劉輝 歐汝威 商慧芳

·專題綜述·

帕金森病疼痛機(jī)制研究進(jìn)展

劉輝 歐汝威 商慧芳

帕金森病是中老年人群常見的神經(jīng)變性病，臨床表現(xiàn)主要包括運(yùn)動(dòng)癥狀和非運(yùn)動(dòng)癥狀，疼痛是常見的非運(yùn)動(dòng)癥狀，因影響患者生活質(zhì)量而倍受關(guān)注。然而目前關(guān)于帕金森病疼痛的發(fā)病機(jī)制仍不明確，尚待進(jìn)一步研究。本文擬就可能的帕金森病疼痛發(fā)病機(jī)制進(jìn)行闡述。

帕金森??； 疼痛； 綜述

帕金森病（PD）是常見于中老年人群的神經(jīng)變性病，臨床主要表現(xiàn)為靜止性震顫、運(yùn)動(dòng)遲緩、肌強(qiáng)直和姿勢(shì)步態(tài)異常等運(yùn)動(dòng)癥狀，以及感覺異常、睡眠障礙、認(rèn)知功能障礙、神經(jīng)精神癥狀、自主神經(jīng)癥狀等非運(yùn)動(dòng)癥狀（NMS）［1］，其中，疼痛是最常見的感覺異常。據(jù)文獻(xiàn)報(bào)道，有40%～60%的帕金森病患者曾經(jīng)歷急性或慢性疼痛［2］，尤其是長(zhǎng)期慢性疼痛給患者帶來嚴(yán)重的身心困擾。Ford［3］將帕金森病疼痛分為5種類型，按照患病率由高至低依次為肌肉骨骼樣疼痛、肌張力障礙樣疼痛、神經(jīng)根性或神經(jīng)性疼痛、中樞性疼痛、靜坐不能相關(guān)疼痛。相關(guān)危險(xiǎn)因素包括女性、高齡、病程、疾病嚴(yán)重程度、運(yùn)動(dòng)并發(fā)癥和抑郁癥狀等，其中，隨著運(yùn)動(dòng)癥狀的加重，疼痛發(fā)生率和嚴(yán)重程度亦升高［4］。目前關(guān)于帕金森病疼痛的發(fā)病機(jī)制尚不明確，中樞神經(jīng)系統(tǒng)和周圍神經(jīng)系統(tǒng)均可能參與其中，本文擬就其可能的發(fā)病機(jī)制進(jìn)行概述。

一、中樞神經(jīng)系統(tǒng)機(jī)制

1.黑質(zhì)紋狀體系統(tǒng) 早在1982年即有研究顯示，黑質(zhì)紋狀體與次級(jí)感覺區(qū)、島葉、扣帶回、前額葉皮質(zhì)和丘腦板內(nèi)核群等疼痛相關(guān)皮質(zhì)區(qū)域均存在纖維聯(lián)系［5］，表明黑質(zhì)紋狀體系統(tǒng)參與疼痛的調(diào)控，主要表現(xiàn)為黑質(zhì)紋狀體對(duì)疼痛強(qiáng)度的主觀感知和對(duì)疼痛的情緒反應(yīng)［6?7］。Anagnostakis等［8］的動(dòng)物實(shí)驗(yàn)顯示，大鼠黑質(zhì)紋狀體內(nèi)注入嗎啡具有鎮(zhèn)痛作用，且這種鎮(zhèn)痛作用可以被納洛酮逆轉(zhuǎn)，證實(shí)黑質(zhì)紋狀體參與疼痛的調(diào)控。多巴胺亦參與疼痛的調(diào)控，主要于脊髓、丘腦、基底節(jié)、扣帶回和島葉等結(jié)構(gòu)進(jìn)行調(diào)控［9］。亦有研究顯示，中腦黑質(zhì)致密部、腹側(cè)被蓋區(qū)（VTA）和下丘腦等多巴胺聚集區(qū)域與疼痛相關(guān)通路如中腦皮質(zhì)通路、中腦邊緣系統(tǒng)、黑質(zhì)紋狀體通路和結(jié)節(jié)漏斗系統(tǒng)均存在廣泛聯(lián)系［10?13］。帕金森病典型病理改變是中腦黑質(zhì)致密部多巴胺能神經(jīng)元變性缺失，導(dǎo)致紋狀體多巴胺水平降低，因此，多巴胺水平降低可能參與帕金森病疼痛的發(fā)病機(jī)制。Brefel?Courbon 等［14］于“關(guān)”期對(duì)帕金森病疼痛患者行PET顯像，結(jié)果顯示，疼痛相關(guān)區(qū)域如右側(cè)島葉、右側(cè)前額葉和左側(cè)前扣帶回活動(dòng)明顯增強(qiáng)；予左旋多巴后于“開”期再行PET顯像，疼痛相關(guān)區(qū)域不再處于過度活動(dòng)狀態(tài)，表明左旋多巴可以改善帕金森病患者疼痛癥狀，進(jìn)一步證實(shí)多巴胺參與帕金森病疼痛的調(diào)控。Shu等［15］對(duì)大鼠紋狀體神經(jīng)元進(jìn)行研究，發(fā)現(xiàn)紋狀體內(nèi)含有腦啡肽、強(qiáng)啡肽和P物質(zhì)，均與疼痛調(diào)控相關(guān)，表明黑質(zhì)紋狀體系統(tǒng)中除多巴胺外，上述物質(zhì)均參與疼痛的調(diào)控，然而是否參與帕金森病疼痛的調(diào)控，尚待進(jìn)一步研究。

