【摘要】：【研究背景及目的】吸煙在我國仍然流行,中國現(xiàn)有煙民3.16億以上,并有7.24億人遭受二手煙危害。吸煙與呼吸系統(tǒng),心血管系統(tǒng)等慢性疾病密切相關(guān),長期吸煙會導(dǎo)致尼古丁依賴,中國每年超過100萬人死于煙草導(dǎo)致的相關(guān)疾病。隨著醫(yī)療技術(shù)的不斷發(fā)展,需要接受外科手術(shù)和全身麻醉治療的吸煙患者人數(shù)亦顯著增加,幾乎所有擇期手術(shù)患者需要進(jìn)行術(shù)前戒煙。吸煙與疼痛息息相關(guān),尼古丁戒斷與術(shù)后疼痛之間的關(guān)系一直是麻醉學(xué)所關(guān)注和研究的熱點。低劑量的尼古丁可以刺激中樞神經(jīng)系統(tǒng)產(chǎn)生鎮(zhèn)痛作用,其鎮(zhèn)痛作用在動物模型以及臨床試驗中都相繼被證實,但尼古丁的鎮(zhèn)痛機制尚不清楚。而尼古丁戒斷的患者卻表現(xiàn)出術(shù)后痛閾降低或痛覺過敏。一項研究表明,尼古丁戒斷患者比吸煙未戒斷者對電刺激和冷覺刺激更加敏感,疼痛閾值更低。我們在前期臨床課題“尼古丁戒斷患者圍手術(shù)期痛閾降低的單中心隊列研究”中,納入了148例因肝占位行肝臟部分切除術(shù)的男性患者,按照其吸煙史分為非吸煙組和吸煙戒斷組,觀察兩組患者圍術(shù)期痛閾變化以及術(shù)后對阿片類藥物需求量的變化。結(jié)果發(fā)現(xiàn)尼古丁戒斷患者較非吸煙患者術(shù)前基礎(chǔ)痛閾降低,術(shù)后疼痛評分增加,鎮(zhèn)痛泵消耗量增加,額外阿片類藥物需求量亦顯著增加。尼古丁戒斷為什么會導(dǎo)致痛閾降低?目前還缺少尼古丁戒斷引起痛閾降低的相關(guān)機制研究。中縫大核(NRM)是位于延髓頭端腹內(nèi)側(cè)區(qū)中央部位與疼痛調(diào)控密切相關(guān)的中樞核團(tuán),更重要的是,NRM區(qū)域富含TPH免疫反應(yīng)陽性神經(jīng)元,且5-HT是腦干內(nèi)源性疼痛調(diào)節(jié)系統(tǒng)的重要神經(jīng)遞質(zhì),可以調(diào)控機體對疼痛的感受。前期研究中我們發(fā)現(xiàn)尼古丁戒斷動物模型腦脊液中5-HT含量明顯減少,同時也發(fā)現(xiàn)尼古丁戒斷大鼠NRM處有顯著的神經(jīng)元丟失現(xiàn)象。根據(jù)前期我們發(fā)現(xiàn)的現(xiàn)象,本課題的研究目的旨在探討:尼古丁戒斷與機體痛閾變化的關(guān)系,尼古丁戒斷與NRM區(qū)神經(jīng)元丟失有何相關(guān)性,NRM區(qū)神經(jīng)元的丟失與中樞神經(jīng)遞質(zhì)5-HT的下降有何關(guān)系,以及中樞5-HT的降低與尼古丁戒斷痛閾降低的相關(guān)性�！狙芯糠椒ā�1、收集臨床病例,比較尼古丁戒斷患者與正�；颊唛g的痛閾變化及鎮(zhèn)痛藥物需求量的差異。2、在整體動物水平建立尼古丁戒斷模型并探索尼古丁戒斷大鼠是否同樣存在痛閾降低的現(xiàn)象。3、檢測尼古丁戒斷大鼠NRM區(qū)神經(jīng)元丟失情況及TPH陽性神經(jīng)元的表達(dá)情況,以及中樞內(nèi)5-HT含量變化。4、對5-HT信號通路水平進(jìn)行上調(diào)及下調(diào)實驗,探索5-HT信號通路在尼古丁戒斷機體痛閾降低中的作用機制�！狙芯拷Y(jié)果】1、尼古丁戒斷患者比正常非吸煙患者術(shù)前基礎(chǔ)痛閾降低,術(shù)后疼痛評分增加,鎮(zhèn)痛藥物需求亦顯著增加。2、尼古丁戒斷大鼠機械痛閾和熱痛閾比對照組顯著降低,并且檢測其腦脊液中神經(jīng)遞質(zhì)含量發(fā)現(xiàn)5-HT水平顯著降低。3、免疫熒光檢測尼古丁戒斷大鼠NRM區(qū)存在大量神經(jīng)元丟失,同時色氨酸羥化酶(TPH)的陽性表達(dá)亦明顯減少。4、在尼古丁戒斷大鼠痛閾降低的水平上,NRM區(qū)注射TPH過表達(dá)病毒及鞘內(nèi)給予5-HT可逆轉(zhuǎn)大鼠痛閾降低;而鞘內(nèi)注射Methysergide(5-HT受體阻斷劑)則使尼古丁戒斷大鼠痛閾水平愈加下降。【結(jié)論】本研究發(fā)現(xiàn)尼古丁戒斷機體痛閾降低,中樞內(nèi)5-HT含量明顯下降,且NRM區(qū)存在大量神經(jīng)元丟失及TPH陽性神經(jīng)元減少。證明了尼古丁戒斷機體NRM區(qū)神經(jīng)元丟失導(dǎo)致的TPH表達(dá)下降,及疼痛抑制性神經(jīng)遞質(zhì)5-HT減少是導(dǎo)致尼古丁戒斷機體痛閾降低的原因。本研究為尼古丁戒斷機體痛閾降低的相關(guān)基礎(chǔ)研究拓展新的研究方向,同時為尼古丁戒斷患者圍手術(shù)期鎮(zhèn)痛藥物的合理運用和安全鎮(zhèn)痛提供理論依據(jù)。
[Abstract]:[BACKGROUND AND OBJECTIVE] Smoking is still prevalent in China, with over 316 million smokers and 724 million people suffering from secondhand smoke. Smoking is closely related to chronic diseases such as respiratory system and cardiovascular system. Long-term smoking can lead to nicotine dependence. More than 1 million people die from tobacco-related diseases every year in China. Smoking is closely related to pain. The relationship between nicotine withdrawal and postoperative pain has always been a hot topic in anesthesiology. The analgesic effects of nicotine on the central nervous system have been confirmed in animal models and clinical trials, but the mechanism of nicotine analgesia remains unclear. Electrical stimulation and cold sensation stimulation were more sensitive and pain thresholds were lower. We included 148 male patients who underwent partial hepatectomy due to hepatic occupancy in a single-center cohort study on the reduction of pain thresholds in nicotine abstinent patients during perioperative period. They were divided into non-smoking group and smoking