涼山彝族自治州第一人民醫(yī)院

張琴，譚婷婷 彭燕Effect and mechanism of action of capsaicin on visceral hyperalgesiaQin Zhang,Ting-Ting Tan,Yan PengQin Zhang, Ting-Ting Tan, Yan Peng，Department of Gastroenterology, Affiliated Hospital of Luzhou Medical College,Luzhou 646000,Sichuan Province,ChinaCorrespondence to:Qin Zhang, Department of Gastroenterology,Affiliated Hospital of Luzhou Medical College,Luzhou 646000,Sichuan Province, China. ziqing0020@sina.comReceived： Revised：AbstractCapsaicin(CAP) has multiple pharmacological actions,and research has been centered on its effect on visceral hyperalgesia(VHL). Relevant studies have shown that low doses of CAP may cause VHL to happen,and high doses can inhibit VHL. The mechanism of action of CAP on VHL may involve vanilloid receptor subtype 1(VR1),VR1’s phosphorylation and dephophory- lation,substance P(SP), calcitonin-gene-related peptide(CGRP) and protease-activated receptor 2(PAR2).CAP has promised as a new drug for VHL.Keywords:capsaicin; visceral hyperalgesia;effect;mechanismZhang Q, Peng Y.Effect and mechanism of action of capsaicin on visceral hyperalgesia.摘要辣椒素（capsaicin，CAP）藥理作用廣泛，其對(duì)內(nèi)臟痛覺(jué)過(guò)敏（visceral hyperalgesia，VHL）的影響已引起廣大學(xué)者的關(guān)注。研究顯示小劑量CAP可能誘發(fā)VHL，而大劑量的CAP可能對(duì)VHL有抑制作用。CAP對(duì)VHL的作用機(jī)制可能與CAP受體（ vanilloid receptor subtype 1，VR1)及其VR1的磷酸化和去磷酸化、P物質(zhì)（SP）、降鈣素基因相關(guān)肽（CGRP）、蛋白水解酶激活型受體2（protease-activated receptor 2, PAR2 ）等有關(guān)。CAP可能成為一種有前景的治療VHL的新藥。關(guān)鍵詞：辣椒素；內(nèi)臟痛覺(jué)過(guò)敏；機(jī)制0 引言功能性胃腸疾病是近年來(lái)導(dǎo)致消化病譜變化的主要因素，此類疾病發(fā)病機(jī)制仍不清楚，患者及實(shí)驗(yàn)動(dòng)物表現(xiàn)出內(nèi)臟痛覺(jué)過(guò)敏（visceral hyperalgesia，VHL）[1-6]。然而目前改善VHL的藥物較少，且作用不理想，隨著對(duì)CAP的深入研究及VR1的克隆表達(dá)，VR1基因敲出小鼠模型的建立，CAP及VR1對(duì)VHL的作用已受到越來(lái)越多的關(guān)注。本文就CAP對(duì)VHL的研究進(jìn)展作一綜述。1 CAP、CAP受體及其作用CAP是辣椒中的主要辛辣成分，其藥理作用廣泛，具有鎮(zhèn)痛、止癢、抗氧化等作用。大量研究顯示CAP對(duì)帶狀皰疹后遺神經(jīng)痛、三叉神經(jīng)痛、糖尿病神經(jīng)痛等有顯著療效。20世紀(jì)50年代，Jancso提出CAP參與了激活感知痛覺(jué)的神經(jīng)元的活動(dòng)。此后，有關(guān)CAP在疼痛中的研究愈來(lái)愈多。