翁志軍　王立東　季亞婕,2　譚琳鎣　謝恒如　劉慧榮　吳煥淦

(1 上海市針灸經(jīng)絡(luò)研究所,上海,200030; 2 上海中醫(yī)藥大學(xué)附屬岳陽中西醫(yī)結(jié)合醫(yī)院,上海,200437)

?

NMDA受體NR2B亞基在慢性內(nèi)臟痛敏及針灸治療中的作用

翁志軍1王立東1季亞婕1,2譚琳鎣1謝恒如1劉慧榮1吳煥淦1

(1 上海市針灸經(jīng)絡(luò)研究所,上海,200030; 2 上海中醫(yī)藥大學(xué)附屬岳陽中西醫(yī)結(jié)合醫(yī)院,上海,200437)

摘要N-甲基-D-天門冬氨酸(N-methyl-D-aspartate,NMDA)受體具有多種不同亞基,且在中樞分布不同,N-甲基-D-天門冬氨酸受體(N-methyl-D-aspartate receptor,NMDAR)參與體內(nèi)各種信號(hào)的傳遞和調(diào)節(jié)神經(jīng)元的興奮性,如介導(dǎo)軀體和內(nèi)臟疼痛的發(fā)生和發(fā)展,NMDA受體中NR2B亞型與疼痛相關(guān)機(jī)制研究關(guān)系最為密切,內(nèi)臟痛(Visceral Pain)是臨床常見的癥狀,主要是由于各臟器及胸腹壁層的感覺神經(jīng)末梢受到強(qiáng)烈機(jī)械、化學(xué)刺激,也可由局部缺血、平滑肌痙攣及代謝產(chǎn)物不能及時(shí)排除而引起的疼痛感覺。電針在內(nèi)臟痛的臨床治療中療效肯定,實(shí)驗(yàn)研究發(fā)現(xiàn)電針對(duì)中樞NMDA受體尤其是NR2B亞基具有調(diào)控作用,初步揭示了電針鎮(zhèn)痛又一潛在靶點(diǎn),本文就NR2B亞基的結(jié)構(gòu)、功能、參與慢性內(nèi)臟痛的機(jī)制,以及近些年針灸治療慢性內(nèi)臟痛的機(jī)制研究進(jìn)行概述。

關(guān)鍵詞NMDA受體;NR2B;內(nèi)臟痛;針灸

疼痛的治療屬于醫(yī)學(xué)領(lǐng)域中的難題,長(zhǎng)期藥物應(yīng)用尚存在諸多弊端,傳統(tǒng)中醫(yī)針灸在鎮(zhèn)痛方面療效已得到臨床證實(shí),但尚缺乏足夠細(xì)胞與分子生物學(xué)方面的證據(jù)。中樞NMDAR在疼痛的發(fā)生與維持方面發(fā)揮著重要作用,包括參與疼痛記憶和可塑性的產(chǎn)生,針灸鎮(zhèn)痛機(jī)制研究中,NMDAR的NR2B亞基的作用逐步得到揭示[1-3],NR2B選擇性阻滯可能會(huì)為內(nèi)臟痛治療提供新的思路[4]。

1NR2B亞基的結(jié)構(gòu)

谷氨酸是介導(dǎo)痛覺信息傳遞的興奮性神經(jīng)遞質(zhì)之一[5],其受體分為離子型(iGluR)和代謝型谷氨酸受體(mGluR),2大類。iGluR主要分布在神經(jīng)元的突觸部位,當(dāng)突觸前釋放的谷氨酸作用于突觸后膜的iGluR時(shí),可誘發(fā)神經(jīng)元興奮反應(yīng),這對(duì)神經(jīng)元之間的信息傳遞、突觸可塑性調(diào)節(jié)以及學(xué)習(xí)記憶的形成等過程具有重要的作用[6-7]。根據(jù)iGluR對(duì)不同的激動(dòng)劑的相對(duì)選擇性及其氨基酸序列同源程度,可分為AMPAR、KAR和NMDAR。NMDAR是一種異聚體復(fù)合物,包括NR1,NR2(A、B、C、D)和NR3(A、B)亞基[8]。NR2B由胞內(nèi)的C端、Ml-M4跨膜區(qū)域和胞外的N端結(jié)構(gòu)域3個(gè)部分組成。胞外N2端含糖苷化位點(diǎn)以及配體結(jié)合位點(diǎn)等結(jié)構(gòu)。M1和M3之間形成孔袢,其近M1側(cè)含有一個(gè)未完全跨膜的M2短螺旋片段。M2端含有天冬酰胺的殘基,對(duì)Ca2+的通透性起著重要作用。NR2B的谷氨酸配體結(jié)合結(jié)構(gòu)域呈球囊形,分別由位于近氨基端的Sl和位于M3和M4之間的S2組成[9]。此外NR1和NR2B組成的NMDA受體通道具有高Ca2+的選擇通透性和溫度敏感性等特點(diǎn)[10]。NR2亞基只有與NR1結(jié)合時(shí)才能形成有功能的NMDA受體,通常是由2個(gè)NR1亞單位和2個(gè)NR2亞單位構(gòu)成的同源或異源聚體,甘氨酸和谷氨酸結(jié)合部位分別在NR1和NR2亞單位的類似區(qū)域[11]。

