電針通過內(nèi)源性大麻素系統(tǒng)緩解山羊內(nèi)臟超敏
發(fā)布時(shí)間：2018-08-12 15:07
【摘要】：內(nèi)臟超敏是腸道疾病的臨床常見癥狀,如炎癥性腸病(IBDs)和腸易激綜合征(IBS)等。大約50%~70%IBDs和20%~90%IBS患者都存在這一癥狀。內(nèi)臟超敏指的是內(nèi)臟組織對(duì)多種刺激的敏感性和反應(yīng)性增強(qiáng),包括痛覺過敏、觸摸痛、腸動(dòng)力異常以及腸道黏膜分泌增多等。內(nèi)臟超敏與中樞神經(jīng)敏感化、外周神經(jīng)致敏和腦腸軸失調(diào)等因素相關(guān),其藥物治療存在嚴(yán)重的副作用,已經(jīng)成為困擾人們多時(shí)的嚴(yán)重醫(yī)療問題。近年來,針刺治療內(nèi)臟超敏在臨床上取得了良好的成效。然而,針刺治療內(nèi)臟超敏的機(jī)制尚未闡明。研究證實(shí)阿片肽系統(tǒng)在電針鎮(zhèn)痛方面具有重要作用,然而在伴有炎癥反應(yīng)的慢性疼痛模型中,阻斷阿片肽系統(tǒng)并不能完全逆轉(zhuǎn)電針鎮(zhèn)痛效果,而阻斷內(nèi)源性大麻素系統(tǒng)能夠成功逆轉(zhuǎn)電針效應(yīng)。這說明了在炎癥條件下內(nèi)源性大麻素系統(tǒng)在電針緩解疼痛方面有獨(dú)特的作用。內(nèi)源性大麻素系統(tǒng)主要是由特殊的G蛋白偶聯(lián)受體(大麻素受體1和大麻素受體2)、內(nèi)源性大麻素配體以及內(nèi)源性大麻素合成和降解酶組成,廣泛存在于中樞神經(jīng)系統(tǒng)和外周神經(jīng)系統(tǒng),尤其是扣帶回皮層、中腦導(dǎo)水管周圍灰質(zhì)、延髓、脊髓背角以及腸道神經(jīng)系統(tǒng)等�；ㄉ南┮掖及�(AEA)和2-花生四烯酰甘油(2-AG)作為主要的內(nèi)源性大麻素,能夠特異性地識(shí)別、結(jié)合并激活大麻素受體1(CB1),從而抑制神經(jīng)元的過度興奮。有研究表明電針治療能夠顯著上調(diào)CB1的表達(dá)量,并抑制關(guān)節(jié)炎大鼠痛覺過敏。脂肪酸酰胺水解酶(FAAH)和單�；视王ッ�(MAGL)分別是AEA和2-AG的降解酶,研究發(fā)現(xiàn)FAAH和MAGL的拮抗劑顯著增加了大鼠體內(nèi)AEA與2-AG的表達(dá)量,同樣能夠緩解大鼠痛敏。然而,CB1、FAAH和MAGL是否同時(shí)參與電針誘導(dǎo)的超敏抑制未見報(bào)道。本實(shí)驗(yàn)采用山羊回腸炎誘導(dǎo)的內(nèi)臟超敏模型研究電針的治療效果及其機(jī)制。選擇24只雄性健康山羊,將三硝基苯磺酸(TNBS)注射到其中的18只山羊回腸壁中建立內(nèi)臟超敏模型;等體積的無菌生理鹽水代替TNBS注射到另外的6只山羊回腸壁中,作為對(duì)照組(Saline)。18只內(nèi)臟超敏山羊被隨機(jī)分為三組:內(nèi)臟超敏組(TNBS)、電針組(EA+TNBS)、假針組(Sham+TNBS),每組6只。TNBS組:不進(jìn)行電針操作;EA+TNBS組:手術(shù)7 d后開始電針,采用雙側(cè)“后三里”穴(ST36),60 Hz,30 min,1次/3 d,總計(jì)6次;Sham+TNBS組:只扎針,不通電,其余與電針組相同。在手術(shù)后第7、10、13、16、19和22進(jìn)行電針,之后立即采用腹肌電圖(EMG)測(cè)量實(shí)驗(yàn)山羊由不同壓力梯度(20、40、60、80和100 mmHg)的結(jié)直腸擴(kuò)張(CRD)刺激引起的內(nèi)臟運(yùn)動(dòng)反應(yīng)(VMR)。第22 d,VMR測(cè)量后立即取山羊腦組織、T11脊髓和回腸樣品,采用免疫組織化學(xué)法檢測(cè)內(nèi)臟感覺相關(guān)的大腦核團(tuán)與區(qū)域(前皮質(zhì)扣帶回、中腦導(dǎo)水管周圍灰質(zhì)、中縫大核、巨細(xì)胞網(wǎng)狀核、孤束核、迷走運(yùn)動(dòng)背核、延髓頭端腹內(nèi)側(cè)核群)、脊髓背角以及回腸中CB1、FAAH和MAGL的表達(dá)量。結(jié)果顯示,TNBS組山羊7 d時(shí)VMR顯著高于Saline組(P0.05),并且維持到第22 d。假針組山羊的VMR與TNBS組相比無顯著性差異(P0.05)。與TNBS組相比,電針組山羊在7 d時(shí)VMR無顯著性變化(P0.05),在10、13、16、19和22 d時(shí)VMR均顯著升高(P0.05),表明回腸受到炎癥損傷后山羊出現(xiàn)內(nèi)臟超敏反應(yīng)而電針能夠有效的緩解內(nèi)臟超敏,且具有累積效應(yīng)。手術(shù)后第22 d,TNBS組山羊前皮質(zhì)扣帶回(ACC)、中腦導(dǎo)水管周圍灰質(zhì)(PAG)、中縫大核(NRM)、巨細(xì)胞網(wǎng)狀核(GI)、孤束核(NTS)、迷走運(yùn)動(dòng)背核(DMV)、延髓頭端腹內(nèi)側(cè)核群(r VLM)、脊髓背角(SDH)以及回腸中CB1的蛋白表達(dá)量均顯著低于對(duì)照組(P0.05),而FAAH和MAGL的蛋白表達(dá)量顯著高于對(duì)照組(P0.05)。與TNBS組相比,電針組山羊上述核團(tuán)和腦區(qū)、脊髓及回腸中CB1的含量顯著上升(P0.05),FAAH和MAGL的含量顯著下降(P0.05),顯示電針能夠促進(jìn)回腸炎誘導(dǎo)的內(nèi)臟超敏模型山羊CB1的上調(diào)和FAAH、MAGL的下調(diào)。本研究通過向山羊回腸壁中注射TNBS誘導(dǎo)回腸炎建造內(nèi)臟超敏模型,探討電針對(duì)山羊內(nèi)臟運(yùn)動(dòng)反應(yīng)以及CB1、FAAH和MAGL表達(dá)水平的影響,表明電針能夠有效的緩解山羊內(nèi)臟超敏并增加CB1和降低FAAH、MAGL在ACC、PAG、NRM、GI、NTS、DMV、RVLM、SDH及回腸中的表達(dá)量。該研究有助于揭示電針緩解山羊回腸炎誘導(dǎo)的內(nèi)臟超敏的中樞和外周機(jī)制,促進(jìn)胃腸道疾病治療的發(fā)展。