CAP是通過(guò)初級(jí)傳人神經(jīng)元末梢和胞膜上特殊的分子受體介導(dǎo)而產(chǎn)生作用的，這一受體稱為VR1 [7-10]，它是一類表達(dá)在感覺(jué)神經(jīng)末梢上的受體，同時(shí)也是一個(gè)配體門控的非選擇性陽(yáng)離子通道，屬于瞬時(shí)感受器電位通道(TRP channel，transient receptor potential channe1)家族，又稱TRPV1[11]。VR1廣泛分布在脊髓背根神經(jīng)節(jié)、三叉神經(jīng)節(jié)和迷走神經(jīng)節(jié)的中、小神經(jīng)元上，因此被認(rèn)為是一種神經(jīng)系統(tǒng)特異的受體[12-13]。近年來(lái)發(fā)現(xiàn)，一些非神經(jīng)組織也有VR1的分布，如膀胱上皮、肝、肺、胃腸道、肥大細(xì)胞、巨噬細(xì)胞等[14-17]。VR1除了可被辣椒素類物質(zhì)激活外,在體內(nèi)還可被傷害性熱刺激(>43℃)和酸性環(huán)境(pH或腹瀉等癥狀的IBS患者的直腸肌層粘膜下層及粘膜層VR1陽(yáng)性細(xì)胞增加，患者直腸對(duì)熱刺激及直腸擴(kuò)張刺激敏感性增強(qiáng)，說(shuō)明VR1在IBS的發(fā)病過(guò)程及內(nèi)臟痛覺(jué)過(guò)敏的產(chǎn)生中可能起作用。我國(guó)學(xué)者梁杰賢等[41,42]研究顯示大鼠去除VR1神經(jīng)元后，對(duì)CAP的刺激不敏感，在直結(jié)腸擴(kuò)張刺激下也不產(chǎn)生內(nèi)臟痛覺(jué)過(guò)敏．也說(shuō)明VR1參與了IBS的VHL的形成。Winston J等[43,44]在大鼠初生時(shí)期給予短暫的傷害性刺激導(dǎo)致大鼠永久的內(nèi)臟感覺(jué)障礙，并證實(shí)在使用傷害性刺激之前使用VR1拮抗劑的大鼠對(duì)內(nèi)臟擴(kuò)張刺激敏感性降低，說(shuō)明了VR1在VHL的形成和維持中都起著十分重要的作用。4 CAP在VHL中的作用機(jī)制CAP在內(nèi)臟痛覺(jué)過(guò)敏形成中的作用機(jī)制非常復(fù)雜，至今尚不完全清楚。大量研究顯示，VR1雖然廣泛分布于背根神經(jīng)節(jié)、三叉神經(jīng)節(jié)和迷走神經(jīng)節(jié)中的神經(jīng)元上，但在腹腔內(nèi)臟傳入神經(jīng)中的分布多于軀體傳入神經(jīng)，在倡導(dǎo)粘膜下神經(jīng)叢和肌間神經(jīng)叢均有VR1陽(yáng)性神經(jīng)元分布，從而對(duì)內(nèi)臟痛產(chǎn)生一定作用，其機(jī)制主要與下列因素有關(guān)。4.1 SP 大多數(shù)試驗(yàn)表明,CAP的鎮(zhèn)痛作用是通過(guò)與含SP的一級(jí)感覺(jué)神經(jīng)終端膜上的某些化合物牢固結(jié)合,使SP釋放增多、合成中斷而衰竭導(dǎo)致;此過(guò)程亦有CGRP和NO參加。大劑量的CAP（≥50 mg／kg）可產(chǎn)生神經(jīng)毒性作用,使細(xì)胞內(nèi)的組織失去統(tǒng)一性開(kāi)始分解,破壞了感覺(jué)神經(jīng)的微管系統(tǒng)致使順行性和逆行性軸索運(yùn)輸缺如,因此微管系統(tǒng)的生化過(guò)程被破壞,使末梢或中樞合成SP的神經(jīng)肽蓄積減少或補(bǔ)充受到抑制。另外還干擾傳入神經(jīng)的營(yíng)養(yǎng)因子的逆向轉(zhuǎn)運(yùn)。該因子有使SP減少的作用,隨著SP合成的不斷減少,數(shù)天或數(shù)小時(shí)后SP逐漸耗竭,隨之,產(chǎn)生CAP易感種屬動(dòng)物不可修復(fù)的感覺(jué)喪失。4.2 CGRP CGRP是一種致炎、致痛的初級(jí)傳入痛覺(jué)遞質(zhì)，富含于CAP敏感性傳入神經(jīng)纖維中。章菲菲等[45]在大鼠胃內(nèi)置入氣囊，誘發(fā)大鼠內(nèi)臟痛覺(jué)過(guò)敏，觀察傷害性擴(kuò)張或靜注CGRP對(duì)大鼠疼痛閾值的影響及給予CGRP受體拮抗劑hCGRP8-37后疼痛閾值的變化，結(jié)果顯示CGRP能使大鼠疼痛閾值降低，hCGRP8-37能逆轉(zhuǎn)傷害性擴(kuò)張和CGRP引起的內(nèi)臟敏感性增高。