2NR2B亞基的分布

NR2B在中樞神經(jīng)系統(tǒng)呈現(xiàn)選擇性分布,尤其在中樞神經(jīng)系統(tǒng)痛覺信息傳遞與調(diào)制相關(guān)通路(如脊髓和前腦),NR2亞基在脊髓分布具有一定規(guī)律,NR2A和NR2D多集中分布在脊髓全層,NR2C的表達(dá)相對(duì)較少,以NR2B為表達(dá)數(shù)量最多、密度最高,主要局限分布在脊髓背角[12],尤以脊髓背角的Ⅰ、Ⅱ?qū)颖磉_(dá)最為明顯。利用胃蛋白酶消化抗原暴露技術(shù)發(fā)現(xiàn),在此兩層觀察到NR2B的分布[13]。有研究使用膜片鉗技術(shù)記錄突觸電流,發(fā)現(xiàn)在脊髓膠狀質(zhì)層[14]亦有NR2B的表達(dá)[15]。NMDA受體主要分布于神經(jīng)細(xì)胞突觸后膜,尤其在致密區(qū)(Postsynaptic Density,PSD),在PSD周圍和非突出胞膜上也有分布,依次稱為突觸后、突觸外NMDAR。此外在膠質(zhì)細(xì)胞[16]上也有分布。NMDAR組成和分布的復(fù)雜性可能是造成NMDAR功能的多樣性的原因。大腦中NR2B的分布也具有選擇性。NR2B在皮質(zhì)、海馬、紋狀體丘腦和嗅球等區(qū)域表達(dá)明顯[17]。Goebel等[18]發(fā)現(xiàn)NR2B mRNA在CNS分布高低順序依次為:皮質(zhì)、嗅球、海馬、紋狀體、上丘,而皮質(zhì)、海馬、紋狀體和嗅球都位于前腦[19]。RT-PCR檢測(cè)發(fā)現(xiàn)小腦浦肯野細(xì)胞、嗅皮層、視皮層和運(yùn)動(dòng)皮層的NR1,NR2(A-D)和NR3(A-B)的表達(dá)[20]。

3NR2B亞基與內(nèi)臟痛外周神經(jīng)敏化

DRG神經(jīng)元含外周突、中樞突,外周突末梢將接受的直接傷害性刺激傳遞至中樞突末梢,引起脊髓背角淺層神經(jīng)遞質(zhì)的釋放來傳遞痛覺沖動(dòng),與此相關(guān)的遞質(zhì)包括谷氨酸、天冬氨酸、CGRP和SP等。NR2B集中表達(dá)在DRG細(xì)初級(jí)傳入纖維,含這類亞基的NMDA受體可能對(duì)神經(jīng)遞質(zhì)的釋放有調(diào)節(jié)作用[21]。IBS大鼠腰骶DRG神經(jīng)元將合成NR2B蛋白傳輸至中樞端(脊髓背角Ⅰ層的突觸前膜),出現(xiàn)表達(dá)的升高,說明NR2B參與了內(nèi)臟通外周傳入敏化過程。結(jié)直腸機(jī)械性擴(kuò)張刺激可以使新生鼠感覺傳入神經(jīng)可塑性受到影響,造成成年鼠的感覺神經(jīng)傳入過敏,NR2B亞基在此病理過程的持續(xù)中起到重要作用。

