【摘要】：背景和目的國(guó)際疼痛協(xié)會(huì)(IASP)將術(shù)后慢性疼痛(CPSP)定義為發(fā)生在手術(shù)后,與手術(shù)相關(guān)的,排除其他原因且持續(xù)至少2個(gè)月的慢性疼痛。CPSP的發(fā)病率居高不下,最近一項(xiàng)國(guó)內(nèi)大樣本研究結(jié)果顯示,3110名納入對(duì)象術(shù)后6月CPSP發(fā)生率達(dá)29.6%,其中30.3%的患者合并焦慮癥狀,24.4%的患者存在抑郁表現(xiàn)。P2X7受體是腺苷三磷酸(ATP)門控的離子通道,屬于嘌呤能P2受體家族,參與細(xì)胞信號(hào)傳導(dǎo)、細(xì)胞因子的分泌等多種生理功能。研究表明,P2X7受體不僅在免疫細(xì)胞中能夠引起細(xì)胞凋亡,且能影響到細(xì)胞許多復(fù)雜的生理生化功能。在神經(jīng)病理性疼痛和炎性疼痛模型大鼠,P2X7受體在脊髓背角水平,通過(guò)調(diào)控炎性因子如腫瘤壞死因子-α(TNF-α)和白細(xì)胞介素-1β(IL-1β)等的分化和釋放,參與神經(jīng)元和膠質(zhì)細(xì)胞的對(duì)話,在中樞敏感化的發(fā)生發(fā)展中扮演重要角色。我們前期研究已證實(shí)P2X7受體在脊髓背角可通過(guò)調(diào)控小膠質(zhì)細(xì)胞的激活及炎性因子的釋放從而參與到術(shù)后急慢性痛的轉(zhuǎn)化過(guò)程中。抑制脊髓背角P2X7受體激活可下調(diào)腫瘤壞死因子-α的釋放并顯著改善SMIR術(shù)后慢性疼痛。背根神經(jīng)(Dorsal root ganglion,DRG)位于脊神經(jīng)后根,是外周神經(jīng)與中樞神經(jīng)的傳遞中樞。DRG上神經(jīng)元胞體為假單極神經(jīng)元,神經(jīng)節(jié)上每個(gè)神經(jīng)元胞體會(huì)發(fā)出一個(gè)軸突進(jìn)而形成兩個(gè)分支,分布在外周各處(皮膚、內(nèi)臟等)接收外周刺激信號(hào)并傳遞到中樞神經(jīng)系統(tǒng)。DRG上神經(jīng)元傳遞傷害性感受,與痛覺(jué)傳導(dǎo)機(jī)制密切相關(guān),是外周痛覺(jué)信號(hào)逐級(jí)傳入至大腦皮層的第一級(jí)神經(jīng)元。當(dāng)機(jī)體受到外周刺激時(shí),首先由DRG感知這一變化,并激活DRG神經(jīng)元,引起外周敏化,進(jìn)而傳遞到脊髓背角,引起脊髓背角投射神經(jīng)元興奮性異常增高,誘發(fā)脊髓背角C纖維LTP產(chǎn)生并引起中樞敏化,傳遞到大腦最終導(dǎo)致病理性疼痛的產(chǎn)生。雖然我們前期的結(jié)果已經(jīng)表明脊髓背角P2X7受體的激活是術(shù)后疼痛慢性化的重要中樞機(jī)制,但關(guān)于CPSP產(chǎn)生的外周機(jī)制我們并不清楚。基于以上,我們把研究焦點(diǎn)轉(zhuǎn)移到背根神經(jīng)節(jié),期望從DRG層面來(lái)探究術(shù)后疼痛慢性化形成的外周機(jī)制。本研究通過(guò)SMIR模型模擬術(shù)后急性疼痛轉(zhuǎn)化為術(shù)后慢性疼痛,探究背根神經(jīng)節(jié)中P2X7受體在術(shù)后慢性疼痛形成中的作用機(jī)制,并深入探討大鼠背根神經(jīng)節(jié)中P2X7受體介導(dǎo)的ERK/MAPK信號(hào)通路的激活在術(shù)后急慢性痛轉(zhuǎn)化中的作用和地位。方法選取體重180~220 g的SD雄性成年大鼠,將其隨機(jī)分為2組:模型組(SMIR組)和假手術(shù)組(Sham組)。SMIR組采用Flatter的下肢皮膚肌肉切開牽拉法(skin/muscle incision and retraction,SMIR)來(lái)建立大鼠手術(shù)后慢性疼痛模型。Sham采用假手術(shù)作為對(duì)照。首先分別測(cè)定術(shù)前一天及術(shù)后各時(shí)間點(diǎn)(1、3、7、12、22及32天)各組大鼠的機(jī)械縮足反應(yīng)閾值(PWT)(n=14)。上述各時(shí)間點(diǎn)痛閾測(cè)試完畢后,分時(shí)間點(diǎn)(0、1、3、7、12、22及32天)取大鼠手術(shù)側(cè)L2-4 DRGs采用免疫印跡試驗(yàn)(Western Blot)及免疫雙標(biāo)染色法的方法對(duì)大鼠背根神經(jīng)節(jié)P2X7受體、ERK/MAPK信號(hào)通路及TNF-α各時(shí)間點(diǎn)蛋白表達(dá)量變化趨勢(shì)及細(xì)胞定位進(jìn)行觀察(n=6)。然后經(jīng)鞘內(nèi)給予ERK抑制劑SCH772984進(jìn)行干預(yù),觀察ERK抑制劑SCH772984對(duì)SMIR術(shù)后大鼠的行為學(xué)的影響,采用免疫印跡試驗(yàn)檢測(cè)術(shù)后第7天各組手術(shù)側(cè)L2-4 DRGs P2X7受體、ERK/MAPK信號(hào)通路及TNF-α表達(dá)量的變化。另外再經(jīng)腹腔注射P2X7受體拮抗劑BBG進(jìn)行干預(yù),觀察BBG對(duì)SMIR術(shù)后大鼠機(jī)械縮足反應(yīng)閾值的影響,并采用Western Blot方法觀察P2X7受體拮抗劑BBG對(duì)SMIR術(shù)后大鼠術(shù)側(cè)L2-4 DRGs P2X7受體、ERK/MAPK信號(hào)通路及TNF-α表達(dá)量的影響。以進(jìn)一步確認(rèn)P2X7受體、ERK/MAPK信號(hào)通路及TNF-α三者之間的關(guān)系。明確背根神經(jīng)節(jié)P2X7受體在術(shù)后急慢性痛轉(zhuǎn)化中的作用。結(jié)果1.SMIR術(shù)后大鼠術(shù)側(cè)縮足反應(yīng)閾值明顯降低通過(guò)對(duì)各時(shí)間點(diǎn)大鼠機(jī)械縮足反應(yīng)閾值進(jìn)行統(tǒng)計(jì)分析,結(jié)果顯示:兩組大鼠術(shù)前的PWT基礎(chǔ)值無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。