恶心呕吐是困扰肿瘤化疗的难题。小半夏汤为止呕之祖方，防治化疗性呕吐疗效确切。我们前期研究表明，5-HT3R是小半夏汤止吐的关键靶点。5-HT激动5-HT3R发生呕吐，需要5-HT3R介导的胞内信号系统的转导和放大。已知5-HT3R介导呕吐与Ca2+/CaMKII/ERK1/2信号通路的活化有关。我们认为：对5-HT3R介导的Ca2+/CaMKII/ERK1/2胞内信号通路的调控，可能是小半夏汤止吐的重要机制。本项目拟在前期工作基础上，以5-HT3R介导呕吐的胞内信号转导系统为切入点，体内外实验相结合，从整体、离体、细胞等水平，采用传统药理学与现代分子生物学相结合的实验技术，从中枢和外周，从行为学、形态、功能等方面，观察小半夏汤及其主要有效成分对5-HT3R介导呕吐的胞内信号系统的影响，深入阐明小半夏汤止呕机制。本项目对于中西医结合肿瘤防治、对于中医经方的现代研究和中药现代化均具有重要意义。

Emesis is a common and severe side effect of anticancer drugs such as cisplatin, which is usually named chemotherapy-induced nausea and vomiting (CINV). CINV is a major reason of non-complicance with cancer treatment. CINV caused by cytotoxic chemotherapeutic drugs is associated with an increase of 5-HT level centrally and peripherally. Cytotoxic drugs stimulate 5-HT release from the enterochromaffin (EC) cells in the small intestine. The released 5-HT activates 5-HT3 receptor on the end of vagal afferent nerves and induces depolarization of the vagal afferent nerves. The impulse of the vagal afferent nerves stimulates the vomiting center located in the brainstem and finally emesis occurs. It is confirmed that 5-HT and 5-HT3 receptor play a key role underlying the phathological mechanism of CINV. There are evidence indicates the pharmacological pivotal roles of 5-HT3 receptor in the control of CINV. Actually, the 5-HT3 receptor antagonists such as ondansetron, palonosetron, are the most efficient anti-emetic drugs in current clinic..Xiaobanxia Decoction (XD) is a traditional anti-emetic remedy, which is recorded in JinGuiYaoLue, a medicinal classic written by Zhang Zhongjing nearly two thousand years ago during Chinese Dong Han dynasty. XD is composed of two crude herbs, Banxia (Pinelliae tuber, Pinellia ternate (Thunb) Breit.) and Shengjiang (ginger, Zingiber officinale Roscoe). Clinical evidence has proved its potentials of anti-emetic effects, including control of CINV. Our previous studies showed that XD has a potent anti-emetic effect in cisplatin-induced rat pica and mink vomiting models, one of the key machenism underlying its anti-emetic effects is decreasing 5-HT level and downregulating 5-HT3 receptor in small intestine and brainstem..It was reported that 5-HT3 receptor-mediated emesis occurs by the activation of Ca2+/CaMKII-dependent ERK1/2 signaling pathway. According to our previous studies combined with the current literature reportings, we predict that regulating 5-HT3 receptor-mediated Ca2+/CaMKII-dependent ERK1/2 signaling pathway could be a pivotal machenism underlying XD’s anti-emetic effect..In the present applying project, we plan to explore the anti-emetic mechanism of XD focusing on 5-HT3 receptor-mediated Ca2+/CaMKII-dependent ERK1/2 transdution signals. In our potocol, intracellular Ca2+ levels in rat brainstem slices incubated with Ca2+ indicator fluo-3/AM will be observed using Laser Scanning Confocal Microscope. Male adult Wistar rat brain slices will be used to to investigate the effect of XD and its active ingredients 6-gingerol, 6-shogaol and alkaloids of Pinellia ternata on 2-Me-5-HT (a selective 5-HT3 receptor agonist) -elicited Ca2+ increase in the AP and NTS regions of the brainstem emetic nuclei. Pica models will be induced in male adult rats by intraperitoneal injection of cisplatin and 2-Me-5-HT, respectively. XD will be observed how to regulate 5-HT3 receptor-mediated Ca2+/CaMKII-dependent ERK1/2 transduction signals in above pica models. In vivo and in vitro methods will be used, including immunohistochemistry, immunoprecipitation, immunocytochemistry and Western blot on tissues of both small intestine and brainstem of rats and isolated EC cells from rat small intestine..The purpuse of the present project will be evaluating XD how to regulate 5-HT3 receptor-mediated Ca2+/CaMKII-dependent ERK1/2 signaling pathway underlying its anti-emetic mechanism. The research results will be helpful to improve the control of CINV in clinic. The project will be an good example of studying classical prescription using modern methods, and will facilitate to modernize traditional Chinese herbs.