4NR2B與內(nèi)臟痛中樞神經(jīng)敏化

內(nèi)臟受到機(jī)械性牽拉、炎性反應(yīng)、缺血、潰瘍、痙攣、梗阻、腫瘤等刺激可導(dǎo)致內(nèi)臟痛,特點(diǎn)是疼痛性質(zhì)模糊,定位不明確,在臨床上是一種極為普遍的癥狀,且往往伴有不愉快的情緒反應(yīng)和防御反應(yīng)。內(nèi)臟痛機(jī)制相當(dāng)復(fù)雜。在內(nèi)臟高敏感(內(nèi)臟痛)狀態(tài)下,已有研究發(fā)現(xiàn),傷害性和非傷害性刺激均能使機(jī)體表現(xiàn)出外周和中樞水平的敏化,其中的中樞敏化是被認(rèn)為是內(nèi)臟痛覺過敏和內(nèi)臟高敏感性發(fā)生發(fā)展過程中最為關(guān)鍵的因素[22-23],是目前研究的熱點(diǎn),越來越多的證據(jù)表明中樞NMDAR的參與是內(nèi)臟痛覺過敏-中樞敏感化的一個(gè)重要環(huán)節(jié)[24-25]。

4.1脊髓神經(jīng)敏化內(nèi)臟將接收到的刺激信號(hào)經(jīng)初級(jí)傳入神經(jīng)投射至胸腰段、腰骶段,NR2B亞基在脊髓水平(以腰骶段為主)的傷害性信息傳遞、痛覺敏化產(chǎn)生和維持方面發(fā)揮重要作用[26-28]。NMDAR的拮抗劑不能改變未致敏大鼠的痛閾,說明NMDAR在內(nèi)臟痛敏中起到某種特異性作用。在IBS模型大鼠胸腰段和腰骶段鏡下觀察到NR2B蛋白呈現(xiàn)高表達(dá),且在大鼠早期生活狀態(tài)中頗為明顯[29],表明IBS慢性內(nèi)臟痛覺敏感可能與胸腰、腰骶水平的NR2B亞單位異常表達(dá)有關(guān),進(jìn)一步研究發(fā)現(xiàn),脊髓水平NR2B亞基的磷酸化能進(jìn)一步放大此種內(nèi)臟痛敏的程度[30],提示NR2B在慢性內(nèi)臟痛的信息傳遞過程中可能起重要作用。傳遞至脊髓背角的持續(xù)性傷害性刺激促進(jìn)谷氨酸釋放增多,激活NMDA受體后導(dǎo)致鈣離子內(nèi)流,進(jìn)一步激活蛋白激酶C(PKC),再通過PKC使NMDA受體磷酸化,同時(shí)神經(jīng)元的興奮性可因一氧化氮而發(fā)生變化,向中樞進(jìn)一步傳遞傷害性信息引起痛覺過敏[31]。70%C類纖維與Aδ纖維的末梢有NR2B表達(dá),說明突觸前膜中的NR2B為主要亞型,且與中樞脊髓水平的痛覺傳遞有密切關(guān)系。脊髓鞘內(nèi)注射NMDA受體的激動(dòng)劑能夠增強(qiáng)內(nèi)臟刺激誘發(fā)的疼痛反應(yīng),并呈現(xiàn)劑量依賴性。NMDA介導(dǎo)了結(jié)直腸機(jī)械性擴(kuò)張刺激引發(fā)的神經(jīng)元的放電增強(qiáng),同時(shí)伴隨強(qiáng)烈的后發(fā)放電[32],在“軀體—內(nèi)臟會(huì)聚神經(jīng)元”可引起相應(yīng)軀體外周感受野的擴(kuò)大,NMDA能易化脊髓水平對(duì)傷害性結(jié)直腸擴(kuò)張刺激的痛行為表現(xiàn),并提高脊髓背角神經(jīng)元的反應(yīng)性,脊髓NMDA受體介導(dǎo)神經(jīng)元對(duì)內(nèi)臟傷害性傳入的高興奮性[33-34]。由于慢性內(nèi)臟痛發(fā)生發(fā)展受多種因素影響,其機(jī)制還有待于進(jìn)一步深入研究。