abstinence group according to their smoking history. The results showed that the baseline pain threshold decreased, the pain score increased, the consumption of analgesic pumps increased, and the demand for additional opioids increased significantly in nicotine abstinence patients compared with non-smokers. Why does nicotine abstinence lead to a decrease in pain threshold? More importantly, the NRM region is rich in TPH immunoreactive neurons, and 5-HT is an important neurotransmitter in the endogenous pain regulatory system of the brain stem. Previous studies showed that the content of 5-HT in the cerebrospinal fluid of nicotine withdrawal animal model was significantly reduced, and that there was significant neuronal loss in NRM of nicotine withdrawal rats. The relationship between nicotine withdrawal and neuronal loss in NRM area, the relationship between neuronal loss in NRM area and the decrease of central neurotransmitter 5-HT, and the correlation between the decrease of central 5-HT and the decrease of nicotine withdrawal pain threshold. [Methods] 1. Clinical cases were collected and compared between nicotine withdrawal patients and normal patients. Changes in pain threshold and the demand for analgesics. 2. Establishment of nicotine withdrawal model at the overall animal level and exploration of nicotine withdrawal in rats with pain threshold reduction. 3. Detection of nicotine withdrawal rats NRM neuron loss and TPH positive neuron expression, and central 5-HT content changes. 5-HT signaling pathway level was up-regulated and down-regulated to explore the mechanism of 5-HT signaling pathway in nicotine withdrawal pain threshold reduction. [Results] Compared with the control group, the mechanical pain threshold and thermal pain threshold were significantly lower, and the neurotransmitter content in the cerebrospinal fluid was significantly lower. 3. There was a large number of neuron loss in NRM area of nicotine withdrawal rats by immunofluorescence detection, and the positive expression of tryptophan hydroxylase (TPH) was also significantly decreased. 4. The pain threshold of nicotine withdrawal rats was decreased. At the same level, injection of TPH overexpression virus into NRM region and intrathecal administration of 5-HT reversed the decrease of pain threshold in rats, while intrathecal injection of methysergide (5-HT receptor blocker) made the pain threshold level of nicotine withdrawal rats decrease further. [Conclusion] This study found that the pain threshold of nicotine withdrawal rats was decreased, the content of 5-HT in the central nervous system was significantly decreased, and the NRM region was large. The loss of neurons and the decrease of TPH-positive neurons in the NRM area of nicotine abstinence rats demonstrated that the decrease of TPH expression and the decrease of pain-inhibiting neurotransmitter 5-HT were responsible for the decrease of pain threshold in nicotine abstinence rats. Direction: To provide theoretical basis for rational use of analgesics and safe analgesia in patients with nicotine abstinence during perioperative period.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R614

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