小半夏汤多靶点抗呕吐作用及胞内信号转导机制的研究

Vomiting is one of mankind's most excruciating pain responses in the clinic. Take vomiting induced by chemotherapy drugs for example, the rate of it can up to 70%-90%. The current clinical antiemetic drugs commonly are single receptor antagonists.These drugs are endowed with limit range usually have many side effects and have to be given in conbination with other agents. It has been proved that the abnormal expression of 5-TH,SP and DA and their receptors are the essential factors called "Triple mechanism"of vomiting. And It has been proved that Xiao-ban-xia-tang, a traditional chinese herbal medicine, can prevent acute and delayed emesis in minks and intervene the abnormal expression of 5-HT,SP and DA, leaved the mechanism to be elucidated..Basised on our preliminary studies, we put forward this issue aimed at revealing and clarifying the muti-target anti-vomiting mechanism of Xiao-ban-xia-tang, using the new mink vomiting model and classic rat pica model, with the help of traditional pharmacological methods and modern bilolgy techniques, making 5-HT, SP, DA and their receptors as main line and TPH-2,NEP,TH as starting point. The point idex of our issue are posecond messenger (cAMP,IP3, Ca2+) of G protein-coupled pathway, membrane potential of ligand-gated ion channels and sodium and potassium flow,to expound the anti-vomiting mechanism which provides the material basis of scientific evidence and new understanding.

呕吐是人类难以忍受的痛苦反应，常见于多种疾病，如肿瘤化疗致呕率可达70%-90%。目前临床止呕药多是单一受体抑制剂，存在靶点单一、副作用大、应用范围受限等问题。研究表明，5-HT、SP、DA及其受体异常表达为呕吐发生最重要的三重机制。我们前期研究发现止呕名方小半夏汤能有效抑制水貂急性和延迟性呕吐，作用与干预5-HT、SP、DA表达有关具体机制亟需研究。.本课题依托前期研究，采用水貂呕吐模型结合大鼠异嗜模型，以特异性激动剂为工具药，从中枢脑组织、外周胃肠组织两个部位，运用小半夏汤与其有效成分相参照的方法，以5-HT、SP、DA及其受体为主线，以TPH-2、NEP、TH等为切入点，以干预胞内G蛋白偶联下游信号转导第二信使cAMP、IP3、Ca2+和配体门控通道膜电位及钠钾流为指标，以期深入探索小半夏汤多靶点止呕作用机制，揭示其药效物质基础和作用靶点，为阐明其止呕药效机制提供科学证据和新的认识。

呕吐是人类难以忍受的痛苦反应，常见于多种疾病，如肿瘤化疗致呕率可达70%-90%。目前临床止呕药多是单一受体抑制剂，存在靶点单一、副作用大、应用范围受限等问题。本课题在前期研究的基础上，采用新型水貂呕吐模型，结合大鼠异嗜模型，以特异性激动剂为工具药，以5-HT3、D2受体拮抗剂为阳性对照药，从中枢脑组织、外周胃肠组织两个部位，动物实验和细胞转导两个方面，运用小半夏汤与小半夏汤有效成分相互参照的方法，利用传统药理学方法和现代分子生物学技术，以5-HT、SP、DA及其受体为主线，探讨小半夏汤多靶点抗呕吐作用；以TPH-2、SERT、PPT、NEP、TH及DAT等为切入点，探讨其多靶点调控机制；并从分子生物学层面，以胞内G蛋白偶联下游信号转导第二信使Ca2+为指标，探讨其胞内信号转导机制。以期深入探索小半夏汤多靶点抗呕吐作用机制，揭示其止呕的药效物质基础和作用靶点，为阐明中药复方小半夏汤止呕药效作用机制，提供科学证据和新的认识。