4.2腦神經(jīng)敏化NMDA等遞質(zhì)在正常大鼠內(nèi)臟感覺及軀體痛覺敏化中發(fā)揮作用[35-36]。在中樞敏化中,NMDAR的重要作用體現(xiàn)在2個(gè)方面:1)NMDA受體激活多發(fā)生在對(duì)C纖維的反復(fù)刺激所致的wind-up現(xiàn)象;2)中樞敏感化可被競(jìng)爭(zhēng)性/非競(jìng)爭(zhēng)性NMDAR拮抗劑抑制[37]。多項(xiàng)研究發(fā)現(xiàn),在長(zhǎng)時(shí)程突觸可塑性變化中有NMDA受體參與介導(dǎo)[38-39],推斷NMDAR在慢性內(nèi)臟痛的中樞敏化形成中起到關(guān)鍵作用。NR2B亞型主要分布于前腦,內(nèi)臟高敏感幼鼠前扣帶回皮質(zhì)(ACC)在內(nèi)臟疼痛調(diào)節(jié)通路中具有重要作用,實(shí)現(xiàn)的方式是通過上調(diào)NMDA受體的數(shù)量和活性[40],ACC區(qū)域有NR2A和NR2B的分布,NR2A、NR2B亞基在前扣帶回皮質(zhì)區(qū)域介導(dǎo)的中樞性內(nèi)臟痛敏反應(yīng)中發(fā)揮調(diào)節(jié)作用[41],且在增強(qiáng)傷害性信號(hào)傳遞的作用中呈正相關(guān)。突觸前膜釋放Glu等興奮性神經(jīng)遞質(zhì)后,結(jié)合NMDAR亞基NR2A、NR2B,導(dǎo)致大量Ca2+自胞外內(nèi)流而觸發(fā)Ca2+依賴性酶反應(yīng)過程是其可能的作用機(jī)制。持續(xù)興奮性突觸后電位導(dǎo)致了長(zhǎng)時(shí)程增強(qiáng)效應(yīng),增強(qiáng)了傷害性信號(hào)的傳遞,同時(shí)ACC內(nèi)磷酸化CaMKII與NMDA受體NB2A/B亞單位可以共同促進(jìn)內(nèi)臟痛覺過敏[42]。