SMIR組手術(shù)側(cè)痛閾術(shù)后1d即發(fā)生降低并持續(xù)至術(shù)后32天后才恢復(fù)至術(shù)前水平,SMIR組大鼠手術(shù)側(cè)PWT值術(shù)后第1d與術(shù)前基礎(chǔ)值相比即發(fā)生降低(P0.01),持續(xù)降低至術(shù)后第22d(P0.001),術(shù)后第12d達(dá)到最低峰值(P0.001),疼痛持續(xù)至術(shù)后32d才基本恢復(fù)正常(P0.05)。SMIR組大鼠手術(shù)對(duì)側(cè)足底PWT值與基礎(chǔ)值相比變化無(wú)統(tǒng)計(jì)學(xué)差異(P0.05),Sham組大鼠雙側(cè)足底術(shù)后的PWT值與基礎(chǔ)值相比均無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。2.SMIR模型組大鼠術(shù)側(cè)背根神經(jīng)節(jié)P2X7受體表達(dá)增多且特異性表達(dá)在衛(wèi)星膠質(zhì)細(xì)胞上。免疫印跡試驗(yàn)方法結(jié)果顯示SMIR模型組大鼠L2-4背根神經(jīng)節(jié)P2X7受體表達(dá)量在術(shù)后第一天開始上調(diào)(P0.05),術(shù)后7d達(dá)峰值(P0.001),隨后逐漸減少,直至術(shù)后第32d恢復(fù)術(shù)前水平(P0.05)。將術(shù)后7d大鼠手術(shù)側(cè)L3 DRG進(jìn)行免疫熒光雙標(biāo)染色,分別將P2X7受體與神經(jīng)元特異性標(biāo)記物NF200、CGRP、Ib4及衛(wèi)星膠質(zhì)細(xì)胞特異性標(biāo)記物GFAP進(jìn)行雙染,結(jié)果顯示,P2X7受體與GFAP大量共標(biāo),而與NF200、CGRP、Ib4未見(jiàn)共標(biāo)。提示,在SMIR模型大鼠背根神經(jīng)節(jié),P2X7受體完全特異性表達(dá)在衛(wèi)星膠質(zhì)細(xì)胞(Satellite glial cells,SGCs)上。3.SMIR模型組大鼠背根神經(jīng)節(jié)ERK/MAPK信號(hào)通路被激活SMIR模型制備后第1d可見(jiàn)大鼠背根神經(jīng)節(jié)p-c Raf、p-MEK及p-ERK蛋白表達(dá)水平顯著性增高(P0.001),并持續(xù)增高至SMIR術(shù)后第12d達(dá)峰值(p0.001),術(shù)后第32d恢復(fù)至術(shù)前水平(P0.05)。SMIR術(shù)后各時(shí)間點(diǎn)p-c Raf、p-MEK及p-ERK蛋白表達(dá)水平與SMIR術(shù)后各時(shí)間對(duì)應(yīng)點(diǎn)的PWT值變化的相關(guān)性分析顯示,p-c Raf、p-MEK及p-ERK都與術(shù)后PWT值的變化具有顯著相關(guān)性,p-c-Raf(Pearson correlation;r=-0.965,P=0.002),p-MEK(Pearson correlation;r=-0.906,P=0.013),p-ERK(Pearson correlation;r=-0.887,P=0.018)。術(shù)后7d SMIR模型組大鼠手術(shù)側(cè)L3 DRG的P2X7受體和p-ERK的免疫雙標(biāo)染色顯示P2X7受體與p-ERK大量共標(biāo)。以上提示SMIR術(shù)后ERK/MAPK信號(hào)通路被激活,且ERK/MAPK信號(hào)通路的激活可能與P2X7受體有關(guān)。4.SMIR模型組大鼠手術(shù)側(cè)脊髓背根神經(jīng)節(jié)TNF-α釋放水平上調(diào)SMIR模型組大鼠L2-4 DRGs各時(shí)間點(diǎn)TNF-α的Western blot結(jié)果分析顯示,模型組大鼠手術(shù)側(cè)L2-4 DRGs TNF-α在術(shù)后第1d即上調(diào),手術(shù)后第12d達(dá)到峰值(P0.001),之后逐漸下調(diào)直至術(shù)后第32d才恢復(fù)至術(shù)前水平(P0.05),SMIR術(shù)后大鼠背根神經(jīng)節(jié)TNF-α的表達(dá)變化與SMIR術(shù)后PWT值變化具有相關(guān)性(Pearson correlation;r=-0.871,P=0.011)。5.ERK的特異性拮抗劑SCH772984可緩解SMIR術(shù)后大鼠疼痛,下調(diào)背根神經(jīng)節(jié)TNF-α釋放水平,但不影響SMIR術(shù)后P2X7受體的激活結(jié)果顯示,鞘內(nèi)注射ERK特異性拮抗劑SCH772984可顯著改善大鼠SMIR術(shù)后的痛覺(jué)過(guò)敏。而單純注射SCH772984對(duì)正常大鼠的PWT值不產(chǎn)生影響(P0.05)。SMIR術(shù)后第1d至術(shù)后第22d各時(shí)間點(diǎn),給藥組和對(duì)照組兩組組間PWT值結(jié)果比較顯示:給藥組PWT值均顯著增加(P0.001)。這表明ERK的特異性拮抗劑SCH772984可緩解SMIR術(shù)后大鼠疼痛。術(shù)后第7d給藥組(SCH+SMIR)和對(duì)照組(DMSO+SMIR)兩組大鼠L2-4DRGs的TNF-α表達(dá)量的結(jié)果分析顯示,與Sham相比,給藥組TNF-α表達(dá)水平發(fā)生下降(P0.01),與Sham相比,對(duì)照組TNF-α表達(dá)水平發(fā)生顯著性上調(diào)(P0.001),而與對(duì)照組相比,給藥組TNF-α表達(dá)水平顯著性降低(P0.001)。手術(shù)后第7d兩組大鼠L2-4 DRGs的P2X7受體的Western blot結(jié)果顯示,與Sham組相比,給藥組和對(duì)照組P2X7受體表達(dá)水平均發(fā)生顯著性上調(diào)(P0.001),與對(duì)照組相比,給藥組P2X7受體表達(dá)水平?jīng)]有明顯改變(P0.05)。