本文關(guān)鍵詞： 嗎啡 導(dǎo)水管 周圍 灰質(zhì) 發(fā)揮 鎮(zhèn)痛 效應(yīng) 機(jī)制　出處：《第四軍醫(yī)大學(xué)》2007年博士論文　論文類型：學(xué)位論文

【摘要】： 導(dǎo)水管周圍灰質(zhì)(periaqueductal gray,PAG)位于中腦,是哺乳動(dòng)物腦干內(nèi)下行痛抑制系統(tǒng)(descending pain inhibitory system,DPIS)內(nèi)的重要組成。PAG的鎮(zhèn)痛作用主要是通過激活其腹外側(cè)區(qū)/柱(ventrolateral column of the PAG,vlPAG)內(nèi)的5-HT能神經(jīng)元的活性而實(shí)現(xiàn)的。vlPAG內(nèi)的5-HT能神經(jīng)元興奮后,可以通過直接或間接的方式抑制脊髓的傷害性感受神經(jīng)元,從而產(chǎn)生鎮(zhèn)痛效應(yīng)。 在PAG內(nèi)同時(shí)存在一個(gè)調(diào)控5-HT能神經(jīng)元活性的局部環(huán)路。其基本構(gòu)成如下:PAG內(nèi)大量存在的γ-氨基丁酸(γ-aminobutyric acid,GABA)能中間神經(jīng)元可以對(duì)5-HT能神經(jīng)元產(chǎn)生持續(xù)性的抑制效應(yīng),而阿片類物質(zhì)通過與表達(dá)在GABA能神經(jīng)元上的μ型阿片受體(MOR)結(jié)合,能夠抑制GABA能神經(jīng)元的活性,從而使5-HT能神經(jīng)元間接激活(脫抑制,disinhibition),最終產(chǎn)生鎮(zhèn)痛效應(yīng)。 內(nèi)嗎啡肽(endomorphin,EM)是新近發(fā)現(xiàn)的一種內(nèi)源性阿片肽,也是MOR高選擇性的內(nèi)源性配體。其鎮(zhèn)痛效應(yīng)與嗎啡相似,但其副作用卻遠(yuǎn)小于嗎啡,在臨床鎮(zhèn)痛治療方面有廣泛的應(yīng)用前景。內(nèi)嗎啡肽可以分為內(nèi)嗎啡肽1( endomorphin 1, EM1)和內(nèi)嗎啡肽2(endomorphin 2, EM2)兩種亞型。內(nèi)嗎啡肽的胞體在脊髓上位腦區(qū)主要分布于下丘腦和孤束核,而纖維則遍布全腦,特別是在PAG的不同亞區(qū)內(nèi)都分布有比較密集的EM能纖維和終末,提示EM可能參與了PAG內(nèi)功能的調(diào)控。但是迄今為止,關(guān)于EM參與PAG內(nèi)鎮(zhèn)痛效應(yīng)機(jī)制的研究還未見報(bào)道。因此,本論文綜合應(yīng)用當(dāng)代神經(jīng)科學(xué)研究方法,對(duì)以下幾個(gè)問題進(jìn)行了探討: 1. PAG內(nèi)大量存在的EM能纖維和終末的來源部位在哪里,其來源部位和PAG的不同亞區(qū)之間是否存在一定的對(duì)應(yīng)關(guān)系? 2. vlPAG是5-HT能DPIS的起源部位,而該部位的EM是否參與了對(duì)DPIS局部調(diào)控的環(huán)路? 3. EM參與DPIS調(diào)控的機(jī)制是什么? 主要結(jié)果: 1.PAG內(nèi)EM陽性纖維和終末的來源 將熒光逆行追蹤劑熒光金(Fluoro-Gold,FG)分別電泳入大鼠PAG的不同亞區(qū),通過結(jié)合EM1或EM2的免疫熒光組織化學(xué)染色技術(shù),我們觀察到EM1/FG和EM2/FG雙重標(biāo)記的神經(jīng)元主要位于下丘腦的不同核團(tuán)/區(qū)域內(nèi),孤束核內(nèi)未見到雙標(biāo)神經(jīng)元分布。其中,下丘腦結(jié)節(jié)乳頭體區(qū)內(nèi)側(cè)的背內(nèi)側(cè)核( dorsomedial hypothalamic nucleus , DMH )、DMH及腹內(nèi)側(cè)核( ventromedial hypothalamic nucleus)之間的中央內(nèi)側(cè)區(qū)(centromedial hypothalamic region,CMH)以及弓狀核(arcuate nucleus of the hypothalamus,Arc)內(nèi)包含了絕大部分雙標(biāo)神經(jīng)元。