèn)痛藥雖然治療NP效果顯著，但因其耐受性和成癮性，臨床使用受到極大限制。因此，越來越多的研究者將目光轉(zhuǎn)向不良反應(yīng)更小的祖國傳統(tǒng)中藥。

有研究表明臭牡丹根提取液具有較強的鎮(zhèn)痛作用，且通過非阿片受體發(fā)揮鎮(zhèn)痛效應(yīng)[77-78]；同時我們前期實驗還發(fā)現(xiàn)臭牡丹對NP所致的熱痛敏和機(jī)械痛敏有明顯的緩解作用，并可顯著降低SNI模型大鼠脊髓中TNF-α、IL-1β、IL-6和谷氨酸的表達(dá)水平[40，79-80]；雷公藤甲素和三七皂甙混合給藥對SNI模型大鼠所致的熱痛覺過敏有一定的鎮(zhèn)痛作用，對機(jī)械痛覺過敏有緩解作用[81]；Jun Tang等同樣發(fā)現(xiàn)雷公藤甲素可通過抑制脊髓背角神經(jīng)炎癥緩解NP，其抗炎效應(yīng)可能與抑制JAK-STAT3有關(guān)[82]；胡珊通過鞘內(nèi)給予黃芩素發(fā)現(xiàn)其可通過抑制骨癌痛大鼠脊髓神經(jīng)炎癥、相關(guān)信號通路激活和脂氧合酶表達(dá)來緩解疼痛[83]；Yan Zhang等研究者提取延胡索的成分——去氫紫堇鱗莖堿(dehydrocorybulbine,DHCB)，發(fā)現(xiàn)DHCB可緩解SNL大鼠痛模型所致的疼痛，且不引起耐受，其鎮(zhèn)痛機(jī)制可能與抑制多巴胺受體拮抗劑的活性相關(guān)[84]；白菖蒲、銀杏等所含的有效成分，為研究新型鎮(zhèn)痛藥物提供新的思路[85]。

2.2神經(jīng)調(diào)制治療近年來，隨著醫(yī)學(xué)科學(xué)和生物技術(shù)的不斷發(fā)展，一些新的治療NP手段也在逐漸被開發(fā)出來，且廣泛應(yīng)用于臨床。

神經(jīng)電刺激技術(shù)臨床常用的是韓氏穴位神經(jīng)電刺激(HANS)。在我國，傳統(tǒng)針灸用于治療疾病距今已有幾千年的歷史。電針(Electroacupuncture,EA)是在傳統(tǒng)針刺的基礎(chǔ)上，應(yīng)用電針儀輸出脈沖電流，用以加強刺激、增強療效的現(xiàn)代針灸療法[86]。動物和臨床試驗均已證實電針對急、慢性痛有治療作用[87-90]。研究發(fā)現(xiàn)電針可以減輕大鼠機(jī)械性痛覺過敏[91-93]和觸誘發(fā)痛現(xiàn)象[94-95]，且不能被納洛酮阻斷[96]。電針鎮(zhèn)痛的神經(jīng)生理機(jī)制比較復(fù)雜，有研究認(rèn)為是通過對穴位區(qū)域進(jìn)行電刺激，激發(fā)脊髓去甲腎上腺素能受體、5-HT以及阿片肽來抑制NMDA受體激活，從而緩解疼痛[97]，也有人認(rèn)為是抑制P2X受體相關(guān)表達(dá)[98-101]；最新研究顯示電針可通過促進(jìn)神經(jīng)營養(yǎng)因子-3(NT-3)的釋放并抑制IL-1β及脊髓膠質(zhì)細(xì)胞的表達(dá)從而達(dá)到鎮(zhèn)痛目的[102]。另有研究表明，某些藥物與電針合用可以加強電針的鎮(zhèn)痛作用，比如NMDA受體阻斷劑氯胺酮可加強電針對神經(jīng)病理性痛機(jī)械痛敏的緩解作用[103]；小劑量曲馬多與電針合用，對CFA致關(guān)節(jié)炎大鼠有更強的鎮(zhèn)痛作用[104]。