這表明ERK的特異性拮抗劑SCH772984可下調(diào)SMIR術(shù)后大鼠背根神經(jīng)節(jié)TNF-α釋放水平,但不影響SMIR術(shù)后P2X7受體的表達(dá)。6.P2X7受體特異性拮抗劑BBG可上調(diào)SMIR模型組大鼠痛閾值并下調(diào)ERK/MAPK信號(hào)通路及TNF-α表達(dá)水平結(jié)果顯示,腹腔注射BBG的給藥組(BBG+SMIR)大鼠機(jī)械縮足反應(yīng)閾值與腹腔注射生理鹽水的對(duì)照組(NS+SMIR)相比有明顯改善。給藥組PWT值大鼠與Sham組相比無(wú)明顯統(tǒng)計(jì)學(xué)差異(P0.05)。而術(shù)后第1d至術(shù)后第22d,給藥組與對(duì)照組相比,對(duì)照組PWT值均顯著性增加(P0.001),表明給予BBG抑制P2X7受體的激活可顯著改善大鼠SMIR術(shù)后疼痛。手術(shù)后第7d兩組大鼠術(shù)側(cè)L2-4 DRGs的ERK/MAPK信號(hào)通路和TNF-α表達(dá)量的Western blot結(jié)果顯示,與Sham組相比,對(duì)照組p-c Raf、p-MEK、p-ERK和TNF-α表達(dá)水平均發(fā)生顯著上調(diào)(P0.001);與Sham組相比,給藥組p-c Raf、p-MEK、p-ERK和TNF-α表達(dá)水平均發(fā)生下調(diào)(P0.05);與對(duì)照組相比,給藥組p-c Raf、p-MEK、p-ERK和TNF-α表達(dá)水平均減少(P0.001)。表明P2X7受體拮抗劑BBG可抑制SMIR術(shù)后大鼠背根神經(jīng)節(jié)ERK/MAPK信號(hào)通路的激活及下調(diào)TNF-α的表達(dá)。結(jié)論本研究通過(guò)大鼠皮膚/肌肉切口牽拉(SMIR)模型模擬術(shù)后急慢性疼痛轉(zhuǎn)化過(guò)程,發(fā)現(xiàn):1、SMIR術(shù)后大鼠術(shù)側(cè)背根神經(jīng)節(jié)衛(wèi)星膠質(zhì)細(xì)胞上P2X7受體表達(dá)上調(diào),ERK/MAPK信號(hào)通路被激活,背根神經(jīng)節(jié)神經(jīng)元上TNF-α釋放增多;2、鞘內(nèi)給予ERK的特異性拮抗劑SCH772984可緩解SMIR誘發(fā)的痛覺(jué)過(guò)敏,下調(diào)背根神經(jīng)節(jié)TNF-α的釋放,但對(duì)不影響SMIR術(shù)后P2X7受體的上調(diào);3、腹腔注射P2X7受體拮抗劑BBG不僅能明顯預(yù)防SMIR術(shù)后疼痛的發(fā)生,而且能抑制SMIR術(shù)后ERK/MAPK信號(hào)通路的激活并下調(diào)TNF-α的釋放。故而,術(shù)后急慢性疼痛的轉(zhuǎn)化可能是由脊髓背根神經(jīng)節(jié)衛(wèi)星膠質(zhì)細(xì)胞P2X7受體上調(diào),進(jìn)而介導(dǎo)ERK/MAPK信號(hào)通路激活,引起DRG神經(jīng)元炎性反應(yīng)增加所導(dǎo)致。
[Abstract]:BACKGROUND AND OBJECTIVE The International Association for Pain (IASP) defines postoperative chronic pain (CPSP) as postoperative, surgery-related, chronic pain lasting at least two months, excluding other causes. The incidence of CPSP remains high. A recent large-sample study in China showed that the incidence of CPSP was 29.6% in 3110 subjects 6 months after surgery. Among them, 30.3% had anxiety symptoms and 24.4% had depression. P2X7 receptor is an ATP-gated ion channel, belonging to the purinergic P2 receptor family, which participates in many physiological functions such as cell signal transduction and cytokine secretion. In neuropathic pain and inflammatory pain model rats, P2X7 receptor is involved in the dialogue between neurons and glial cells at the level of spinal dorsal horn and is sensitive in the central nervous system by regulating the differentiation and release of inflammatory factors such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1bet). Inhibition of P2X7 receptor activation in the spinal dorsal horn can down-regulate the release of tumor necrosis factor-alpha and significantly improve SMIR. Postoperative chronic pain. The dorsal root ganglion (DRG) is located in the posterior root of the spinal nerve and is the transmission center of the peripheral and central nerves. The neurons on