它們的分布特點(diǎn)如下: 1)將FG注入vlPAG后,DMH內(nèi)18.0%的EM1(15.7±6.0)和14.0%的EM2(8.2±2.6)陽性神經(jīng)元,CMH內(nèi)15%的EM1(30.7±5.9)和18.6%的EM2(17.2±4.7)陽性神經(jīng)元以及Arc內(nèi)10.5%的EM1(6.3±1.9)和12.1%的EM2(5.7±2.0)陽性神經(jīng)元同時(shí)被FG逆行標(biāo)記; 2)將FG注入PAG外側(cè)區(qū)(lateral column of the PAG, lPAG)后,DMH內(nèi)14.8%的EM1(12.2±4.3)和10.8%的EM2(6.7±2.7)陽性神經(jīng)元,CMH內(nèi)11.1%的EM1(23.7±7.9)和10.3%的EM2(9.0±3.2)陽性神經(jīng)元以及Arc內(nèi)9.2%的EM(15.2±2.6)和5.6%的EM(22.8±1.2)陽性神經(jīng)元同時(shí)被FG逆行標(biāo)記; 3)將FG注入PAG背外側(cè)區(qū)(dorsolateral column of the PAG, dlPAG)后,DMH內(nèi)7.0%的EM1(6.2±3.3)和6.2%的EM2(3.8±2.3)陽性神經(jīng)元,CMH內(nèi)5.3%的EM(111.6±3.6)和3.4%的EM(23.0±1.6)陽性神經(jīng)元以及Arc內(nèi)2.0%的EM(11.2±0.8)和2.4%的EM(21.0±0.7)陽性神經(jīng)元同時(shí)被FG逆行標(biāo)記; 4)將FG注入PAG背內(nèi)側(cè)區(qū)(dorsomedial column of the PAG,dmPAG)后,DMH內(nèi)8.5%的EM1(7.8±2.9)和7.0%的EM2(4.6±1.8)陽性神經(jīng)元,CMH內(nèi)9.5%的EM(119.2±8.1)和5.7%的EM(24.8±2.4)陽性神經(jīng)元以及Arc內(nèi)3.5%的EM1(2.0±1.2)和3.9%的EM(21.8±1.8)陽性神經(jīng)元同時(shí)被FG逆行標(biāo)記。 綜合以上結(jié)果,可以看出:①下丘腦內(nèi)EM1/FG雙標(biāo)神經(jīng)元的數(shù)量遠(yuǎn)多于EM2/FG雙標(biāo)神經(jīng)元的數(shù)量(802 vs. 392);②在下丘腦的不同核團(tuán)和區(qū)域中,CMH內(nèi)的EM/FG雙標(biāo)神經(jīng)元數(shù)目最多(480 EM1/FG;196 EM2/FG),隨后是DMH(237 EM1/FG;131 EM2/FG)及Arc(85 EM1/FG;65 EM2/FG);③將FG注入vlPAG后,在下丘腦內(nèi)的EM/FG雙標(biāo)神經(jīng)元數(shù)目最多,說明下丘腦內(nèi)的EM能神經(jīng)元向vlPAG發(fā)出最多的投射,隨后是lPAG及dmPAG,最少的是dlPAG。 以上結(jié)果說明:①PAG的不同亞區(qū)內(nèi)的EM能纖維和終末主要來源于下丘腦而不是孤束核;②下丘腦的不同核團(tuán)和區(qū)域與PAG內(nèi)的不同亞區(qū)之間存在明確的對(duì)應(yīng)關(guān)系;③來源于下丘腦的EM能纖維和終末可能參與了PAG的多種功能活動(dòng),特別是痛覺的調(diào)制。 2.對(duì)于EM參與vlPAG內(nèi)痛覺調(diào)控環(huán)路的機(jī)制問題,我們分別從形態(tài)學(xué)和行為藥理學(xué)角度進(jìn)行了論證。 2.1 EM參與vlPAG內(nèi)痛覺調(diào)控環(huán)路的電鏡觀察 通過使用電鏡雙重標(biāo)記技術(shù),我們觀察了大鼠vlPAG內(nèi)EM1或EM2陽性的軸突終末與谷氨酸脫羧酶( glutamate decarboxylase,GAD)、MOR以及5-HT陽性的神經(jīng)元胞體及樹突之間的突觸聯(lián)系。GAD是GABA合成中的限速酶,也是GABA能神經(jīng)元的標(biāo)志,其分布與GABA相一致,GAD陽性結(jié)構(gòu)即可認(rèn)為是GABA陽性結(jié)構(gòu)。結(jié)果顯示: 1) vlPAG內(nèi)含有大量的EM1和EM2陽性的軸突以及軸突終末以及GAD、MOR以及5-HT陽性的胞體和樹突存在; 2) EM1以及EM2陽性的軸突終末能夠與MOR、GAD及5-HT陽性的胞體和樹突形成突觸。