Propofol促睡眠作用機(jī)制研究
發(fā)布時(shí)間：2018-10-13 09:29
【摘要】：睡眠和覺(jué)醒的發(fā)生及轉(zhuǎn)換被認(rèn)為是腦內(nèi)神經(jīng)遞質(zhì)和內(nèi)源性睡眠促進(jìn)物質(zhì)共同作用的結(jié)果,同時(shí)受晝夜節(jié)律調(diào)控。動(dòng)物實(shí)驗(yàn)和臨床證實(shí)propofol導(dǎo)致動(dòng)物或人產(chǎn)生意識(shí)喪失和睡眠,低劑量的propofol具有良好的鎮(zhèn)靜作用,但機(jī)制尚不清。我們推測(cè)propofol麻醉作用可能與睡眠通路相關(guān),可能通過(guò)興奮睡眠中樞系統(tǒng),抑制覺(jué)醒系統(tǒng)而起作用。本研究采用睡眠覺(jué)醒記錄解析的方法和即刻早基因表達(dá)和相關(guān)神經(jīng)遞質(zhì)免疫組織化學(xué)雙標(biāo)記技術(shù)揭示propofol對(duì)睡眠覺(jué)醒時(shí)相的調(diào)節(jié)作用和中樞作用靶點(diǎn)及通路,為全面了解propofol作用機(jī)制和指導(dǎo)臨床應(yīng)用提供實(shí)驗(yàn)和理論依據(jù)。 方法： SD大鼠隨機(jī)分為4組：vehicle (saline)注射組,propofol 1 mg/kg、5 mg/kg和10 mg/kg注射組。肌電(EMG)和腦電(EEG)電極分別植入項(xiàng)肌和腦皮質(zhì)表面以備記錄。術(shù)后恢復(fù)七天,記錄各組EEG和EMG 24 h后22：00分別腹腔注射saline或propofol,解析各組睡眠覺(jué)醒時(shí)相的改變。藥效作用高峰期1.5小時(shí),處死動(dòng)物行Fos蛋白標(biāo)記和調(diào)節(jié)睡眠覺(jué)醒重要神經(jīng)遞質(zhì)免疫組化雙標(biāo)記,觀察propofol的作用導(dǎo)致Fos在睡眠覺(jué)醒相關(guān)核團(tuán)表達(dá)活性的變化。 結(jié)果： 1.腹腔注射10 mg/kg propofol抑制大鼠覺(jué)醒,EEG顯示為高幅慢波,EMG活動(dòng)減少,24小時(shí)時(shí)程為給藥后持續(xù)5小時(shí)深慢波睡眠(deep slow wave sleep, SWS2), SWS2平均持續(xù)時(shí)間增多,長(zhǎng)時(shí)程睡眠(960秒)發(fā)生次數(shù)增加,而對(duì)其它時(shí)相發(fā)生次數(shù)和各時(shí)相相互轉(zhuǎn)化次數(shù)無(wú)顯著影響,對(duì)異相睡眠/快動(dòng)眼睡眠(paradoxical sleep, PS/rapid eye move sleep, REM sleep)無(wú)改變。Propofol 5 mg/kg EEG、EMG以及睡眠圖表現(xiàn)與10 mg/kg相似,但是SWS2時(shí)相持續(xù)時(shí)間較短,長(zhǎng)時(shí)程覺(jué)醒被破壞,淺慢波睡眠(light slow wave sleep,SWS1)向SWS2以及SWS2向覺(jué)醒的轉(zhuǎn)換此時(shí)增加。1 mg/kg propofol對(duì)睡眠覺(jué)醒行為無(wú)顯著影響。 2.與生理覺(jué)醒組和生理鹽水組相比,10 mg/kg propofol (10 mg/kg)組動(dòng)物睡眠關(guān)鍵核團(tuán)腹外側(cè)視前區(qū)(ventrolateral preoptic nucleus, VLPO)區(qū)Fos-IR表達(dá)增多,覺(jué)醒相關(guān)核團(tuán)結(jié)節(jié)乳頭體核(tuberomammillary nucleus, TMN)、穹窿周區(qū)(perifornical nucleus, PeF),外側(cè)下丘腦(lateral hypothalamic area, LH)、中腦導(dǎo)水管周圍灰質(zhì)腹側(cè)(ventrolateral periaquiductal gray, vPAG)、中縫核(dorsal raphe nucleus, DRN)Fos-IR均有不同程度的降低,且具有統(tǒng)計(jì)學(xué)意義,與生理睡眠組動(dòng)物Fos-IR表達(dá)區(qū)域類似。藍(lán)斑(locus coeruleus, LC)、中腦被蓋區(qū)(pedunculopontine tegmental bucleus, PPT)以及黑質(zhì)(substantia nigra pars compacta, SNC)Fos-IR各組均無(wú)明顯表達(dá)。 結(jié)論 1. Propofol劑量依賴性促進(jìn)SWS2睡眠,縮短睡眠潛伏期,但對(duì)PS和SWS1睡眠無(wú)明顯影響。 2. Propofol 10 mg/kg引發(fā)SWS2片段的平均持續(xù)時(shí)間和長(zhǎng)時(shí)程發(fā)生次數(shù)增加,但改變其它時(shí)相片段發(fā)生次數(shù)及轉(zhuǎn)化次數(shù)與對(duì)照組相比無(wú)顯著性。提示高劑量propofol引起的睡眠主要是通過(guò)增加長(zhǎng)時(shí)程SWS2時(shí)相的持續(xù)時(shí)間增加睡眠量。 3. Propofol 5 mg/kg引發(fā)的覺(jué)醒,SWS1和SWS2片段發(fā)生次數(shù)以及SWS1向SWS2和SWS2向覺(jué)醒轉(zhuǎn)化次數(shù)顯著增加,同時(shí)覺(jué)醒的平均持續(xù)時(shí)間和長(zhǎng)時(shí)程覺(jué)醒發(fā)生次數(shù)減少。提示中劑量可能是通過(guò)破壞覺(jué)醒的發(fā)生并降低覺(jué)醒的持續(xù)時(shí)間而增加睡眠量。 4. Propofol通過(guò)激活睡眠中樞VLPO神經(jīng)元和抑制覺(jué)醒中樞的結(jié)節(jié)乳頭體核、穹窿周區(qū),外側(cè)下丘腦、中腦導(dǎo)水管周圍灰質(zhì)腹側(cè)及中縫核而促進(jìn)睡眠。
[Abstract]:The occurrence and conversion of sleep and wakefulness is considered to be the result of common action of neurotransmitter and endogenous sleep promoting substance in brain, and is regulated by circadian rhythm. Animal experiments and clinical studies demonstrated that propol resulted in loss of consciousness and sleep in animals or humans, and low doses of propoofol had a good sedative effect, but the mechanism was not clear. We speculate that propool anesthesia may be associated with sleep pathways, possibly by stimulating the central nervous system and inhibiting the wake-up system. The method and the immediate early gene expression of the sleep awakening record and the double labeling technique of the related neurotransmitter are used to disclose the regulating effect and the central action target and the pathway of propol on the sleep awakening, It provides experimental and theoretical basis for comprehensive understanding of propol action mechanism and guiding