DRG transmit nociceptive sensation, which is closely related to the mechanism of pain conduction. It is the first stage of peripheral nociceptive signal that passes into the cerebral cortex step by step. The activation of P2X7 receptors in the dorsal horn of the spinal cord has been shown to be an important central mechanism of postoperative pain chronicity. The peripheral mechanism of CPSP is unclear. Based on the above, we shifted our focus to the DRG level to explore the peripheral mechanism of chronic pain after surgery. Methods Male SD rats weighing 180-220 g were randomly divided into two groups: model group (SMIR group) and sham operation group (Sham group). Sham used sham operation as control. Firstly, the mechanical shrinkage thresholds (PWT) (n=14) of the rats in each group were measured at 1, 3, 7, 12, 22 and 32 days before and after operation. L2-4 DRGs were harvested at different time points (0,1,3,7,12,22 and 32 days) after the time point pain threshold test. The expression of P2X7 receptor, ERK/MAPK signaling pathway and TNF-alpha protein in dorsal root ganglion of rats were observed by Western Blot and immunostaining (n=6). The effects of ERK inhibitor SCH772984 on the behavior of rats after SMIR were observed. The changes of L2-4 DRGs P2X7 receptor, ERK/MAPK signaling pathway and TNF-alpha expression were detected by Western blotting on the 7th day after SMIR. Intervention was conducted to observe the effect of BBG on the threshold of mechanical foot contraction in rats after SMIR. Western Blot method was used to observe the effects of BBG, a P2X7 receptor antagonist, on L2-4 DRGs P2X7 receptor, ERK/MAPK signaling pathway and TNF-alpha expression on the operative side of rats after SMIR. Results 1. After SMIR, the threshold of contraction reaction was significantly reduced. By statistical analysis of the threshold of mechanical contraction reaction at each time point, the results showed that there was no significant difference in the baseline value of PWT between the two groups (P 0.05). In SMIR group, the PWT value on the operative side decreased at the first day after operation (P 0.01), and continued to decrease until the 22nd day after operation (P 0.001), and reached the lowest peak at the 12th day after operation (P 0.001). The pain did not return to normal until 32 days after operation (P 0.05). There was no significant difference in PWT value between the contralateral plantar ganglia and the baseline values (P 0.05). There was no significant difference in PWT value between the sham group and the baseline values (P 0.05). 