[Abstract]:Visceral hypersensitivity is a common clinical symptom of intestinal diseases, such as inflammatory bowel disease (IBDs) and irritable bowel syndrome (IBS). It occurs in about 50%-70% of IBDs and 20%-90% of IBS patients. Visceral hypersensitivity refers to the increased sensitivity and responsiveness of visceral tissues to a variety of stimuli, including hyperalgesia, touch pain, abnormal bowel motility and intestinal mucus. Visceral hypersensitivity is associated with central nervous system sensitization, peripheral nervous system sensitization and brain-gut axis disorder. Its drug treatment has serious side effects, which has been a serious medical problem for many years. In recent years, acupuncture treatment of visceral hypersensitivity has achieved good results in clinical practice. However, acupuncture treatment of visceral hypersensitivity has been proved effective. Studies have shown that opioid peptide system plays an important role in EA analgesia. However, blocking the opioid peptide system does not completely reverse EA analgesia in chronic pain models with inflammation, and blocking the endocannabinoid system can successfully reverse EA effect. Endogenous cannabinoid system plays a unique role in pain relief by electroacupuncture. The endogenous cannabinoid system consists of special G protein-coupled receptors (cannabinoid receptor 1 and cannabinoid receptor 2), endogenous cannabinoid ligands, and endogenous cannabinoid synthase and degrading enzymes, which are widely distributed in the central nervous system and peripheral nervous system. Arachidonethanolamine (AEA) and 2-arachidonyl glycerol (2-AG), as the main endogenous cannabinoids, can specifically recognize, bind and activate cannabinoid receptor 1 (CB1), thereby inhibiting neuronal hyperexcitability. Fatty acid amide hydrolase (FAAH) and monoacylglycerol esterase (MAGL) are degrading enzymes of AEA and 2-AG, respectively. It is found that antagonists of FAAH and MAGL can significantly increase the expression of AEA and 2-AG in rats, and also alleviate the pain sensitivity of rats. However, it has not been reported whether CB1, FAAH and MAGL are involved in EA-induced hypersensitivity inhibition. The therapeutic effect and mechanism of EA were studied by using the visceral hypersensitivity model induced by goat ileitis. Twenty-four healthy male goats were injected with TNBS into the ileum wall to establish visceral hypersensitivity models. 