clinical application. Methods: SD rats were randomly divided into four groups: vehicle injection group, propol 1 mg/ kg, 5mg/ kg and 10m g/ kg injection group. Myoelectric (EMG) and brain electrical (EEG) electrodes were implanted with muscle and brain respectively. The quality surface was prepared for recording. After 7 days of postoperative recovery, the EEG and EMG 24h of each group were recorded, followed by injection of saline or propol, respectively, to analyze the sleep of each group. The effects of propol on sleep-wakefulness-related nuclei were observed. expression of living Results: 1. Intraperitoneal injection of 10 mg/ kg propol inhibited the awakening of rats, EEG was shown as high amplitude slow wave, EMG activity decreased, and after 24 hours, the average duration of SWS2 increased, and the average duration of SWS2 increased. The number of times of onset of sleep (960 seconds) increased, while there was no significant effect on the number of times of phase change and the number of transformation times of each time phase. Sleep and REM sleep were unchanged. Propofol 5 mg/ kg EEG, EMG and sleep patterns were similar to 10 mg/ kg, but the duration of the phase was shorter in SWS2, the long-stroke awakening was destroyed, the transition of light slow wave sleep (SWS1) to SWS2 and SWS2 increased at this time. 1 mg/ kg propo Fol has no significant effect on sleep awakening behavior. Compared with physiological arousal group and physiological saline group, 10 mg/ kg propoofol (10 mg/ kg) group animal sleep key nucleus in the ventral lateral visual anterior region (VLPO) region. Hornical natus, PeF, lateral hypothalamic area (LH), periaqueductal gray system (LH), periaqueductal gray area (vsl), middle-slit nucleus (DRN) and DMR-IR all have a different degree of decrease, and have statistical significance. In physiological sleep group, it is similar to that of the IR-expressing region of the animal. The locus coeruleus (LC), the mesencephalic region of the mesencephalic zone (PPT), and the substeantia nigra pars compacta, S No significant expression was found in each group of NC. Conclusion 1. Propofol dose-dependent promotes SWS2. Sleep, shortened sleep latency, but no significant effect on PS and SWS1 sleep. 2. Propofol 10 mg/ kg induced average duration and duration of SWS2 fragments There was no significant difference between the number of times and the number of conversion times compared with the control group. The resulting sleep was mainly due to increased sleep by increasing the duration of the phase during the long time SWS2. 3. The number of awakening, SWS1 and SWS2 fragments induced by Propofol 5 mg/ kg, and SWS1 to SWS2 and SWS2 The number of awakening transformation was significantly increased, while the average duration of awakening and the number of times of wake-up were decreased. Less. The suggested dose may increase the amount of sleep by destroying the onset of the awakening and decreasing the duration of the awakening. 4. Propoofol activates the central VLPO neuron and inhibits the awakening center.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2011
【分類號(hào)】：R338.63
本文編號(hào)：2268110
[Abstract]:The occurrence and conversion of sleep and wakefulness is considered to be the result of common action of neurotransmitter and endogenous sleep promoting substance in brain, and is regulated by circadian rhythm. Animal experiments and clinical studies demonstrated that propol resulted in loss of consciousness and sleep in animals or humans, and low doses of propoofol had a good sedative effect, but the mechanism was not clear. We speculate that propool anesthesia may be associated with sleep pathways, possibly by stimulating the central nervous system and inhibiting the wake-up system. The