2. The expression of P2X7 receptor in the dorsal root ganglia of the SMIR model group increased and expressed specifically on the satellite glia. The results showed that the expression of P2X7 receptor in the L2-4 dorsal root ganglion of SMIR model rats was up-regulated at the first day after operation (P 0.05), peaked at 7 days after operation (P 0.001), then decreased gradually until the preoperative level was restored at 32 days after operation (P 0.05). The results showed that P2X7 receptor was highly co-labeled with GFAP, but not with NF200, CGRP and Ib4. It was suggested that P2X7 receptor was completely and specifically expressed on the satellite glial cells (SGCs) in the dorsal root ganglion of SMIR rats. The expression of P-C Raf, p-MEK and p-ERK protein in rat dorsal root ganglion was significantly increased on the first day after SMIR (P 0.001), and reached the peak at the 12th day after SMIR (P 0.001), and returned to the preoperative level at the 32nd day after SMIR (P 0.05). Correlation analysis showed that P-C Raf, p-MEK and p-ERK were significantly correlated with the changes of PWT after SMIR, P-C Raf (Pearson correlation; r=-0.965, P=0.002), p-MEK (Pearson correlation; r=-0.906, P=0.013), p-ERK (Pearson correlation; r=-0.887, P=0.018). Immunodouble-labeled staining of P2X7 receptor and p-ERK in L3 DRG of SMIR rats on the 7th day revealed a large number of P2X7 receptor and p-ERK co-labeled. These results suggest that ERK/MAPK signaling pathway is activated after SMIR, and the activation of ERK/MAPK signaling pathway may be related to P2X7 receptor. 4. TNF-alpha release level in dorsal root ganglion of spinal cord in SMIR rats Western blot analysis showed that the expression of TNF-alpha in the dorsal root ganglion of SMIR rats was up-regulated on the first day after operation, peaked at the 12th day after operation (P 0.001), and then gradually decreased until the 32nd day after operation (P 0.05). The expression of TNF-alpha in the dorsal root ganglion of SMIR rats was restored to the preoperative level (P 0.05). The changes were correlated with the changes of PWT after SMIR (Pearson correlation; r = - 0.871, P = 0.011). 5. SCH772984, a specific antagonist of ERK, could alleviate the pain after SMIR in rats, and down-regulate the release of TNF-a in dorsal root ganglion, but did not affect the activation of P2X7 receptor after SMIR. SCH772984, a specific antagonist of ERK, could be significantly injected intrathecally. Compared with the control group, the PWT values of the two groups were significantly increased (P 0.001). This indicated that the specific antagonist of ERK, SCH772984, could be slowed down. The expression of TNF-alpha in L2-4DRGs in SCH+SMIR group and DMSO+SMIR group was significantly higher than that in Sham group (P 0.01) and control group (P 0.001). The expression of P2X7 receptor in L2-4 DRGs was significantly increased in both groups on the 7th day