臨床上還可根據(jù)不同病情酌情選擇其他神經(jīng)調(diào)制治療方法，如經(jīng)皮神經(jīng)電刺激(TENS)、脊髓電刺激(SCS)、神經(jīng)叢或神經(jīng)干刺激、腦深部電刺激(DBS)、運動皮質(zhì)刺激和經(jīng)顱磁刺激(TMS)等。

2.3微創(chuàng)技術(shù)治療微創(chuàng)技術(shù)被認(rèn)為是挑戰(zhàn)NP治療難題的希望。它包括射頻神經(jīng)調(diào)控術(shù)、神經(jīng)阻滯、神經(jīng)損毀、臭氧療法和保護(hù)神經(jīng)的其他各種新介入方法[105-107]。需注意神經(jīng)毀損治療為不可逆的治療，應(yīng)嚴(yán)格掌握適應(yīng)證，并取得患者的知情同意。

3　小　結(jié)

NP作為人類疾病中的難題，其主要特點表現(xiàn)為痛覺過敏、痛覺超敏和炎癥區(qū)域持續(xù)性的自發(fā)痛，NP的產(chǎn)生是多個因素相互級聯(lián)的復(fù)雜過程，經(jīng)過不懈努力，各種相關(guān)的發(fā)病機(jī)制已經(jīng)逐漸顯出真面目，學(xué)者普遍認(rèn)為外周和中樞機(jī)制共同參與了NP的發(fā)生發(fā)展過程，且外周機(jī)制發(fā)生在先，中樞機(jī)制發(fā)生在后[108]。外周神經(jīng)損傷后，早期的異位放電不僅導(dǎo)致早期急性痛，而且這些異位沖動不斷轟擊脊髓背角等中樞部位，誘發(fā)產(chǎn)生脊髓背角長時程增強(long term potentiation，LTP)等中樞敏化現(xiàn)象[109]。在中樞敏化過程中，脊髓膠質(zhì)細(xì)胞活性的增強(細(xì)胞激活)、背角抑制性中間神經(jīng)元活性降低、下行痛抑制系統(tǒng)的削弱以及下行易化系統(tǒng)的增強等均在神經(jīng)病理性痛發(fā)生和后期維持中發(fā)揮重要作用。

盡管NP的治療已取得了一定進(jìn)展，但多數(shù)患者不能治愈，需長期用藥，經(jīng)濟(jì)負(fù)擔(dān)沉重。目前NP的治療仍以藥物治療為主。隨著人們對NP發(fā)病機(jī)制的深入研究，人們將有可能發(fā)現(xiàn)更多的潛在藥物靶點，比如針對神經(jīng)膠質(zhì)細(xì)胞，新開發(fā)的SLC 022處在Ⅱa期試驗階段，紐拉司汀(neublastin)處于Ⅰ期試驗[110]。大多數(shù)藥物因其有一定的不良反應(yīng)而限制了臨床應(yīng)用。已有研究報道三七皂甙、大黃素、葛根素、燈盞細(xì)辛、川芎嗪和丹參酮等中藥有抑制TNF-α或IL-1β等炎性細(xì)胞因子的作用，從而減輕細(xì)胞因子所介導(dǎo)的NP[111]。筆者認(rèn)為，傳統(tǒng)中藥對NP具有一定的治療作用，且不良反應(yīng)小，其可能是今后的一個研究方向。

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國家自然科學(xué)基金項目(No：31160213)

黃誠，男，教授，博士，碩士生導(dǎo)師。研究方向：電針鎮(zhèn)痛及慢性痛研究。E-mail:huangc6a2013@163.com

R741.02

A

1001-5779(2016)04-0500-07

10.3969/j.issn.1001-5779.2016.04.001

2016-01-14)(責(zé)任編輯：敖慧斌)