其中: EM1及EM2陽性軸突終末與MOR陽性胞體和樹突主要形成對(duì)稱性/抑制性突觸(EM1:非對(duì)稱/對(duì)稱=37.8/62.2×100%;EM2:非對(duì)稱/對(duì)稱=41.4/58.6×100%)。 EM1及EM2陽性軸突終末與GAD陽性胞體和樹突也主要形成對(duì)稱性突觸(EM1:非對(duì)稱/對(duì)稱=17.5/82.5×100%;EM2:非對(duì)稱/對(duì)稱=13.6/86.4×100%)。 EM1及EM2陽性軸突終末與5-HT陽性胞體和樹突則主要形成非對(duì)稱性/興奮性突觸(EM1:非對(duì)稱/對(duì)稱=58.3/41.7×100%;EM2:非對(duì)稱/對(duì)稱=56.7/43.3×100%)。 3) EM2陽性軸突終末間也可形成以非對(duì)稱性突觸(92%)為主的突觸聯(lián)系。 以上結(jié)果從電鏡水平證實(shí)了vlPAG內(nèi)EM能夠?qū)ABA能神經(jīng)元產(chǎn)生抑制效應(yīng),且對(duì)5-HT能神經(jīng)元存在直接興奮效應(yīng),而以上的效應(yīng)可能是通過MOR介導(dǎo)。 2.2 EM參與vlPAG內(nèi)痛覺調(diào)控環(huán)路的共聚焦顯微鏡觀察 通過使用谷氨酸脫羧酶67-綠色熒光蛋白(GAD67-GFP)基因敲入小鼠,我們進(jìn)一步觀察了vlPAG內(nèi)EM1及EM2陽性纖維和終末以及表達(dá)GFP的GAD陽性胞體與MOR或5-HT陽性胞體之間的共存情況。結(jié)果顯示: 1) GFP陽性胞體與MOR存在廣泛的共存關(guān)系,幾乎所有的GFP陽性神經(jīng)元(98%)都表達(dá)MOR。而EM1或EM2陽性纖維和終末能夠與GFP/MOR雙標(biāo)神經(jīng)元形成密切接觸; 2)部分GFP陽性胞體發(fā)出纖維與5-HT能神經(jīng)元形成密切接觸,而EM1或EM2陽性纖維和終末又能夠與該GFP陽性胞體發(fā)生密切接觸。 以上結(jié)果從形態(tài)學(xué)光鏡水平為vlPAG內(nèi)EM抑制GABA能神經(jīng)元(通過MOR介導(dǎo)),從而間接興奮5-HT能神經(jīng)元的局部環(huán)路的存在提供了形態(tài)學(xué)依據(jù)。 2.3 EM參與vlPAG內(nèi)痛覺調(diào)控環(huán)路的行為學(xué)觀察 大鼠vlPAG區(qū)埋管制備動(dòng)物模型,經(jīng)管給予EM、GABAA受體的激動(dòng)劑和拮抗劑以及MOR受體的拮抗劑,觀察了大鼠給藥前后對(duì)于熱刺激反應(yīng)潛伏期以及機(jī)械刺激反應(yīng)閾值的變化,探討EM在vlPAG內(nèi)作用的機(jī)制。結(jié)果如下: 1)不同劑量的EM1(4、8、16、32 nmol/0.5μl)以及EM2(2、4、8、16 nmol/0.5μl)可以引發(fā)實(shí)驗(yàn)動(dòng)物產(chǎn)生明顯的鎮(zhèn)痛效應(yīng)。而該效應(yīng)可以被MOR拮抗劑完全翻轉(zhuǎn); 2) GABAA受體的拮抗劑與EM能夠產(chǎn)生強(qiáng)力的協(xié)同鎮(zhèn)痛效應(yīng),而GABAA受體的激動(dòng)劑則可以完全抑制EM的鎮(zhèn)痛效應(yīng)。 以上結(jié)果從行為學(xué)角度說明了EM的作用通過抑制GABA能神經(jīng)元活性實(shí)現(xiàn),而該效應(yīng)通過MOR介導(dǎo)。 總之,上述形態(tài)學(xué)和行為學(xué)實(shí)驗(yàn)說明vlPAG內(nèi)EM可以產(chǎn)生明確的鎮(zhèn)痛效應(yīng),而該效應(yīng)主要是通過抑制表達(dá)MOR的GABA能神經(jīng)元的活性,進(jìn)而使表達(dá)GABAA受體的5-HT能神經(jīng)元擺脫GABA抑制而間接實(shí)現(xiàn)的。
