NMDA受體NR2B亞基在慢性內臟痛敏及針灸治療中的作用

翁志軍　王立東　季亞婕,2　譚琳鎣　謝恒如　劉慧榮　吳煥淦

(1 上海市針灸經絡研究所,上海,200030; 2 上海中醫藥大學附屬岳陽中西醫結合醫院,上海,200437)

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NMDA受體NR2B亞基在慢性內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 上海市針灸經絡研究所,上海,200030; 2 上海中醫藥大學附屬岳陽中西醫結合醫院,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)參與體內各種信號的傳遞和調節神經元的興奮性,如介導軀體和內臟疼痛的發生和發展,NMDA受體中NR2B亞型與疼痛相關機制研究關系最為密切,內臟痛(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末梢受到強烈機械、化學刺激,也可由局部缺血、平滑肌痙攣及代謝產物不能及時排除而引起的疼痛感覺。電針在內臟痛的臨床治療中療效肯定,實驗研究發現電針對中樞NMDA受體尤其是NR2B亞基具有調控作用,初步揭示了電針鎮痛又一潛在靶點,本文就NR2B亞基的結構、功能、參與慢性內臟痛的機制,以及近些年針灸治療慢性內臟痛的機制研究進行概述。

關鍵詞NMDA受體;NR2B;內臟痛;針灸

疼痛的治療屬于醫學領域中的難題,長期藥物應用尚存在諸多弊端,傳統中醫針灸在鎮痛方面療效已得到臨床證實,但尚缺乏足夠細胞與分子生物學方面的證據。中樞NMDAR在疼痛的發生與維持方面發揮著重要作用,包括參與疼痛記憶和可塑性的產生,針灸鎮痛機制研究中,NMDAR的NR2B亞基的作用逐步得到揭示[1-3],NR2B選擇性阻滯可能會為內臟痛治療提供新的思路[4]。

1NR2B亞基的結構

谷氨酸是介導痛覺信息傳遞的興奮性神經遞質之一[5],其受體分為離子型(iGluR)和代謝型谷氨酸受體(mGluR),2大類。iGluR主要分布在神經元的突觸部位,當突觸前釋放的谷氨酸作用于突觸后膜的iGluR時,可誘發神經元興奮反應,這對神經元之間的信息傳遞、突觸可塑性調節以及學習記憶的形成等過程具有重要的作用[6-7]。根據iGluR對不同的激動劑的相對選擇性及其氨基酸序列同源程度,可分為AMPAR、KAR和NMDAR。NMDAR是一種異聚體復合物,包括NR1,NR2(A、B、C、D)和NR3(A、B)亞基[8]。NR2B由胞內的C端、Ml-M4跨膜區域和胞外的N端結構域3個部分組成。胞外N2端含糖苷化位點以及配體結合位點等結構。M1和M3之間形成孔袢,其近M1側含有一個未完全跨膜的M2短螺旋片段。M2端含有天冬酰胺的殘基,對Ca2+的通透性起著重要作用。NR2B的谷氨酸配體結合結構域呈球囊形,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[10]。NR2亞基只有與NR1結合時才能形成有功能的NMDA受體,通常是由2個NR1亞單位和2個NR2亞單位構成的同源或異源聚體,甘氨酸和谷氨酸結合部位分別在NR1和NR2亞單位的類似區域[11]。

2NR2B亞基的分布

NR2B在中樞神經系統呈現選擇性分布,尤其在中樞神經系統痛覺信息傳遞與調制相關通路(如脊髓和前腦),NR2亞基在脊髓分布具有一定規律,NR2A和NR2D多集中分布在脊髓全層,NR2C的表達相對較少,以NR2B為表達數量最多、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層表達最為明顯。利用胃蛋白酶消化抗原暴露技術發現,在此兩層觀察到NR2B的分布[13]。有研究使用膜片鉗技術記錄突觸電流,發現在脊髓膠狀質層[14]亦有NR2B的表達[15]。NMDA受體主要分布于神經細胞突觸后膜,尤其在致密區(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。此外在膠質細胞[16]上也有分布。NMDAR組成和分布的復雜性可能是造成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、海馬、紋狀體丘腦和嗅球等區域表達明顯[17]。Goebel等[18]發現NR2B mRNA在CNS分布高低順序依次為:皮質、嗅球、海馬、紋狀體、上丘,而皮質、海馬、紋狀體和嗅球都位于前腦[19]。RT-PCR檢測發現小腦浦肯野細胞、嗅皮層、視皮層和運動皮層的NR1,NR2(A-D)和NR3(A-B)的表達[20]。