5NMDA受體在針灸治療慢性內(nèi)臟痛的作用

針灸療法具有“簡(jiǎn)、便、驗(yàn)、廉”的優(yōu)點(diǎn),且不良反應(yīng)少,在臨床治療中應(yīng)用廣泛。近來關(guān)于針灸鎮(zhèn)痛的研究亦受到國(guó)內(nèi)外的持續(xù)關(guān)注。電針能夠明顯抑制急性內(nèi)臟痛和IBS大鼠在不同等級(jí)壓力刺激下的腹壁撤回反射評(píng)分(Abdominal Withdrawal Reflex，AWR)以及腹直肌電(Rectus Abdominis Electromyogram,EMG)[43]。針灸鎮(zhèn)痛的同時(shí),對(duì)于中樞NMDA受體尤其是NR2B亞基及其磷酸化的表達(dá)存在抑制效應(yīng)。電針可能通過下調(diào)NR2B亞基的表達(dá),干預(yù)中樞敏化的形成和維持,發(fā)揮一定的鎮(zhèn)痛效果[44]。在NR2B基因表達(dá)方面,針灸亦可通過對(duì)引起中樞敏化相關(guān)脊髓神經(jīng)元NR2B亞單位mRNA表達(dá)的下調(diào)作用,發(fā)揮其調(diào)整大鼠痛覺信息調(diào)控機(jī)制的作用[45]。NMDA受體是對(duì)Ca2+通透性最高的配體門控通道之一,其對(duì)Ca2+的通透性是對(duì)Na+和K+通透性的5～10倍。體內(nèi)Ca2+的過度激活則會(huì)引起Ca2+的過量?jī)?nèi)流,促進(jìn)細(xì)胞內(nèi)的痛覺信號(hào)轉(zhuǎn)導(dǎo)及一系列與疼痛有關(guān)的神經(jīng)遞質(zhì)的釋放。因此,針灸除了能夠通過調(diào)節(jié)NMDA受體NR2B亞基在中樞的表達(dá),是否能夠通過改變NR2B亞基的電生理特性,調(diào)控其功能狀態(tài),來抑制疼痛信號(hào)的傳遞,值得進(jìn)一步的探索研究。針灸治療內(nèi)臟痛具有良好的療效[46-48],但NMDA受體參與內(nèi)臟痛覺信息的轉(zhuǎn)導(dǎo)是復(fù)雜的病理過程,且針灸緩解內(nèi)臟痛的作用機(jī)制亦較為復(fù)雜,有待進(jìn)一步的研究?，F(xiàn)有研究表明,針灸可能通過影響中樞NMDA受體尤其是NR1和NR2B亞基的表達(dá),實(shí)現(xiàn)其緩解內(nèi)臟痛的作用。這可能是針灸緩解內(nèi)臟痛的一個(gè)潛在靶點(diǎn)[49]。電針對(duì)慢性內(nèi)臟痛敏IBS大鼠具有良好的治療作用,其作用機(jī)制可能通過下調(diào)腦內(nèi)RVM中NMDAR-1受體表達(dá)來發(fā)揮的[50]。胃擴(kuò)張?zhí)弁创笫蠹顾璞辰侵蠳R-2B陽性細(xì)胞數(shù)顯著升高,對(duì)足三里穴給予不同刺激強(qiáng)度針刺后,緩解了胃擴(kuò)張引發(fā)的大鼠應(yīng)激反應(yīng)[51],針刺信號(hào)在脊髓背角水平抑制了NR2B的表達(dá),還有研究發(fā)現(xiàn),足三里穴區(qū)的初級(jí)感覺傳入神經(jīng)與胃的傳入神經(jīng)的節(jié)段存在部分重疊,足三里穴給予電針刺激后,能夠翻轉(zhuǎn)/拮抗胃部擴(kuò)張出現(xiàn)的背角神經(jīng)元放電[52],因此足三里穴能通過減少胃腸傷害性刺激產(chǎn)生、并抑制疼痛遞質(zhì)的合成釋放,最終減少了疼痛物質(zhì)向中樞傳遞來發(fā)揮對(duì)胃擴(kuò)張?zhí)弁创笫箧?zhèn)痛作用。

6小結(jié)

NR2B亞型在慢性內(nèi)臟痛敏過程中扮演著較為重要的角色,但發(fā)揮作用的具體機(jī)制尚待進(jìn)一步研究。一方面,針灸療法對(duì)中樞NMDA受體的調(diào)控作用,體現(xiàn)在可通過降低NR2B受體在中樞的過度表達(dá)來實(shí)現(xiàn)。另一方面,針灸療法是否能夠通過改變NR2B亞基的電生理特性,調(diào)控其功能狀態(tài),來抑制疼痛信號(hào)的產(chǎn)生、傳遞和放大等,發(fā)揮其鎮(zhèn)痛的效應(yīng)機(jī)制,值得進(jìn)一步的探索研究。同時(shí),多種其他受體蛋白對(duì)NR2B亞基的交叉作用尚需更多深入研究證據(jù)的揭示。NMDA受體NR2B亞基做為內(nèi)臟痛發(fā)生機(jī)制中的一個(gè)重要方面,深入揭示并完善其在針灸治療內(nèi)臟痛的作用機(jī)制,以冀為應(yīng)用針灸治療內(nèi)臟痛的推廣,提供實(shí)驗(yàn)數(shù)據(jù)和理論依據(jù),這可能是值得今后重點(diǎn)研究的方向。

參考文獻(xiàn)

[1]Choi JW,Kang SY,Choi JG,et al.Analgesic effect of electroacupuncture on paclitaxel-induced neuropathic pain via spinal opioidergic and adrenergic mechanisms in mice[J].Am J Chin Med,2015,43(1):57-70.

[2]Feng XM,Chen SP,Wang JY,et al.Effect of electroacupuncture intervention on expression of pain sensory and affection processing related corticotropin-releasing factor receptor mRNA,etc.in the amygdala in neuropathic pain and negative affection rats[J].Zhen Ci Yan Jiu,2014,39(6):448-555.

[3]Zhang Y,Zhang RX,Zhang M,et al.Electroacupuncture inhibition of hyperalgesia in an inflammatory pain rat model：involvement of distinct spinal serotonin and norepinephrine receptor subtypes[J].Br J Anaesth,2012,109(2):245-252.