18 visceral hypersensitivity goats were randomly divided into three groups: visceral hypersensitivity group (TNBS), electroacupuncture group (EA + TNBS), sham acupuncture group (Sham + TNBS), 6 goats in each group. In the Sham + TNBS group, only needling was done, and the rest was the same as the electroacupuncture group. Electroacupuncture was performed at 7, 10, 13, 16, 19 and 22 postoperatively, and then abdominal electromyography (EMG) was used to measure the colorectal dilatation (CRD) induced by different pressure gradients (20, 40, 60, 80 and 100 mmHg). Visceral motor response (VMR). Immediately after the measurement of VMR on the 22nd day, brain tissue, T11 spinal cord and ileum were taken from goats. Immunohistochemical method was used to detect the visceral sensory-related brain nuclei and regions (anterior cingulate gyrus, periaqueductal gray matter, raphe magnus nucleus, giant cell reticular nucleus, solitary tract nucleus, dorsal vagal motor nucleus, ventral end of medulla oblongata). The results showed that the expression of CB1, FAAH and MAGL in the dorsal horn of spinal cord and ileum of the goats in TNBS group was significantly higher than that in Saline group at 7 d (P 0.05) and maintained until 22 D. There was no significant difference between the goats in sham acupuncture group and TNBS group (P 0.05). Compared with TNBS group, there was no significant change in VMR at 7 d in EA group (P 0.05), and at 10, 13, 1 D in TNBS group. VMR increased significantly at 6, 19 and 22 days (P 0.05), indicating that EA could effectively alleviate visceral hypersensitivity in goats with ileal inflammation injury, and had cumulative effect. The expression levels of CB1 in NTS, DMV, R VLM, SDH and ileum were significantly lower than those in control group (P 0.05), while the expression levels of FAAH and MAGL were significantly higher in EA group than those in TNBS group (P 0.05). The amount of FAAH and MAGL increased significantly (P 0.05), and the content of FAAH and MAGL decreased significantly (P 0.05), indicating that EA could promote the up-regulation of CB1 and the down-regulation of FAAH and MAGL in visceral hypersensitivity model goats induced by ileitis. The effects of AAH and MAGL on the expression of AAH and MAGL showed that EA could effectively alleviate visceral hypersensitivity and increase CB1 and decrease FAAH in goats. The expression of MAGL in ACC, PAG, NRM, GI, NTS, DMV, RVLM, SDH and ileum was increased. This study will help to reveal the central and peripheral mechanisms of EA in alleviating visceral hypersensitivity induced by ileitis in goats and promote the treatment of gastrointestinal diseases. Development.