3NR2B亞基與內臟痛外周神經敏化

DRG神經元含外周突、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遞質的釋放來傳遞痛覺沖動,與此相關的遞質包括谷氨酸、天冬氨酸、CGRP和SP等。NR2B集中表達在DRG細初級傳入纖維,含這類亞基的NMDA受體可能對神經遞質的釋放有調節作用[21]。IBS大鼠腰骶DRG神經元將合成NR2B蛋白傳輸至中樞端(脊髓背角Ⅰ層的突觸前膜),出現表達的升高,說明NR2B參與了內臟通外周傳入敏化過程。結直腸機械性擴張刺激可以使新生鼠感覺傳入神經可塑性受到影響,造成成年鼠的感覺神經傳入過敏,NR2B亞基在此病理過程的持續中起到重要作用。

4NR2B與內臟痛中樞神經敏化

內臟受到機械性牽拉、炎性反應、缺血、潰瘍、痙攣、梗阻、腫瘤等刺激可導致內臟痛,特點是疼痛性質模糊,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和防御反應。內臟痛機制相當復雜。在內臟高敏感(內臟痛)狀態下,已有研究發現,傷害性和非傷害性刺激均能使機體表現出外周和中樞水平的敏化,其中的中樞敏化是被認為是內臟痛覺過敏和內臟高敏感性發生發展過程中最為關鍵的因素[22-23],是目前研究的熱點,越來越多的證據表明中樞NMDAR的參與是內臟痛覺過敏-中樞敏感化的一個重要環節[24-25]。

4.1脊髓神經敏化內臟將接收到的刺激信號經初級傳入神經投射至胸腰段、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、痛覺敏化產生和維持方面發揮重要作用[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蛋白呈現高表達,且在大鼠早期生活狀態中頗為明顯[29],表明IBS慢性內臟痛覺敏感可能與胸腰、腰骶水平的NR2B亞單位異常表達有關,進一步研究發現,脊髓水平NR2B亞基的磷酸化能進一步放大此種內臟痛敏的程度[30],提示NR2B在慢性內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性傷害性刺激促進谷氨酸釋放增多,激活NMDA受體后導致鈣離子內流,進一步激活蛋白激酶C(PKC),再通過PKC使NMDA受體磷酸化,同時神經元的興奮性可因一氧化氮而發生變化,向中樞進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,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系。脊髓鞘內注射NMDA受體的激動劑能夠增強內臟刺激誘發的疼痛反應,并呈現劑量依賴性。NMDA介導了結直腸機械性擴張刺激引發的神經元的放電增強,同時伴隨強烈的后發放電[32],在“軀體—內臟會聚神經元”可引起相應軀體外周感受野的擴大,NMDA能易化脊髓水平對傷害性結直腸擴張刺激的痛行為表現,并提高脊髓背角神經元的反應性,脊髓NMDA受體介導神經元對內臟傷害性傳入的高興奮性[33-34]。由于慢性內臟痛發生發展受多種因素影響,其機制還有待于進一步深入研究。

4.2腦神經敏化NMDA等遞質在正常大鼠內臟感覺及軀體痛覺敏化中發揮作用[35-36]。在中樞敏化中,NMDAR的重要作用體現在2個方面:1)NMDA受體激活多發生在對C纖維的反復刺激所致的wind-up現象;2)中樞敏感化可被競爭性/非競爭性NMDAR拮抗劑抑制[37]。多項研究發現,在長時程突觸可塑性變化中有NMDA受體參與介導[38-39],推斷NMDAR在慢性內臟痛的中樞敏化形成中起到關鍵作用。NR2B亞型主要分布于前腦,內臟高敏感幼鼠前扣帶回皮質(ACC)在內臟疼痛調節通路中具有重要作用,實現的方式是通過上調NMDA受體的數量和活性[40],ACC區域有NR2A和NR2B的分布,NR2A、NR2B亞基在前扣帶回皮質區域介導的中樞性內臟痛敏反應中發揮調節作用[41],且在增強傷害性信號傳遞的作用中呈正相關。突觸前膜釋放Glu等興奮性神經遞質后,結合NMDAR亞基NR2A、NR2B,導致大量Ca2+自胞外內流而觸發Ca2+依賴性酶反應過程是其可能的作用機制。持續興奮性突觸后電位導致了長時程增強效應,增強了傷害性信號的傳遞,同時ACC內磷酸化CaMKII與NMDA受體NB2A/B亞單位可以共同促進內臟痛覺過敏[42]。

