乳香酸治疗神经病理性痛和磷丙泊酚钠-阿芬太尼协同镇痛作用研究
发布时间：2018-11-19 18:13
【摘要】：上篇:乳香酸治疗神经病理性痛的作用及机制研究背景:神经病理性疼痛(Neuropathic pain)是疼痛中最难治疗、最为复杂的类型,严重危害人类身心健康,影响生活质量,是当前神经科学研究的热点。神经病理性痛发生发展机制及治疗靶点尚未完全阐明,临床尚无明显有效的治疗药物和措施。目前应用于临床的治疗药物和策略治疗效果差强人意,且伴随着众多药物副作用。因此,探索研发针对性治疗药物对神经病理性疼痛的治疗具有重要意义。神经胶质细胞炎性反应是神经病理性疼痛产生和维持的关键。前期研究证实中药乳香的最重要有效成分群乳香酸具有强大的抗炎和抗肿瘤作用,但尚未有研究阐述其对神经病理性疼痛治疗效果如何,本实验拟探讨乳香酸对神经病理性疼痛的作用和机制,从而为神经病理性疼痛针对性治疗药物的研发提供理论和实验依据。方法:本研究基于小鼠坐骨神经分支选择性损伤模型(spared nerve injury,SNI)所诱导的神经病理性痛,应用von Frey及热刺激行为学测试,观察口服给予乳香酸对小鼠基础痛阈和SNI所致的神经病理性痛的影响。通过免疫组织化学和Western blot检测乳香酸对正常和SNI小鼠脊髓背角星形胶质细胞活化的影响,以及p JNK表达的情况,通过ELISA检测乳香酸对炎症因子(IL-6、IL-1β和TNF-α)以及MCP-1表达变化的影响。结果:行为学结果显示乳香酸剂量依赖性的降低SNI诱导的机械性痛觉敏感和热痛觉敏感。结合免疫组织化学实验结果和Western blot定量检测结果发现乳香酸可以降低SNI诱导的星形胶质细胞活化,降低纤维酸性蛋白(glial fibrillary acidic protein,GFAP)的表达。乳香酸可以剂量依赖性的抑制SNI诱导的星形胶质细胞JNK通路的激活,以及炎症因子(IL-6、IL-1β和TNF-α)和MCP-1的表达。结论:综上所述,乳香酸通过抑制脊髓背角星形胶质细胞内JNK信号通路的活化,缓解由SNI诱导的神经病理性痛。下篇:磷丙泊酚钠-阿芬太尼协同镇痛作用研究背景:临床麻醉的主流趋势是复合麻醉,即联合使用两种以上的麻醉药物来达到理想效果的麻醉方式。复合麻醉以期几种药物同时使用时能够产生协同作用,比如麻醉诱导更迅速,麻醉维持更平稳,不良反应更少,应用更安全。丙泊酚(Propofol)因其起效迅速、诱导平稳、苏醒快等优点常和阿片类药物应用于各类手术麻醉,但在临床中发现丙泊酚存在呼吸抑制、注射痛以及丙泊酚输注综合征等不良反应。磷丙泊酚钠(Fospropofol)是丙泊酚的一种水溶性前药,静脉注射之后几分钟内代谢为活性药物丙泊酚,磷丙泊酚钠具有更好的安全性,更适用于那些不需要立刻起效但是需要维持时间较长的手术麻醉。磷丙泊酚钠与阿片类药物之间的相互作用研究鲜少有文献报道。本实验拟根据药效学结论,采用等辐射分析的方法来验证二者联用是否能够产生药效的镇痛协同效应,为研发具有镇静镇痛作用的复合麻醉药物提供理论和实验依据。方法:本研究采用热板法、热辐射甩尾法和福尔马林实验研究磷丙泊酚钠和阿芬太尼以及二者联用的镇痛作用。通过对数剂量效应曲线计算出磷丙泊酚钠和阿芬太尼的镇痛ED50,按照固定比例(1,1/2,1/4,1/8)物理混合两药,计算混合药物的镇痛ED50。应用等辐射分析法(Isobologrphic analysis)研究两种药物镇痛相互作用。结果:在三种疼痛模型中磷丙泊酚钠和阿芬太尼均可明显缓解疼痛的发生,并呈剂量依赖性。通过等辐射分析法发现三种疼痛模型中的ED50mix均显著小于ED50add(P0.05)相互作用指数γ均小于1。结论:综上所述,磷丙泊酚钠和阿芬太尼具有协同镇痛作用,这为磷丙泊酚钠-阿芬太尼复方制剂的研发提供了一定的理论依据。
[Abstract]:Previous: Neuropathy pain (Neuropathic Pain) is the most difficult to treat in pain. Neuropathy pain is the most difficult to treat in pain. It is the most complicated type, which seriously affects the physical and mental health of human and affects the quality of life. It is a hot spot in the research of the present neuroscience. The mechanism of the development of the neuropathic pain and the therapeutic target have not been fully set out, and there is no obvious and effective treatment of the drugs and measures in the clinic. The present invention is applied to the treatment of the medicine and the treatment effect of the strategy, and is accompanied by many side effects of the medicine. Therefore, it is of great significance to explore the treatment of neuropathic pain by research and development of targeted therapeutic drugs. The inflammatory response of glial cells is the key to the generation and maintenance of neuropathic pain. The preliminary study confirmed that the most important effective component group of the traditional Chinese medicine frankincense has strong anti-inflammatory and anti-tumor effects, but has not yet studied how to effect the treatment effect on the neuropathic pain, and the experiment is to explore the role and mechanism of the frankincense acid on the neuropathic pain, so as to provide a theoretical and experimental basis for the research and development of the drug for the treatment of the neuropathic pain. Methods: The effects of oral administration of boswellic acid on the base pain threshold of mice and the neuropathic pain caused by SNI were observed based on the neuropathic pain induced by the selective injury model (SNI) of the sciatic nerve