Propofol促睡眠作用机制研究
发布时间：2018-10-13 09:29
【摘要】：睡眠和觉醒的发生及转换被认为是脑内神经递质和内源性睡眠促进物质共同作用的结果,同时受昼夜节律调控。动物实验和临床证实propofol导致动物或人产生意识丧失和睡眠,低剂量的propofol具有良好的镇静作用,但机制尚不清。我们推测propofol麻醉作用可能与睡眠通路相关,可能通过兴奋睡眠中枢系统,抑制觉醒系统而起作用。本研究采用睡眠觉醒记录解析的方法和即刻早基因表达和相关神经递质免疫组织化学双标记技术揭示propofol对睡眠觉醒时相的调节作用和中枢作用靶点及通路,为全面了解propofol作用机制和指导临床应用提供实验和理论依据。 方法： SD大鼠随机分为4组：vehicle (saline)注射组,propofol 1 mg/kg、5 mg/kg和10 mg/kg注射组。肌电(EMG)和脑电(EEG)电极分别植入项肌和脑皮质表面以备记录。术后恢复七天,记录各组EEG和EMG 24 h后22：00分别腹腔注射saline或propofol,解析各组睡眠觉醒时相的改变。药效作用高峰期1.5小时,处死动物行Fos蛋白标记和调节睡眠觉醒重要神经递质免疫组化双标记,观察propofol的作用导致Fos在睡眠觉醒相关核团表达活性的变化。 结果： 1.腹腔注射10 mg/kg propofol抑制大鼠觉醒,EEG显示为高幅慢波,EMG活动减少,24小时时程为给药后持续5小时深慢波睡眠(deep slow wave sleep, SWS2), SWS2平均持续时间增多,长时程睡眠(960秒)发生次数增加,而对其它时相发生次数和各时相相互转化次数无显著影响,对异相睡眠/快动眼睡眠(paradoxical sleep, PS/rapid eye move sleep, REM sleep)无改变。Propofol 5 mg/kg EEG、EMG以及睡眠图表现与10 mg/kg相似,但是SWS2时相持续时间较短,长时程觉醒被破坏,浅慢波睡眠(light slow wave sleep,SWS1)向SWS2以及SWS2向觉醒的转换此时增加。1 mg/kg propofol对睡眠觉醒行为无显著影响。 2.与生理觉醒组和生理盐水组相比,10 mg/kg propofol (10 mg/kg)组动物睡眠关键核团腹外侧视前区(ventrolateral preoptic nucleus, VLPO)区Fos-IR表达增多,觉醒相关核团结节乳头体核(tuberomammillary nucleus, TMN)、穹窿周区(perifornical nucleus, PeF),外侧下丘脑(lateral hypothalamic area, LH)、中脑导水管周围灰质腹侧(ventrolateral periaquiductal gray, vPAG)、中缝核(dorsal raphe nucleus, DRN)Fos-IR均有不同程度的降低,且具有统计学意义,与生理睡眠组动物Fos-IR表达区域类似。蓝斑(locus coeruleus, LC)、中脑被盖区(pedunculopontine tegmental bucleus, PPT)以及黑质(substantia nigra pars compacta, SNC)Fos-IR各组均无明显表达。 结论 1. Propofol剂量依赖性促进SWS2睡眠,缩短睡眠潜伏期,但对PS和SWS1睡眠无明显影响。 2. Propofol 10 mg/kg引发SWS2片段的平均持续时间和长时程发生次数增加,但改变其它时相片段发生次数及转化次数与对照组相比无显著性。提示高剂量propofol引起的睡眠主要是通过增加长时程SWS2时相的持续时间增加睡眠量。 3. Propofol 5 mg/kg引发的觉醒,SWS1和SWS2片段发生次数以及SWS1向SWS2和SWS2向觉醒转化次数显著增加,同时觉醒的平均持续时间和长时程觉醒发生次数减少。提示中剂量可能是通过破坏觉醒的发生并降低觉醒的持续时间而增加睡眠量。 4. Propofol通过激活睡眠中枢VLPO神经元和抑制觉醒中枢的结节乳头体核、穹窿周区,外侧下丘脑、中脑导水管周围灰质腹侧及中缝核而促进睡眠。
[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.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R338.63
本文编号：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.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R338.63
【参考文献】
相关期刊论文 前1条
1 汤斌,章功良,王烈成,张瑾,钟明奎,赵乐章,张景行;腹外侧视前区GABA能神经元对大鼠睡眠-觉醒周期的影响[J];安徽医科大学学报;2003年05期
，本文编号：2268110
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