[Abstract]:The periaqueductal gray (periaqueductal gray PAG) is located in the midbrain, mammalian brain stem descending inhibitory system (descending pain inhibitory system, DPIS) is an important component in the analgesic effect of.PAG is mainly through the activation of the ventrolateral column (ventrolateral / column of the PAG, vlPAG) and 5-HT in neuron activity the.VlPAG in 5-HT neurons after excitation, can inhibit the spinal cord through direct or indirect way to nociceptive neurons, resulting in analgesic effect.
A 5-HT can control local circuit neuron activity exist simultaneously in PAG. The basic structure is as follows: PAG in the presence of a large number of gamma amino butyric acid (GABA -aminobutyric acid, GABA) interneurons can 5-HT can inhibit the effect of neuronal persistent, and opioid substances with expression in GABA mu opioid receptor neurons (MOR) combined with GABA, can inhibit the neuron activity, so that the indirect activation of 5-HT neurons (antisuppression, disinhibition), eventually produce analgesic effect.
Endomorphin (endomorphin, EM) is a newly discovered endogenous opioid peptide, is the endogenous ligand for the MOR. The analgesic effect similar to morphine, but its side effect is far lower than that of morphine, and has wide application prospect in clinical analgesic treatment. Endomorphins can be divided into endomorphine 1 (endomorphin 1, EM1) and endomorphin 2 (endomorphin 2, EM2 two) subtypes. The soma of endomorphins in supraspinal brain areas are mainly distributed in the hypothalamus and the nucleus of the solitary tract, and fibers throughout the whole brain, especially in the different sub area of PAG is distributed more intensive the EM fibers and terminals, suggesting that EM may be involved in the regulation of PAG function. But so far, the research on EM in PAG in the mechanism of analgesic effect has not been reported. Therefore, the scientific research method of comprehensive application of the contemporary nerve, the following problems are discussed:
In 1. PAG, where is the source of a large number of EM fibers and terminals, and whether there is a certain correspondence between the sources of the source and the different subregions of the PAG?