of mice. The effect of boswellic acid on the activation of the dorsal horn of spinal cord in normal and SNI mice and the expression of p-JNK were detected by immunohistochemistry and Western blot, and the effect of the expression of frankincense on the inflammatory factors (IL-6, IL-1 and TNF-1) and the expression of MCP-1 was detected by ELISA. Results: The results of behavior show that the dose-dependent decrease of the dose-dependent mechanical hyperalgesia and thermal hyperalgesia induced by SNI. The results of immunohistochemistry and Western blot were used to detect the activation of the astrocyte induced by SNI and to decrease the expression of the fiber acidic protein (GFAP). The boswellic acid can inhibit the activation of the JNK pathway of the astrocytes induced by SNI and the expression of the inflammatory factors (IL-6, IL-1 and TNF-1) and MCP-1 in a dose-dependent manner. Conclusion: In conclusion, the activation of the JNK signaling pathway in the astrocytes of the spinal dorsal horn of the spinal cord is inhibited, and the neuropathic pain induced by the SNI is relieved. Background: The main trend of clinical anesthesia is compound anesthesia, that is, the combination of more than two kinds of narcotic drugs to achieve the desired effect. The compound anesthesia can produce a synergistic effect in the simultaneous use of several medicines, such as more rapid anesthesia induction, more stable and more stable anesthesia, less adverse reaction and safer application. Propanol has the advantages of rapid onset of action, stable induction and fast recovery, and the application of opioids in all kinds of surgical anesthesia, but it is found in the clinic that there are adverse reactions such as the respiratory depression, the injection pain, and the propofol infusion syndrome. Focopodool is a water-soluble pre-drug for propafenol, which is metabolically active in a few minutes after intravenous injection, which has better safety and is more suitable for those who do not need immediate action but require longer maintenance time. The study of the interaction between the sodium and the opioids is less and less reported. Based on the results of the pharmacodynamics, it is proposed to use the method of equal radiation analysis to verify whether the combination of the two drugs can produce the analgesic synergistic effect of the drug effect, and provides the theoretical and experimental basis for the research and development of the compound anesthetic drugs with the effects of sedation and analgesia. Methods: The analgesic effects of P-and-Fentanyl and Fentanyl were studied by hot plate method, heat radiation tail-throwing method and formalin test. The analgesic ED50 of P-and Fentanyl was calculated by the log-dose effect curve, and the analgesic ED50 of the mixed drug was calculated according to the fixed ratio (1, 1/ 2, 1/ 4, 1/ 8). Isothermal analysis was used to study the analgesic interaction of two drugs. Results: In the three pain models, both P-and Fentanyl could alleviate the occurrence of pain and dose-dependently. The ED50mix in the three pain models was significantly lower than that of ED50add (P0.05). Conclusion: To sum up, the co-analgesic effect of P-propafenone and Fentanyl is a theoretical basis for R & D of the compound preparation of P-propafenone and Fentanyl.