2.腦干 疼痛信號(hào)首先經(jīng)內(nèi)源性痛覺控制系統(tǒng)調(diào)控，再從脊髓傳入高級(jí)疼痛中樞［16］。內(nèi)源性痛覺控制系統(tǒng)主要由中腦導(dǎo)水管周圍灰質(zhì)、延髓頭端腹內(nèi)側(cè)核（RVM）和部分腦橋背外側(cè)網(wǎng)狀結(jié)構(gòu)組成，其軸突經(jīng)脊髓背外側(cè)束傳導(dǎo)傷害性刺激信號(hào)而調(diào)控疼痛。病理學(xué)研究顯示，帕金森病患者下行通路中的中腦導(dǎo)水管周圍灰質(zhì)、中縫大核（NRM）、巨細(xì)胞網(wǎng)狀核等在疾病早期即已變性［17］，表明帕金森病患者內(nèi)源性痛覺控制系統(tǒng)早期即已損害，其中，中縫大核屬延髓頭端腹內(nèi)側(cè)核，是5?羥色胺（5?HT）能神經(jīng)元，發(fā)出的5?羥色胺下行纖維投射至后角，參與疼痛的調(diào)控［18］。帕金森病患者予抗抑郁藥5?羥色胺和去甲腎上腺素再攝取抑制劑（SNRI）度洛西汀，可以改善疼痛，提示5?羥色胺主要發(fā)揮抑制疼痛作用［19］。Tong等［20］的研究顯示，帕金森病患者外周血5?羥色胺水平低于正常人群。動(dòng)物實(shí)驗(yàn)顯示，5?羥色胺具有鎮(zhèn)痛作用，例如，Wei等［21］采用RNA干擾（RNAi）技術(shù)處理帕金森病模型大鼠，使延髓頭端腹內(nèi)側(cè)核尤其是中縫大核5?羥色胺水平降低，可以顯著改善甲醛溶液誘導(dǎo)的疼痛行為，表明延髓頭端腹內(nèi)側(cè)核5?羥色胺能系統(tǒng)在脊髓后角加重疼痛。因此，帕金森病疼痛是否與延髓頭端腹內(nèi)側(cè)核5?羥色胺能神經(jīng)元損害有關(guān)，尚待進(jìn)一步研究。藍(lán)斑位于第四腦室底部和腦橋前背部，是合成去甲腎上腺素的主要部位，亦參與疼痛的調(diào)控。一方面，藍(lán)斑可以激活脊髓后角神經(jīng)元突觸的腎上腺素受體，繼而激活磷酯酶C（PLC）以增加細(xì)胞內(nèi)鈣濃度，提高脊髓神經(jīng)元興奮性，從而加重疼痛［22］；另一方面，藍(lán)斑可以發(fā)出投射纖維至丘腦，進(jìn)而參與疼痛調(diào)控［23］。帕金森病早期藍(lán)斑即出現(xiàn)路易小體變性［24］，提示藍(lán)斑變性可能影響帕金森病患者對(duì)疼痛信號(hào)的轉(zhuǎn)導(dǎo)和處理。