2. vlPAG is the origin of 5-HT DPIS, and is the EM involved in the loop of local regulation of DPIS?
3. what is the mechanism that EM participates in DPIS regulation?
Main results:
The source of EM positive fibers and terminals in 1.PAG
The fluorescent retrograde tracer Fluorogold (Fluoro-Gold, FG) in different sub regions respectively into the rat PAG electrophoresis technology, via immunofluorescence histochemistry combined with EM1 or EM2, different nucleus / region we observed EM1/FG and EM2/FG double labeled neurons were mainly located in the hypothalamus, the NTS did not see double labeled neurons distributed. The tuberomammillary hypothalamic dorsomedial nucleus of the medial zone (dorsomedial hypothalamic, nucleus, DMH, DMH) and the ventromedial nucleus (ventromedial hypothalamic nucleus) between the central medial area (centromedial hypothalamic region CMH (arcuate) and nucleus of the in arcuate nucleus hypothalamus, Arc) contains most of the double the distribution characteristics of their neurons:
1) FG after injection of vlPAG, DMH 18% EM1 (15.7 + 6) and 14% EM2 (8.2 + 2.6) CMH positive neurons within 15% EM1 (30.7 + 5.9) and 18.6% EM2 (17.2 + 4.7) positive neurons and Arc within 10.5% EM1 (6.3 + 1.9) and 12.1% the EM2 (5.7 + 2) positive neurons were retrogradely labeled with FG;
2) FG into PAG (lateral column of the lateral region of PAG, lPAG, DMH) in 14.8% EM1 (12.2 + 4.3) and 10.8% EM2 (6.7 + 2.7) CMH positive neurons within 11.1% EM1 (23.7 + 7.9) and 10.3% EM2 (9 + 3.2) positive neurons and Arc in 9.2% EM (15.2 + 2.6) and 5.6% EM (22.8 + 1.2) positive neurons were retrogradely labeled with FG;
3) FG was injected into the dorsal lateral region of PAG (dorsolateral column of the PAG, dlPAG DMH), 7% EM1 (6.2 + 3.3) and 6.2% EM2 (3.8 + 2.3) CMH positive neurons within 5.3% EM (111.6 + 3.6) and 3.4% EM (23 + 1.6) positive neurons and Arc 2% EM (11.2 + 0.8) and 2.4% EM (21 + 0.7) positive neurons were retrogradely labeled with FG;
4) FG was injected into the dorsal medial area (PAG dorsomedial column of the PAG, dmPAG DMH), 8.5% EM1 (7.8 + 2.9) and 7% EM2 (4.6 + 1.8) CMH positive neurons within 9.5% EM (119.2 + 8.1) and 5.7% EM (24.8 + 2.4) positive neurons and Arc 3.5% EM1 (2 + 1.2) and 3.9% EM (21.8 + 1.8) positive neurons were retrogradely labeled with FG.
Based on the above results, we can see that the number of EM1/FG double labeled neurons in the hypothalamus of far more than EM2/FG of double labeled neurons (802 vs. 392); in the hypothalamic nuclei and different regions, the number of EM/FG double labeled neurons in CMH (up to 480 EM1/FG; 196 EM2/FG), followed by DMH (237 EM1/FG; 131 EM2/FG) and Arc (85 EM1/FG; 65 EM2/FG); 3 FG after injection of vlPAG, the number of EM/FG double labeled neurons in the hypothalamus in most EM neurons in the hypothalamus that issued the most projecting to vlPAG, followed by lPAG and dmPAG, the least is dlPAG.
The above results showed that: the PAG of different sub region EM fibers and terminals mainly come from the hypothalamus but not the nucleus of the solitary tract; there is a clear relationship between different sub regions of hypothalamic nuclei and different regions and within PAG; the source in the hypothalamus EM fibers and terminals may participate in the a variety of functional activities of PAG, especially in pain modulation.
2. we demonstrate the mechanism of EM participation in the mechanism of the vlPAG internal pain control loop from the morphological and behavioral pharmacology point of view.