有研究顯示全身應(yīng)用CAP可使CGRP耗竭[46]，佟世義等[47]通過(guò)行為學(xué)、免疫組化觀察正常大鼠硬膜外間隙注射CAP的鎮(zhèn)痛效果，發(fā)現(xiàn)注射0.1%CAP組由于濃度較低，神經(jīng)刺激作用較小，使初級(jí)痛覺(jué)傳入纖維釋放的CGRP較少，且痛閾升高可能僅由其阻斷作用引起；而注射0.2%CAP組可引起CGRP大量釋放，而CAP的短期鎮(zhèn)痛效應(yīng)可能是由初級(jí)痛覺(jué)遞質(zhì)耗竭和轉(zhuǎn)運(yùn)障礙雙重因素引起的。這些均說(shuō)明了CGRP在CAP所致的痛覺(jué)過(guò)敏中起著非常重要的作用。4.3 VR1的磷酸化和去磷酸化 VR1的磷酸化和去磷酸化調(diào)節(jié)著其對(duì)刺激物的敏感性，Mandadi S等[48.49]實(shí)驗(yàn)結(jié)果證明，去磷酸化的VR1產(chǎn)生急性脫敏，重新磷酸化后可以恢復(fù)對(duì)CAP的敏感性，這對(duì)于痛覺(jué)過(guò)敏和鎮(zhèn)痛有重要意義。炎癥時(shí)可以產(chǎn)生許多細(xì)胞因子，如PGE2、緩激肽等，同時(shí)局部的溫度和H+濃度較高。大多數(shù)細(xì)胞因子可以激活PKA而使感覺(jué)神經(jīng)末梢的VR1對(duì)溫度和H+高度敏感[50.51],這可能與炎癥時(shí)疼痛和熱痛覺(jué)過(guò)敏有關(guān)。VR1的功能受很多因素影響，如細(xì)胞因子和蛋白激酶等，而蛋白激酶又是通過(guò)其對(duì)VR1的磷酸化和去磷酸化調(diào)節(jié)而發(fā)揮作用。Lee等[52]用CAP處理轉(zhuǎn)染VR1的HEK（人胚腎）293細(xì)胞后，發(fā)現(xiàn)VR1對(duì)CAP的反應(yīng)增強(qiáng)，同時(shí)伴有VR1的磷酸化顯著增加， Mohapatra等[53]的實(shí)驗(yàn)進(jìn)一步說(shuō)明FSK通過(guò)激活PKA而使VR1對(duì)CAP的敏感性增強(qiáng)，并且PKA磷酸化Thr 370在VR1敏感性增強(qiáng)中起著關(guān)鍵作用。Wang等[54-57]研究證實(shí)，蛋白激酶C直接磷酸化VR1的ser 116而增強(qiáng)CAP對(duì)溫度及酸的反應(yīng)性?？梢灶A(yù)測(cè)，抑制PKA和PKC的激活，或者抑制TRPV1的某些關(guān)鍵部位的磷酸化，將產(chǎn)生良好的鎮(zhèn)痛效應(yīng)，這或許是將來(lái)鎮(zhèn)痛藥開(kāi)發(fā)研究的方向。4.4 PAR2 研究顯示，多種物質(zhì)可通過(guò)易化VR1的作用引起VHL,PAR2 被激活時(shí)可以激活蛋白激酶C（protein kinase c,PKC），從而增強(qiáng)VR1對(duì)CAP的敏感性[58-61]，大鼠結(jié)腸內(nèi)給藥，可引起內(nèi)臟痛覺(jué)過(guò)敏[62-66]，梁杰賢等[41]的研究顯示，通過(guò)PKC途徑激活VR1從而引起實(shí)驗(yàn)大鼠VHL是可能的原因之一。Amadesi S等[59,60]報(bào)道注射PAR2拮抗劑可導(dǎo)致實(shí)驗(yàn)大鼠持久的熱痛覺(jué)過(guò)敏，而這種情況卻可以被使用VR1拮抗劑或缺少VR1者所抑制，且CAP誘導(dǎo)的VHL也可以被缺失VR1或使用PKC拮抗劑后抑制。同時(shí)還發(fā)現(xiàn)PAR2能同時(shí)激活PKCe和PKA,后兩者磷酸化VR1，而增強(qiáng)其敏感性，這可能與炎癥時(shí)的痛覺(jué)過(guò)敏有關(guān)。5 結(jié)論總之，CAP及其受體仍是目前研究的熱點(diǎn)，其對(duì)VHL的形成和維持有重要作用,可能通過(guò)SP、CGRP、VR1的磷酸化與去磷酸化及PAR2產(chǎn)生作用，然而這僅僅是一個(gè)粗略的了解，參與其中的分子及其相互間的作用等仍有許多不夠明確之處，進(jìn)一步探討CAP與VHL的關(guān)系,對(duì)認(rèn)識(shí)CAP新用途和對(duì)VHL的治療具有重要意義，同時(shí)也對(duì)功能性胃腸病的治療開(kāi)辟了一條新的途徑。6 參考文獻(xiàn)：[1]Drossman DA. 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