3.脊髓 脊髓對(duì)疼痛的調(diào)控主要位于脊髓后角，來自初級(jí)感覺傳入纖維末梢，脊髓下行纖維與脊髓后角局部中間神經(jīng)元共同組成復(fù)雜的神經(jīng)網(wǎng)絡(luò)；而且，脊髓后角含有豐富的生物活性物質(zhì)，不僅接受和傳遞傷害性傳入信息，而且對(duì)傷害性信息進(jìn)行加工和處理［25］。病理學(xué)研究顯示，帕金森病患者不僅存在黑質(zhì)紋狀體系統(tǒng)神經(jīng)元變性，而且在疾病早期即已發(fā)生脊髓后角病理改變［26］。因此，脊髓后角病變可能影響帕金森病患者對(duì)疼痛信號(hào)的處理，從而導(dǎo)致疼痛。脊髓后角傳遞疼痛過程中，興奮性氨基酸（主要是谷氨酸）發(fā)揮重要作用，谷氨酸能神經(jīng)元在脊髓后角激活N?甲基?D?天冬氨酸（NMDA）受體，使突觸后膜NMDA受體功能增強(qiáng)，導(dǎo)致神經(jīng)元敏化［27］。NMDA受體激活進(jìn)一步引起γ?氨基丁酸（GABA）受體磷酸化，導(dǎo)致GABA受體介導(dǎo)的興奮性抑制作用減弱［28］，從而引起疼痛。研究顯示，帕金森病患者血清谷氨酸水平明顯高于正常對(duì)照者［29］，表明帕金森病患者對(duì)疼痛的敏感程度高于正常人群。此外，谷氨酸作為腦組織主要興奮性氨基酸，其神經(jīng)毒性亦參與帕金森病的發(fā)生［30］。傷害性退縮反射（NWR）屬脊髓反射，傷害性刺激作用于皮膚感受器，經(jīng)傳入纖維傳遞至脊髓膠狀質(zhì)，經(jīng)突觸與脊髓固有神經(jīng)元系統(tǒng)的眾多中間神經(jīng)元連接，從而產(chǎn)生疼痛屈肌反射。因此，中縫大核可用于檢測(cè)脊髓對(duì)疼痛的調(diào)控［31?32］。Perrotta等［33］發(fā)現(xiàn)，與正常對(duì)照者相比，帕金森病患者中縫大核疼痛閾值降低，表明帕金森病患者在脊髓平面出現(xiàn)異常的疼痛調(diào)控。

4.神經(jīng)膠質(zhì)細(xì)胞 既往研究多選擇神經(jīng)元闡述疼痛機(jī)制［6?8，13］，而忽略中樞神經(jīng)系統(tǒng)分布最廣泛、數(shù)目最多的神經(jīng)膠質(zhì)細(xì)胞。目前研究顯示，神經(jīng)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）可以釋放細(xì)胞因子、炎性介質(zhì)和神經(jīng)活性物質(zhì)，包括疼痛相關(guān)活性物質(zhì)如谷氨酸、ATP等小分子物質(zhì)，從而參與疼痛信號(hào)的轉(zhuǎn)導(dǎo)和調(diào)控［34］。膠質(zhì)纖維酸性蛋白（GFAP）是細(xì)胞骨骼蛋白，是星形膠質(zhì)細(xì)胞標(biāo)志物。各種物理或代謝刺激以及神經(jīng)損害均可使星形膠質(zhì)細(xì)胞激活并增生，成為反應(yīng)性星形膠質(zhì)細(xì)胞，升高膠質(zhì)纖維酸性蛋白水平［35］。離子鈣結(jié)合蛋白1（Iba1）是小膠質(zhì)細(xì)胞表達(dá)的特異性鈣結(jié)合蛋白，小膠質(zhì)細(xì)胞激活后離子鈣結(jié)合蛋白1表達(dá)上調(diào)［36］，因此，可以通過膠質(zhì)纖維酸性蛋白和離子鈣結(jié)合蛋白1表達(dá)變化判斷星形膠質(zhì)細(xì)胞和小膠質(zhì)細(xì)胞活性。研究顯示，帕金森病進(jìn)展過程中不僅有神經(jīng)元變性，還有星形膠質(zhì)細(xì)胞和小膠質(zhì)細(xì)胞激活［37?39］。Park 等［39］采用 1?甲基?4?苯基?1，2，3，6?四氫吡啶（MPTP）誘導(dǎo)損傷建立急性帕金森病疼痛小鼠模型，檢測(cè)中樞神經(jīng)系統(tǒng)膠質(zhì)纖維酸性蛋白和離子鈣結(jié)合蛋白1表達(dá)變化，結(jié)果顯示，與正常對(duì)照組相比，帕金森病疼痛組小鼠丘腦底核（STN）膠質(zhì)纖維酸性蛋白以及丘腦底核、尾狀核和蒼白球離子鈣結(jié)合蛋白1表達(dá)上調(diào)，提示上述區(qū)域神經(jīng)膠質(zhì)細(xì)胞激活，推測(cè)上述區(qū)域神經(jīng)膠質(zhì)細(xì)胞可能參與帕金森病疼痛的調(diào)控。丘腦底核腦深部電刺激術(shù)（DBS）不僅可以緩解帕金森病運(yùn)動(dòng)癥狀，還可以減輕疼痛癥狀［40］。晚近研究顯示，腦深部電刺激術(shù)的作用機(jī)制與神經(jīng)膠質(zhì)細(xì)胞功能密切相關(guān)［41］。

