【摘要】：目的：神經(jīng)病理性疼痛是指由軀體感覺神經(jīng)系統(tǒng)的損傷或疾病而直接引起的疼痛綜合征，通常呈慢性，患者常伴有由于痛覺引發(fā)不同程度的睡眠障礙和情緒異常。普瑞巴林（Pregabalin，PGB）為γ-氨基丁酸（Gamma-aminobutyric acid，GABA）類藥物，作為一種癲癇病的治療藥物在英美等國已成功上市。本課題擬在成功建立動物神經(jīng)病理性疼痛（坐骨神經(jīng)部分結(jié)扎）模型的基礎(chǔ)上，深入的考察普瑞巴林對神經(jīng)病理性疼痛及其引起的睡眠障礙的治療作用，并探討其可能機(jī)制。 方法：采用小鼠坐骨神經(jīng)部分結(jié)扎術(shù)（Partial sciatic nerve ligation，PSL）建立神經(jīng)病理性疼痛小鼠模型；在此基礎(chǔ)結(jié)合高度自動化睡眠覺醒記錄與解析系統(tǒng)，建立神經(jīng)痛性睡眠障礙小鼠模型。通過測定小鼠機(jī)械痛閾和熱痛潛伏期觀察普瑞巴林對PSL模型小鼠熱痛敏、機(jī)械痛敏的改善作用。并通過分析睡眠時間與覺醒時間、睡眠結(jié)構(gòu)、睡眠波能譜（睡眠深度）、睡眠時相轉(zhuǎn)換等指標(biāo)探討普瑞巴林對PSL模型小鼠日間入睡期（07:00-11:00）睡眠障礙的改善作用；以及普瑞巴林對PSL模型小鼠和正常小鼠夜間活動期（21:00-01:00）睡眠覺醒結(jié)構(gòu)的影響。利用免疫組織化學(xué)方法觀察普瑞巴林對入睡期PSL模型小鼠前扣帶回皮層（Anteriorcingulate cortex，ACC）c-Fos陽性神經(jīng)元數(shù)量的影響。 結(jié)果：①PSL模型小鼠出現(xiàn)持續(xù)一個月的觸發(fā)痛覺過敏、熱痛覺過敏以及日間入睡期睡眠障礙癥狀。②于09:00灌胃給予普瑞巴林（25mg/kg）使PSL模型小鼠給藥后第3h機(jī)械痛閾增加3.1倍，熱痛潛伏期延長59%，且不影響PSL模型小鼠Rota-rod停留時間。③于06:30灌胃給予普瑞巴林（25mg/kg）使PSL模型小鼠在入睡期（07:00-11:00）非快速動眼（non rapid eye movement，NREM）睡眠量增加40%，覺醒量減少38%；長時程N(yùn)REM睡眠、快速動眼（rapid eyemovement，REM）睡眠片段數(shù)量增加；覺醒片段總數(shù)減少；NREM睡眠向覺醒轉(zhuǎn)換次數(shù)減少，，NREM睡眠向REM睡眠轉(zhuǎn)換次數(shù)增加。④于20:30灌胃給予普瑞巴林（25mg/kg）不影響正常小鼠和PSL模型小鼠活動期（21:00-01:00）睡眠覺醒結(jié)構(gòu)。⑤于06:30灌胃給予普瑞巴林（25mg/kg）能顯著降低PSL模型小鼠ACC區(qū)域c-Fos陽性神經(jīng)元數(shù)量。 結(jié)論：普瑞巴林對神經(jīng)病理性疼痛模型小鼠具有顯著的鎮(zhèn)痛作用。普瑞巴林產(chǎn)生鎮(zhèn)痛作用的同時，能有效改善痛覺誘發(fā)的睡眠障礙癥狀。普瑞巴林的鎮(zhèn)痛及促眠作用可能與抑制神經(jīng)病理性疼痛模型動物前扣帶回皮層神經(jīng)元異常性興奮有關(guān)。
[Abstract]:Objective: neuropathic pain is a kind of pain syndrome caused directly by the injury or disease of somatosensory nervous system. PreBahrain (Pregabalin,PGB) is a kind of 緯-aminobutyric acid (Gamma-aminobutyric acid,GABA). As an epileptic drug, it has been successfully listed in Britain and America. Based on the successful establishment of animal model of neuropathic pain (partial ligation of sciatic nerve), the therapeutic effect of PreBahrain on neuropathic pain and its sleep disorder was investigated and its possible mechanism was discussed. Methods: the mouse model of neuropathic pain was established by partial ligation of sciatic nerve (Partial sciatic nerve ligation,PSL), and the model of neuropathic sleep disorder was established based on the highly automated sleep arousal recording and analysis system. By measuring the mechanical pain threshold and the latent period of heat pain in mice, the effect of Preabine on the improvement of thermal pain sensitivity and mechanical pain sensitivity in PSL model mice was observed. By analyzing sleep time and wakefulness time, sleep structure, sleep wave energy spectrum (sleep depth), sleep phase transformation, etc., the effect of Pregabin on sleep disorder in PSL model mice during daytime sleep period (07: 00-11: 00) was studied. And the effects of PreBahrain on the structure of sleep arousal in PSL model mice and normal mice during nocturnal activity (21: 00-01: 00). The effect of Premarin on the number of c-Fos positive neurons in the anterior cingulate cortex (Anteriorcingulate cortex,ACC) of PSL model mice during sleep was observed by immunohistochemical method. Results: 1PSL model mice developed a one-month trigger of hyperalgesia. The symptoms of hyperthermia and sleep disturbance during daytime sleep. (2) at 09:00, 25mg/kg was administered intragastrically to PSL model mice. The mechanical pain threshold was increased by 3.1 times, and the latent period of heat pain was prolonged by 59 times at the 3rd hour after administration of the drug in PSL model mice. The Rota-rod residence time of PSL model mice was not affected. 3 25mg/kg was given intragastric at 06:30 to increase the sleep volume of PSL model mice during the sleep period (07: 00-11: 00) non-REM (non rapid eye movement,NREM. The arousal decreased by 38. In long-term NREM sleep, the number of rapid eye movement (rapid eyemovement,REM) sleep fragments increased, and the total number of wakefulness fragments decreased. The conversion of NREM sleep to arousal decreased, The conversion of NREM sleep to REM sleep increased. 4 25mg/kg was given orally at 20:30 without affecting the awake structure of normal mice and PSL model mice during the active period (21: 00-01: 00). Gastric administration of 25mg/kg could significantly reduce the number of c-Fos positive neurons in the ACC region of PSL model mice. Conclusion: Premarin has a significant analgesic effect on neuropathic pain model mice. The analgesic effect of PreBahrain can effectively improve the symptoms of sleep disorder induced by pain. The analgesic and hypnotic effects of Premarin may be related to the inhibition of abnormal sexual excitability of cortical neurons in the anterior cingulate cortex of neuropathic pain model animals.
【學(xué)位授予單位】：皖南醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R965

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