[4]Swartjes M,Morariu A,Niesters M,et al.Nonselective and NR2B-selective N-methyl-D-aspartic acid receptor antagonists produce antinociception and long-term relief of allodynia in acute and neuropathic pain[J].Anesthesiology,2011,115(1):165-174.

[5]Liu Y,Abdel SO,Zhang L,et al.VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch[J].Neuron,2010,68(3):543-556.

[6]Paoletti P,Bellone C,Zhou Q.NMDA receptor subunit diversity:impact on receptor properties，synaptic plasticity and disease[J].Nat Rev Neurosci，2013,14(6):383-400.

[7]Flores-Soto ME，Chaparro-Huerta V,Escoto-Delgadillo M，et al.Receptor to glutamate NMDA-type：the functional diversity of the nr1 isoforms and pharmacological properties[J].Curr Pharm Des，2013,19(38):6709-6719.

[8]Hassel B,Dingledine R.Glutamate.In：Siegel GJ,Albers RW,Brady ST,Price DL,editors.Basic neurochemistry，molecular，cellular，and medical aspects[M].7th ed.Burlington,MA:Elsevier Academic Press,2006:267-290.

[9]Flores-Soto ME,Chaparro-Huerta V,Escoto-Delgadillo M,et al.Structure and function of NMDA-type glutamate receptor subunits[J].Neurologia,2012,27(5):301-310.

[10]Cais O,Sedlacek M,Horak M,et al.Temperature dependence of NR1/NR2B NMDA receptor channels[J].Neuroscience,2008,151(2):428-438.

[11]Vyklicky V,Korinek M,Smejkalova T,et al.Structure，function，and pharmacology of NMDA receptor channels[J].Physiol Res,2014,63(1):S191-203.

[12]Boyce S,Wyatt A,Webb JK,et al.Selective NMDA NR2B antagonists induce antinociception without motor dysfunction：correlation with restricted localisation of NR2B subunit in dorsal horn[J].Neuropharmacology,1999,38(5):611-623.

[13]Nagy GG,Watanabe M,Fukaya M,et al.Synaptic distribution of the NR1,NR2A and NR2B subunits of the N-methyl-d-aspartate receptor in the rat lumbar spinal cord revealed with an antigen-unmasking technique[J].Eur J Neurosci,2004,20(12):3301-3312.

[14]Salter MG,Fern R.NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury[J].Nature,2005,438(7071):1167-1171.

[15]Momiyama A.Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord[J].J Physiol,2000,523(3):621-628.

[16]Lalo U,Pankratov Y,Kirchhoff F,et al.NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes[J].J Neurosci,2006,26(10):2673-2683.

[17]Chen Y,Chen AQ,Luo XQ,et al.Hippocampal NR2B-containing NMDA receptors enhance long-term potentiation in rats with chronic visceral pain[J].Brain Res,2014,1570:43-53.

[18]Goebel DJ,Poosch MS.NMDA receptor subunit gene expression in the rat brain:a quantitative analysis of endogenous mRNA levels of NR1Com,NR2A,NR2B,NR2C，NR2D and NR3A[J].Brain Res Mol Brain Res,1999,69(2):164-170.

[19]Cull-Candy S,Brickley S,Farrant M.NMDA receptor subunits：diversity，development and disease[J].Curr Opin Neurobiol，2001,11(3):327-335.

[20]Sun L,Shipley MT,Lidow MS.Expression of NR1,NR2A-D,and NR3 subunits of the NMDA receptor in the cerebral cortex and olfactory bulb of adult rat[J].Synapse,2000,35(3):212-221.

[21]Ma QP,Hargreaves RJ.Localization of N-methyl-D-aspartate NR2B subunits on primary sensory neurons that give rise to small-caliber sciatic nerve fibers in rats[J].Neuroscience,2000,101(3):699-707.

[22]Zhou Q,Price DD,Callam CS,et al.Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain(wind-up)in irritable bowel syndrome[J].J Pain,2011,12(2):297-303.

[23]楊敏,陳東風(fēng).內(nèi)臟高敏感性-中樞敏感化機(jī)制的研究進(jìn)展[J].重慶醫(yī)學(xué),2009,38(15):1958-1960.