二、周圍神經(jīng)系統(tǒng)機(jī)制

生理狀態(tài)下，外周疼痛刺激經(jīng)外周感受器產(chǎn)生疼痛信號(hào)，通過傳入纖維傳至脊髓；病理狀態(tài)下，脊髓背角神經(jīng)節(jié)和周圍神經(jīng)系統(tǒng)敏化，使原本無法引起疼痛的低強(qiáng)度刺激即產(chǎn)生疼痛，稱為外周敏化。一方面，周圍神經(jīng)系統(tǒng)損害可以引起組胺、緩激肽（BK）、細(xì)胞因子、腫瘤壞死因子?α（TNF?α）和白細(xì)胞介素（IL）等釋放，產(chǎn)生異常自發(fā)電位；另一方面，疼痛信號(hào)傳入C纖維（無髓鞘纖維），引起C纖維與神經(jīng)元之間突觸產(chǎn)生長(zhǎng)時(shí)程增強(qiáng)（LTP），導(dǎo)致脊髓后角神經(jīng)元持續(xù)激活［42?43］。

帕金森病患者外周感受器和傳入纖維均可能參與疼痛的調(diào)控。Nolano等［44］對(duì)帕金森病患者進(jìn)行皮膚組織活檢術(shù)，發(fā)現(xiàn)表皮感受器存在退行性變和外周去神經(jīng)化，亦存在抵抗退行性變而產(chǎn)生的神經(jīng)芽生現(xiàn)象和血管床。然而，該項(xiàng)研究中帕金森病患者疼痛閾值升高，與既往研究結(jié)果相反，例如，Zambito Marsala等［45］和 Mylius等［46］發(fā)現(xiàn)，與正常對(duì)照者相比，帕金森病疼痛患者對(duì)電刺激的疼痛耐受性和疼痛閾值降低；Brefel?Courbon 等［47］也認(rèn)為，帕金森病患者冷痛覺閾值降低。上述研究結(jié)果相反的原因，可能與各項(xiàng)研究疼痛評(píng)價(jià)方法或樣本量不同有關(guān)。因此，外周敏化是否參與帕金森病疼痛的調(diào)控尚待進(jìn)一步研究。亦有研究顯示，帕金森病患者外周感受器存在退行性變［48］，外周無髓鞘纖維密度減少［49］，表明周圍感覺神經(jīng)病變可能參與帕金森病疼痛的發(fā)生。

綜上所述，帕金森病疼痛的發(fā)病機(jī)制并非孤立、無聯(lián)系，而是密切相關(guān)的。疼痛極大地影響患者生活質(zhì)量，因此，研究疼痛發(fā)生、發(fā)展與維持機(jī)制，可以針對(duì)性地緩解和有效控制疼痛。然而，目前關(guān)于帕金森病疼痛的具體機(jī)制尚不明確，進(jìn)一步探討其確切發(fā)病機(jī)制并開展針對(duì)性治療研究，有助于帕金森病患者擺脫疼痛的困擾。

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Advances in mechanism research of pain in Parkinson's disease

LIU Hui,OU Ru?wei,SHANG Hui?fang
Department of Neurology,West China Hospital,Sichuan University,Chengdu 610041,Sichuan,China
Corresponding author:SHANG Hui?fang(Email:hfshang2002@126.com)

Parkinson's disease(PD),a neurodegenerative disease,is very common in middle aged and older people.There are two kinds of symptoms:motor symptoms and non?motor symptoms(NMS).Pain,a commonly reported NMS of PD,can significantly affect the quality of life,thus causing more attention.However,mechanisms of pain in PD is not clear,and need to be further researched.

Parkinson disease; Pain; Review

This study was supported by the National Natural Science Foundation of China(No.81571247).

10.3969/j.issn.1672?6731.2017.08.006

國(guó)家自然科學(xué)基金資助項(xiàng)目（項(xiàng)目編號(hào)：81571247）

610041成都，四川大學(xué)華西醫(yī)院神經(jīng)內(nèi)科

商慧芳（Email：hfshang2002@126.com）

2017?06?05）