method and the immediate early gene expression of the sleep awakening record and the double labeling technique of the related neurotransmitter are used to disclose the regulating effect and the central action target and the pathway of propol on the sleep awakening, It provides experimental and theoretical basis for comprehensive understanding of propol action mechanism and guiding clinical application. Methods: SD rats were randomly divided into four groups: vehicle injection group, propol 1 mg/ kg, 5mg/ kg and 10m g/ kg injection group. Myoelectric (EMG) and brain electrical (EEG) electrodes were implanted with muscle and brain respectively. The quality surface was prepared for recording. After 7 days of postoperative recovery, the EEG and EMG 24h of each group were recorded, followed by injection of saline or propol, respectively, to analyze the sleep of each group. The effects of propol on sleep-wakefulness-related nuclei were observed. expression of living Results: 1. Intraperitoneal injection of 10 mg/ kg propol inhibited the awakening of rats, EEG was shown as high amplitude slow wave, EMG activity decreased, and after 24 hours, the average duration of SWS2 increased, and the average duration of SWS2 increased. The number of times of onset of sleep (960 seconds) increased, while there was no significant effect on the number of times of phase change and the number of transformation times of each time phase. Sleep and REM sleep were unchanged. Propofol 5 mg/ kg EEG, EMG and sleep patterns were similar to 10 mg/ kg, but the duration of the phase was shorter in SWS2, the long-stroke awakening was destroyed, the transition of light slow wave sleep (SWS1) to SWS2 and SWS2 increased at this time. 1 mg/ kg propo Fol has no significant effect on sleep awakening behavior. Compared with physiological arousal group and physiological saline group, 10 mg/ kg propoofol (10 mg/ kg) group animal sleep key nucleus in the ventral lateral visual anterior region (VLPO) region. Hornical natus, PeF, lateral hypothalamic area (LH), periaqueductal gray system (LH), periaqueductal gray area (vsl), middle-slit nucleus (DRN) and DMR-IR all have a different degree of decrease, and have statistical significance. In physiological sleep group, it is similar to that of the IR-expressing region of the animal. The locus coeruleus (LC), the mesencephalic region of the mesencephalic zone (PPT), and the substeantia nigra pars compacta, S No significant expression was found in each group of NC. Conclusion 1. Propofol dose-dependent promotes SWS2. Sleep, shortened sleep latency, but no significant effect on PS and SWS1 sleep. 2. Propofol 10 mg/ kg induced average duration and duration of SWS2 fragments There was no significant difference between the number of times and the number of conversion times compared with the control group. The resulting sleep was mainly due to increased sleep by increasing the duration of the phase during the long time SWS2. 3. The number of awakening, SWS1 and SWS2 fragments induced by Propofol 5 mg/ kg, and SWS1 to SWS2 and SWS2 The number of awakening transformation was significantly increased, while the average duration of awakening and the number of times of wake-up were decreased. Less. The suggested dose may increase the amount of sleep by destroying the onset of the awakening and decreasing the duration of the awakening. 4. Propoofol activates the central VLPO neuron and inhibits the awakening center.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2011
【分類號(hào)】：R338.63
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
1 湯斌,章功良,王烈成,張瑾,鐘明奎,趙樂(lè)章,張景行;腹外側(cè)視前區(qū)GABA能神經(jīng)元對(duì)大鼠睡眠-覺(jué)醒周期的影響[J];安徽醫(yī)科大學(xué)學(xué)報(bào);2003年05期
，本文編號(hào)：2268110
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