[24]Lü N,Han M,Yang ZL,et al.Nociceptin/Orphanin FQ in PAG modulates the release of amino acids，serotonin and norepinephrine in the rostral ventromedial medulla and spinal cord in rats[J].Pain,2010,148(3):414-425.

[25]Carozzi V,Marmiroli P,Cavaletti G.Focus on the role of Glutamate in the pathology of the peripheral nervous system[J].CNS Neurol Disord Drug Targets,2008,7(4):348-360.

[26]Narita M,Miyoshi K,Narita M,et al.Changes in function of NMDA receptor NR2B subunit in spinal cord of rats with neuropathy following chronic ethanol consumption[J].Life Sci,2007,80(9):852-859.

[27]Tan PH,Yang LC,Shih HC,et al.Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat[J].Gene Ther,2005,12(1):59-66.

[28]Miranda A,Mickle A,Bruckert M,et al.NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation[J].Eur J Pharmacol,2014,744:28-35.

[29]林春,林國(guó)威,鄭偉,等.NMDA受體NR2B亞單位在慢性內(nèi)臟痛覺敏化中的作用[J].中國(guó)藥理學(xué)通報(bào),2008,24(8):1015-1018.

[30]Luo XQ,Cai QY,Chen Y,et al.Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord contributes to chronic visceral pain in rats[J].Brain Res，2014,1542:167-75.

[31]李靜,李麗,趙磊,等.N-甲酰-D-天門冬氨酸受體與疼痛[J].包頭醫(yī)學(xué)院學(xué)報(bào),2009,25(5):106-108.

[32]Kolhekar R,Meller ST,Gebhart GF.Characterization of the role of spinal N-methyl-D-aspartate receptors in thermal nociception in the rat[J].Neuroscience,1993,57(2):385-395.

[33]Kolhekar R,Gebhart GF.NMDA and quisqualate modulation of visceral nociception in the rat[J].Brain Res,1994,651(1-2):215-226.

[34]Traub RJ,Zhai Q,Ji Y,et al.NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression in the spinal cord and the visceromotor reflex[J].Neuroscience,2002,113(1):205-211.

[35]王永洪,孫蘭云,張勵(lì)才,等.內(nèi)臟痛覺過敏及其中樞敏感化[J].國(guó)際麻醉學(xué)與復(fù)蘇雜志,2006,27(4):246-248.

[36]Wang DS,Tian Z,Guo YY,et al.Anxiolytic-like effects of translocator protein(TSPO)ligand ZBD-2 in an animal model of chronic pain[J].Mol Pain,2015,11:16.

[37]Gaunitz C,Schüttler A,Gillen C,et al.Formalin-induced changes of NMDA receptor subunit expression in the spinal cord of the rat[J].Amino Acids,2002,23(1-3):177-182.

[38]Zhuo M.Glutamate receptors and persistent pain：targeting forebrain NR2B subunits[J].Drug Discov Today,2002,7(4):259-267.

[39]Zhou L,Huang J,Gao J,et al.NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats[J].Cell Immunol,2014,287(2):86-90.

[40]Cao Z,Wu X,Chen S,et al.Anterior cingulate cortex modulates visceral pain as measured by visceromotor responses in viscerally hypersensitive rats[J].Gastroenterology,2008,134(2):535-543.

[41]Wu LJ,Xu H,Ren M,et al.Pharmacological isolation of postsynaptic currents mediated by NR2A-and NR2B-containing NMDA receptors in the anterior cingulate cortex[J].Mol Pain,2007,3:11.

[42]Li Y,Zhang X,Liu H,et al.Phosphorylated CaMKII post-synaptic binding to NR2B subunits in the anterior cingulate cortex mediates visceral pain in visceral hypersensitive rats[J].J Neurochem,2012,121(4):662-671.

[43]李為民,崔可密,吳根誠(chéng).電針對(duì)急性內(nèi)臟痛大鼠腹部撤回反射和腹直肌肌電的影響[J].中國(guó)臨床康復(fù),2004,8(10):1899-1901.

[44]王公明,田玉科,戴體俊.NMDA受體2B亞基:一個(gè)潛在的鎮(zhèn)痛治療靶點(diǎn)[J].國(guó)際麻醉學(xué)與復(fù)蘇雜志,2006,27(5):309-312.