5NMDA受體在針灸治療慢性內臟痛的作用

針灸療法具有“簡、便、驗、廉”的優點,且不良反應少,在臨床治療中應用廣泛。近來關于針灸鎮痛的研究亦受到國內外的持續關注。電針能夠明顯抑制急性內臟痛和IBS大鼠在不同等級壓力刺激下的腹壁撤回反射評分(Abdominal Withdrawal Reflex，AWR)以及腹直肌電(Rectus Abdominis Electromyogram,EMG)[43]。針灸鎮痛的同時,對于中樞NMDA受體尤其是NR2B亞基及其磷酸化的表達存在抑制效應。電針可能通過下調NR2B亞基的表達,干預中樞敏化的形成和維持,發揮一定的鎮痛效果[44]。在NR2B基因表達方面,針灸亦可通過對引起中樞敏化相關脊髓神經元NR2B亞單位mRNA表達的下調作用,發揮其調整大鼠痛覺信息調控機制的作用[45]。NMDA受體是對Ca2+通透性最高的配體門控通道之一,其對Ca2+的通透性是對Na+和K+通透性的5～10倍。體內Ca2+的過度激活則會引起Ca2+的過量內流,促進細胞內的痛覺信號轉導及一系列與疼痛有關的神經遞質的釋放。因此,針灸除了能夠通過調節NMDA受體NR2B亞基在中樞的表達,是否能夠通過改變NR2B亞基的電生理特性,調控其功能狀態,來抑制疼痛信號的傳遞,值得進一步的探索研究。針灸治療內臟痛具有良好的療效[46-48],但NMDA受體參與內臟痛覺信息的轉導是復雜的病理過程,且針灸緩解內臟痛的作用機制亦較為復雜,有待進一步的研究。現有研究表明,針灸可能通過影響中樞NMDA受體尤其是NR1和NR2B亞基的表達,實現其緩解內臟痛的作用。這可能是針灸緩解內臟痛的一個潛在靶點[49]。電針對慢性內臟痛敏IBS大鼠具有良好的治療作用,其作用機制可能通過下調腦內RVM中NMDAR-1受體表達來發揮的[50]。胃擴張疼痛大鼠脊髓背角中NR-2B陽性細胞數顯著升高,對足三里穴給予不同刺激強度針刺后,緩解了胃擴張引發的大鼠應激反應[51],針刺信號在脊髓背角水平抑制了NR2B的表達,還有研究發現,足三里穴區的初級感覺傳入神經與胃的傳入神經的節段存在部分重疊,足三里穴給予電針刺激后,能夠翻轉/拮抗胃部擴張出現的背角神經元放電[52],因此足三里穴能通過減少胃腸傷害性刺激產生、并抑制疼痛遞質的合成釋放,最終減少了疼痛物質向中樞傳遞來發揮對胃擴張疼痛大鼠鎮痛作用。

6小結

NR2B亞型在慢性內臟痛敏過程中扮演著較為重要的角色,但發揮作用的具體機制尚待進一步研究。一方面,針灸療法對中樞NMDA受體的調控作用,體現在可通過降低NR2B受體在中樞的過度表達來實現。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,調控其功能狀態,來抑制疼痛信號的產生、傳遞和放大等,發揮其鎮痛的效應機制,值得進一步的探索研究。同時,多種其他受體蛋白對NR2B亞基的交叉作用尚需更多深入研究證據的揭示。NMDA受體NR2B亞基做為內臟痛發生機制中的一個重要方面,深入揭示并完善其在針灸治療內臟痛的作用機制,以冀為應用針灸治療內臟痛的推廣,提供實驗數據和理論依據,這可能是值得今后重點研究的方向。

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(2015-06-10收稿責任編輯：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

基金項目:國家自然科學基金項目(編號:81202752);國家重點基礎研究發展計劃(“973”計劃)項目資助(編號:2015CB554500);上海市衛計委項目資助(編號:20144Y0227)

通信作者:劉慧榮(1976.07—),女,博士,研究員,上海中醫藥大學博士研究生導師,上海市針灸經絡研究所針灸免疫實驗室主任,主要從事針灸治療腸腑病癥的臨床與基礎研究,E-mail:lhr_tcm@139.com

中圖分類號：R245.3

文獻標識碼：A

doi：10.3969/j.issn.1673-7202.2016.06.048