after operation (P 0.001). Compared with Sham group, the expression of P2X7 receptor was significantly increased in both groups (P 0.001). Compared with the control group, the expression of P2X7 receptor was not significantly changed (P 0.05). ERK-specific antagonist SCH772984 could down-regulate the release of TNF-a in the dorsal root ganglion of rats after SMIR, but did not affect the expression of P2X7 receptor after SMIR. 6. P2X7 receptor-specific antagonist BBG could up-regulate the pain threshold and down-regulate the expression of ERK/MAPK signaling pathway and TNF-a in the SMIR model rats. The results showed that the intraperitoneal injection of BBG could up-regulate the pain threshold and down-regulate the expression of TNF-a Compared with the control group (NS + SMIR), there was no significant difference in PWT between the two groups (P 0.05). However, from the 1st day to the 22nd day after operation, the PWT of the control group was significantly increased (P 0.001), indicating that BBG inhibited P2X7. The ERK/MAPK signaling pathway and the expression of TNF-alpha in the L2-4 DRGs were significantly increased in the control group (P 0.001) and the Sham group (P 0.001) on the 7th day after SMIR. The expression levels of p-ERK and TNF-alpha were down-regulated (P 0.05). Compared with the control group, the expression levels of P-C Raf, p-MEK, p-ERK and TNF-alpha were decreased in the treatment group (P 0.001). It indicated that BBG, a P2X7 receptor antagonist, could inhibit the activation of ERK/MAPK signaling pathway and down-regulate the expression of TNF-alpha in the dorsal root ganglion of SMIR rats. The incision traction (SMIR) model simulated the process of acute and chronic pain transformation after SMIR. It was found that: 1. P2X7 receptor expression was up-regulated, ERK/MAPK signaling pathway was activated and TNF-a release was increased in dorsal root ganglion neurons after SMIR; 2. SCH772984, a specific antagonist of ERK, could alleviate SMIR-induced pain. Hyperalgesia can down-regulate the release of TNF-a in dorsal root ganglion, but does not affect the up-regulation of P2X7 receptor after SMIR. 3. Intraperitoneal injection of BBG, a P2X7 receptor antagonist, can not only significantly prevent pain after SMIR, but also inhibit the activation of ERK/MAPK signaling pathway and down-regulate the release of TNF-a after SMIR. P2X7 receptor is up-regulated by the satellite glial cell P2X7 receptor in the dorsal root ganglion of the spinal cord, and then mediates the activation of ERK/MAPK signaling pathway, resulting in an increased inflammatory response of DRG neurons.
【學(xué)位授予單位】：廣州醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R402

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