【學(xué)位授予單位】：華中農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R-332
本文編號(hào)：2179431
[Abstract]:Visceral hypersensitivity is a common clinical symptom of intestinal diseases, such as inflammatory bowel disease (IBDs) and irritable bowel syndrome (IBS). It occurs in about 50%-70% of IBDs and 20%-90% of IBS patients. Visceral hypersensitivity refers to the increased sensitivity and responsiveness of visceral tissues to a variety of stimuli, including hyperalgesia, touch pain, abnormal bowel motility and intestinal mucus. Visceral hypersensitivity is associated with central nervous system sensitization, peripheral nervous system sensitization and brain-gut axis disorder. Its drug treatment has serious side effects, which has been a serious medical problem for many years. In recent years, acupuncture treatment of visceral hypersensitivity has achieved good results in clinical practice. However, acupuncture treatment of visceral hypersensitivity has been proved effective. Studies have shown that opioid peptide system plays an important role in EA analgesia. However, blocking the opioid peptide system does not completely reverse EA analgesia in chronic pain models with inflammation, and blocking the endocannabinoid system can successfully reverse EA effect. Endogenous cannabinoid system plays a unique role in pain relief by electroacupuncture. The endogenous cannabinoid system consists of special G protein-coupled receptors (cannabinoid receptor 1 and cannabinoid receptor 2), endogenous cannabinoid ligands, and endogenous cannabinoid synthase and degrading enzymes, which are widely distributed in the central nervous system and peripheral nervous system. Arachidonethanolamine (AEA) and 2-arachidonyl glycerol (2-AG), as the main endogenous cannabinoids, can specifically recognize, bind and activate cannabinoid receptor 1 (CB1), thereby inhibiting neuronal hyperexcitability. Fatty acid amide hydrolase (FAAH) and monoacylglycerol esterase (MAGL) are degrading enzymes of AEA and 2-AG, respectively. It is found that antagonists of FAAH and MAGL can significantly increase the expression of AEA and 2-AG in rats, and also alleviate the pain sensitivity of rats. However, it has not been reported whether CB1, FAAH and MAGL are involved in EA-induced hypersensitivity inhibition. The therapeutic effect and mechanism of EA were studied by using the visceral hypersensitivity model induced by goat ileitis. Twenty-four healthy male goats were injected with TNBS into the ileum wall to establish visceral hypersensitivity models. 18 visceral hypersensitivity goats were randomly divided into three groups: visceral hypersensitivity group (TNBS), electroacupuncture group (EA + TNBS), sham acupuncture group (Sham + TNBS), 6 goats in each group. In the Sham + TNBS group, only needling was done, and the rest was the same as the electroacupuncture group. Electroacupuncture was performed at 7, 10, 13, 16, 19 and 22 postoperatively, and then abdominal electromyography (EMG) was used to measure the colorectal dilatation (CRD) induced by different pressure gradients (20, 40, 60, 80 and 100 mmHg). Visceral motor response (VMR). Immediately after the measurement of VMR on the 22nd day, brain tissue, T11 spinal cord and ileum were taken from goats. Immunohistochemical method was used to detect the visceral sensory-related brain nuclei and regions (anterior cingulate gyrus, periaqueductal gray matter, raphe magnus nucleus, giant cell reticular nucleus, solitary tract nucleus, dorsal vagal motor nucleus, ventral end of medulla oblongata). The results showed that the expression of CB1, FAAH and MAGL in the dorsal horn of spinal cord and ileum of the goats in TNBS group was significantly higher than that in Saline group at 7 d (P 0.05) and maintained until 22 D. There was no significant difference between the goats in sham acupuncture group and TNBS group (P 0.05). Compared with TNBS group, there was no significant change in VMR at 7 d in EA group (P 0.05), and at 10, 13, 1 D in TNBS group. VMR increased significantly at 6, 19 and 22 days (P 0.05), indicating that EA could effectively alleviate visceral hypersensitivity in goats with ileal inflammation injury, and had cumulative effect. The expression levels of CB1 in NTS, DMV, R VLM, SDH and ileum were significantly lower than those in control group (P 0.05), while the expression levels of FAAH and MAGL were significantly higher in EA group than those in TNBS group (P 0.05). The amount of FAAH and MAGL increased significantly (P 0.05), and the content of FAAH and MAGL decreased significantly (P 0.05), indicating that EA could promote the up-regulation of CB1 and the down-regulation of FAAH and MAGL in visceral hypersensitivity model goats induced by ileitis. The effects of AAH and MAGL on the expression of AAH and MAGL showed that EA could effectively alleviate visceral hypersensitivity and increase CB1 and decrease FAAH in goats. The expression of MAGL in ACC, PAG, NRM, GI, NTS, DMV, RVLM, SDH and ileum was increased. This study will help to reveal the central and peripheral mechanisms of EA in alleviating visceral hypersensitivity induced by ileitis in goats and promote the treatment of gastrointestinal diseases. Development.
【學(xué)位授予單位】：華中農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R-332
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