2.1 EM participates in the electron microscope observation of the internal pain control loop of vlPAG
By using electron microscope double labeling technique, we observed the rat vlPAG in EM1 or EM2 positive axon terminals and glutamate decarboxylase (glutamate decarboxylase, GAD), between MOR and 5-HT positive neurons and dendrites of the synaptic connections between.GAD is the rate limiting enzyme in the synthesis of GABA, but also a symbol of GABA neurons and its distribution consistent with GABA, GAD positive structures can be considered GABA positive results show that structure:
1) vlPAG contained a large number of EM1 and EM2 positive axons and end of axons, as well as GAD, MOR and 5-HT positive cells and dendrites.
2) EM1 and EM2 positive axonal terminals are capable of forming synapses with MOR, GAD and 5-HT positive cells and dendrites.
EM1 and EM2 positive axon terminals were mainly formed with symmetric and inhibitory synapses with MOR positive cells and dendrites (EM1: asymmetric / symmetric =37.8/62.2 * 100%; EM2: asymmetric / symmetric =41.4/58.6 * 100%).
EM1, EM2 positive axon terminals and GAD positive cell bodies and dendrites also form symmetrical synapses (EM1: asymmetric / symmetric =17.5/82.5 * 100%; EM2: asymmetric / symmetric =13.6/86.4 * 100%).
EM1 and EM2 positive axon terminals and 5-HT positive cell bodies and dendrites mainly form asymmetric / excitatory synapses (EM1: asymmetric / symmetric =58.3/41.7 * 100%; EM2: asymmetric / symmetric =56.7/43.3 * 100%).
3) the synaptic connections with asymmetric synapses (92%) can also be formed between the EM2 positive axons.
The above results confirm that EM can inhibit GABA neurons and have direct excitation effect on 5-HT neurons in vlPAG, and the above effects may be mediated by MOR.
Confocal microscope observation of 2.2 EM involved in the internal pain control loop of vlPAG
Through the use of glutamic acid decarboxylase 67- green fluorescent protein (GAD67-GFP) gene knock in mice, we further investigate the colocalization between vlPAG EM1 and EM2 positive fibers and terminals and GAD positive cell expression of GFP and MOR or 5-HT positive neurons. The results showed that:
1) there is a wide range of coexistence between GFP positive cell bodies and MOR. Almost all GFP positive neurons (98%) express MOR., while EM1 or EM2 positive fibers and terminals can form close contacts with GFP/MOR double labeled neurons.
2) some GFP positive cells emit close contact with 5-HT neurons, while EM1 or EM2 positive fibers and terminals can also be closely related to the GFP positive cell body.
The above results provide a morphological basis for indirectly stimulating the existence of the local loop of 5-HT neurons from the level of morphological light microscopy, which inhibits GABA neurons in vlPAG (mediated by MOR), and thus indirectly excite the existence of the local loop of EM neurons.
2.3 EM participates in the behavioral observation of the internal pain control loop of vlPAG
The rat vlPAG control area buried animal model, and give EM, GABAA receptor agonists and antagonists of MOR receptor antagonist, rats were observed before and after administration for the thermal stimulus response latency and changes in response to mechanical stimulation threshold, to explore the mechanism of EM in vlPAG. The results are as follows:
1) different doses of EM1 (4,8,16,32 nmol/0.5 and L) and EM2 (2,4,8,16 nmol/0.5 L) can induce obvious analgesic effect in experimental animals, and this effect can be completely reversed by MOR antagonists.
2) the antagonist of GABAA receptor and EM can produce a strong synergistic analgesic effect, and the agonist of GABAA receptor can completely inhibit the analgesic effect of EM.
The above results show that the role of EM is achieved by inhibiting the activity of GABA neurons, which is mediated by MOR.
In conclusion, the above morphological and behavioral experiments show that EM can produce a clear analgesic effect in vlPAG, and this effect is mainly achieved by inhibiting the activity of GABA neurons that express MOR, thereby enabling the expression of GABAA receptor 5-HT neurons to get rid of GABA inhibition.

【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2007
【分類號(hào)】：R338

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