【学位授予单位】：第四军医大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R96
[Abstract]:Previous: Neuropathy pain (Neuropathic Pain) is the most difficult to treat in pain. Neuropathy pain is the most difficult to treat in pain. It is the most complicated type, which seriously affects the physical and mental health of human and affects the quality of life. It is a hot spot in the research of the present neuroscience. The mechanism of the development of the neuropathic pain and the therapeutic target have not been fully set out, and there is no obvious and effective treatment of the drugs and measures in the clinic. The present invention is applied to the treatment of the medicine and the treatment effect of the strategy, and is accompanied by many side effects of the medicine. Therefore, it is of great significance to explore the treatment of neuropathic pain by research and development of targeted therapeutic drugs. The inflammatory response of glial cells is the key to the generation and maintenance of neuropathic pain. The preliminary study confirmed that the most important effective component group of the traditional Chinese medicine frankincense has strong anti-inflammatory and anti-tumor effects, but has not yet studied how to effect the treatment effect on the neuropathic pain, and the experiment is to explore the role and mechanism of the frankincense acid on the neuropathic pain, so as to provide a theoretical and experimental basis for the research and development of the drug for the treatment of the neuropathic pain. Methods: The effects of oral administration of boswellic acid on the base pain threshold of mice and the neuropathic pain caused by SNI were observed based on the neuropathic pain induced by the selective injury model (SNI) of the sciatic nerve of mice. The effect of boswellic acid on the activation of the dorsal horn of spinal cord in normal and SNI mice and the expression of p-JNK were detected by immunohistochemistry and Western blot, and the effect of the expression of frankincense on the inflammatory factors (IL-6, IL-1 and TNF-1) and the expression of MCP-1 was detected by ELISA. Results: The results of behavior show that the dose-dependent decrease of the dose-dependent mechanical hyperalgesia and thermal hyperalgesia induced by SNI. The results of immunohistochemistry and Western blot were used to detect the activation of the astrocyte induced by SNI and to decrease the expression of the fiber acidic protein (GFAP). The boswellic acid can inhibit the activation of the JNK pathway of the astrocytes induced by SNI and the expression of the inflammatory factors (IL-6, IL-1 and TNF-1) and MCP-1 in a dose-dependent manner. Conclusion: In conclusion, the activation of the JNK signaling pathway in the astrocytes of the spinal dorsal horn of the spinal cord is inhibited, and the neuropathic pain induced by the SNI is relieved. Background: The main trend of clinical anesthesia is compound anesthesia, that is, the combination of more than two kinds of narcotic drugs to achieve the desired effect. The compound anesthesia can produce a synergistic effect in the simultaneous use of several medicines, such as more rapid anesthesia induction, more stable and more stable anesthesia, less adverse reaction and safer application. Propanol has the advantages of rapid onset of action, stable induction and fast recovery, and the application of opioids in all kinds of surgical anesthesia, but it is found in the clinic that there are adverse reactions such as the respiratory depression, the injection pain, and the propofol infusion syndrome. Focopodool is a water-soluble pre-drug for propafenol, which is metabolically active in a few minutes after intravenous injection, which has better safety and is more suitable for those who do not need immediate action but require longer maintenance time. The study of the interaction between the sodium and the opioids is less and less reported. Based on the results of the pharmacodynamics, it is proposed to use the method of equal radiation analysis to verify whether the combination of the two drugs can produce the analgesic synergistic effect of the drug effect, and provides the theoretical and experimental basis for the research and development of the compound anesthetic drugs with the effects of sedation and analgesia. Methods: The analgesic effects of P-and-Fentanyl and Fentanyl were studied by hot plate method, heat radiation tail-throwing method and formalin test. The analgesic ED50 of P-and Fentanyl was calculated by the log-dose effect curve, and the analgesic ED50 of the mixed drug was calculated according to the fixed ratio (1, 1/ 2, 1/ 4, 1/ 8). Isothermal analysis was used to study the analgesic interaction of two drugs. Results: In the three pain models, both P-and Fentanyl could alleviate the occurrence of pain and dose-dependently. The ED50mix in the three pain models was significantly lower than that of ED50add (P0.05). Conclusion: To sum up, the co-analgesic effect of P-propafenone and Fentanyl is a theoretical basis for R & D of the compound preparation of P-propafenone and Fentanyl.
【学位授予单位】：第四军医大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R96
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