[45]馬騁,余黎,閆麗萍.電針對(duì)神經(jīng)病理性疼痛模型大鼠脊髓腰段神經(jīng)元離子型谷氨酸受體相關(guān)亞單位蛋白及其基因表達(dá)的影響[J].針刺研究,2010,35(6):403-408.

[46]Park JW,Lee BH,Lee H.Moxibustion in the management of irritable bowel syndrome：systematic review and meta-analysis[J].BMC Complement Altern Med,2013,13:247.

[47]Tang XW.Acupuncture combined with large amount of moxibustion for 78 cases of chronic gastritis[J].Zhongguo Zhen Jiu,2012,32(10):907-908.

[48]Huang Lechun,Li Junxiong.Clinical Study on the Treatment of Renal Colic by Body and Auricular Acupuncture[J].J Acupunct Tuina Sci,2011,9(2):104-106.

[49]梁宜,方劍喬,房軍帆,等.中樞NMDA受體在疼痛中的作用及電針的干預(yù)研究[J].浙江中醫(yī)藥大學(xué)學(xué)報(bào),2012,36(1):109-112.

[50]祁德波,李為民.電針對(duì)慢性內(nèi)臟痛敏大鼠延髓頭端腹內(nèi)側(cè)核NMDA-R1受體表達(dá)的影響[J].上海針灸雜志,2011,30(7):491-494.

[51]彭艷,易受鄉(xiāng),李振海,等.毫針不同刺激強(qiáng)度對(duì)胃擴(kuò)張?zhí)弁创笫蠹顾璞辰荖MDA受體和P物質(zhì)的影響[J].世界華人消化雜志,2009,17(13):1339-1345.

[52]張建梁,晉志高,逯波,等.脊髓背角神經(jīng)元對(duì)胃擴(kuò)張及電針“足三里”穴的反應(yīng)[J].針刺研究,2001,26(4):268-273.

(2015-06-10收稿責(zé)任編輯：王明)

Effects of NR2B Subsets of NMDA Receptor in Acupuncture Treatment For Chronic Visceral Pain

Weng Zhijun1,Wang Lidong1,Ji Yajie1,2,Tan Linying1,Xie Hengru1,Liu Huirong1,Wu Huangan1

(1ShanghaiResearchInstituteofAcupunctureandMeridian,Shanghai200030,China; 2YueyangHospitalofIntegratedTraditionalChineseandWesternMedicineShanghaiUniversityofTraditionalChineseMedicine,Shangha200437,China)

AbstractN-methyl-D-aspartate receptor (NMDAR) has a variety of different subsets that are located differently on the central nerve.It involves in the transmission of signals in the body and regulates the excitability of neurons,such as mediating development of somatic and visceral pain.The NR2B subset of NMDAR is mostly common researched in its pain-related mechanism.Also,visceral pain is a common clinical symptom,which was induced by mechanical and chemical stimulation to the sensory nerve endings of the organs and chest and abdominal walls or local ischemia,smooth muscle spasm and retained metabolite.Electric acupuncture was proved to have significant effect in the treatment of visceral pain and studies found that electric acupuncture can regulate NMDA receptors,especially NR2B subset,revealing a potential analgesia target of electric acupuncture.This article analyzed the structure,function,and mechanism of NR2B subset and discussed its mechanism in reliving chronic visceral pain on the basis of the TCM (traditional Chinese medicine) researches in this field in recent years.

Key WordsNMDA receptor; NR2B; Visceral pain; Acupuncture

基金項(xiàng)目:國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào):81202752);國(guó)家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃(“973”計(jì)劃)項(xiàng)目資助(編號(hào):2015CB554500);上海市衛(wèi)計(jì)委項(xiàng)目資助(編號(hào):20144Y0227)

通信作者:劉慧榮(1976.07—),女,博士,研究員,上海中醫(yī)藥大學(xué)博士研究生導(dǎo)師,上海市針灸經(jīng)絡(luò)研究所針灸免疫實(shí)驗(yàn)室主任,主要從事針灸治療腸腑病癥的臨床與基礎(chǔ)研究,E-mail:lhr_tcm@139.com

中圖分類號(hào)：R245.3

文獻(xiàn)標(biāo)識(shí)碼：A

doi：10.3969/j.issn.1673-7202.2016.06.048