5-HT下行调控通路在尼古丁戒断机体痛阈降低中的机制研究
发布时间：2018-08-23 09:09
【摘要】：【研究背景及目的】吸烟在我国仍然流行,中国现有烟民3.16亿以上,并有7.24亿人遭受二手烟危害。吸烟与呼吸系统,心血管系统等慢性疾病密切相关,长期吸烟会导致尼古丁依赖,中国每年超过100万人死于烟草导致的相关疾病。随着医疗技术的不断发展,需要接受外科手术和全身麻醉治疗的吸烟患者人数亦显著增加,几乎所有择期手术患者需要进行术前戒烟。吸烟与疼痛息息相关,尼古丁戒断与术后疼痛之间的关系一直是麻醉学所关注和研究的热点。低剂量的尼古丁可以刺激中枢神经系统产生镇痛作用,其镇痛作用在动物模型以及临床试验中都相继被证实,但尼古丁的镇痛机制尚不清楚。而尼古丁戒断的患者却表现出术后痛阈降低或痛觉过敏。一项研究表明,尼古丁戒断患者比吸烟未戒断者对电刺激和冷觉刺激更加敏感,疼痛阈值更低。我们在前期临床课题“尼古丁戒断患者围手术期痛阈降低的单中心队列研究”中,纳入了148例因肝占位行肝脏部分切除术的男性患者,按照其吸烟史分为非吸烟组和吸烟戒断组,观察两组患者围术期痛阈变化以及术后对阿片类药物需求量的变化。结果发现尼古丁戒断患者较非吸烟患者术前基础痛阈降低,术后疼痛评分增加,镇痛泵消耗量增加,额外阿片类药物需求量亦显著增加。尼古丁戒断为什么会导致痛阈降低?目前还缺少尼古丁戒断引起痛阈降低的相关机制研究。中缝大核(NRM)是位于延髓头端腹内侧区中央部位与疼痛调控密切相关的中枢核团,更重要的是,NRM区域富含TPH免疫反应阳性神经元,且5-HT是脑干内源性疼痛调节系统的重要神经递质,可以调控机体对疼痛的感受。前期研究中我们发现尼古丁戒断动物模型脑脊液中5-HT含量明显减少,同时也发现尼古丁戒断大鼠NRM处有显著的神经元丢失现象。根据前期我们发现的现象,本课题的研究目的旨在探讨:尼古丁戒断与机体痛阈变化的关系,尼古丁戒断与NRM区神经元丢失有何相关性,NRM区神经元的丢失与中枢神经递质5-HT的下降有何关系,以及中枢5-HT的降低与尼古丁戒断痛阈降低的相关性。【研究方法】1、收集临床病例,比较尼古丁戒断患者与正常患者间的痛阈变化及镇痛药物需求量的差异。2、在整体动物水平建立尼古丁戒断模型并探索尼古丁戒断大鼠是否同样存在痛阈降低的现象。3、检测尼古丁戒断大鼠NRM区神经元丢失情况及TPH阳性神经元的表达情况,以及中枢内5-HT含量变化。4、对5-HT信号通路水平进行上调及下调实验,探索5-HT信号通路在尼古丁戒断机体痛阈降低中的作用机制。【研究结果】1、尼古丁戒断患者比正常非吸烟患者术前基础痛阈降低,术后疼痛评分增加,镇痛药物需求亦显著增加。2、尼古丁戒断大鼠机械痛阈和热痛阈比对照组显著降低,并且检测其脑脊液中神经递质含量发现5-HT水平显著降低。3、免疫荧光检测尼古丁戒断大鼠NRM区存在大量神经元丢失,同时色氨酸羟化酶(TPH)的阳性表达亦明显减少。4、在尼古丁戒断大鼠痛阈降低的水平上,NRM区注射TPH过表达病毒及鞘内给予5-HT可逆转大鼠痛阈降低;而鞘内注射Methysergide(5-HT受体阻断剂)则使尼古丁戒断大鼠痛阈水平愈加下降。【结论】本研究发现尼古丁戒断机体痛阈降低,中枢内5-HT含量明显下降,且NRM区存在大量神经元丢失及TPH阳性神经元减少。证明了尼古丁戒断机体NRM区神经元丢失导致的TPH表达下降,及疼痛抑制性神经递质5-HT减少是导致尼古丁戒断机体痛阈降低的原因。本研究为尼古丁戒断机体痛阈降低的相关基础研究拓展新的研究方向,同时为尼古丁戒断患者围手术期镇痛药物的合理运用和安全镇痛提供理论依据。
[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.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R614
本文编号：2198577
[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.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R614
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