下丘脑弓状核-延髓背侧迷走复合体Orexin通路构成及抑制呕吐调控研究

Vomiting is one of the most common clinical syndrome, and the severe vomiting (such as chemotherapy induced vomiting) can aggravate the illness and decrease the curative effect. Until now, it is unclear about the complex pathogenic mechanism of vomiting. It was showed in the recent studies that hypothalamus plays an important role in regulating the vomiting center in the medulla, and the gut-brain peptide Orexin could regulate vomiting by influencing the gastrointestinal motility. Our works has found that the Orexin immunoreactive neurons in ARC projected fibers into the dorsal vagal complex (DVC) in the medulla, and electrical stimulation in ARC improved the discharging of orexin-gastric distention responsive neurons in the DVC , enhanced the gastric motility and relieved the cisplatin-induced vomiting significantly in rat. These results suggested that there might be an orexinergic neural/functional pathway between ARC and DVC, and it is involved in the modulation of vomiting. In this study the techniques such as extracellular discharge recording, fluorescent retrograde tracing combined with immunohistochemistry and gastric motility recording in vivo are applied to investigate the constitution of orexinergic neural/functional pathway from ARC to DVC and the mechanism of orexin in regulating vomiting via this pathway. The object is to supplement the central regulating theory of vomiting, and find a novel targeting for prevention and cure of the chemotherapy-induced vomiting.

呕吐是临床常见症状之一，严重呕吐（如化疗性呕吐等）不但使病情加重，且影响治疗效果。呕吐发病机制复杂，至今尚未完全阐明。近年研究显示，下丘脑在调控延髓呕吐中枢方面具有重要作用，且脑肠肽增食欲素（Orexin）可通过影响胃肠动力参与呕吐调控。我们前期研究显示，下丘脑弓状核（ARC）内Orexin神经元可发出纤维投射至延髓呕吐中枢背侧迷走复合体（DVC）；电刺激ARC显著改变DVC内Orexin-胃牵张相关神经元放电活动，并使顺铂致呕吐大鼠胃运动加强，呕吐症状减轻。结果提示，ARC-DVC可能存在Orexin通路；Orexin在该通路可能参与呕吐的调控。本课题拟采用单细胞外放电记录、荧光逆行示踪结合免疫组化染色、在体胃运动等方法，探讨ARC–DVC Orexin神经/功能通路的构成，以及Orexin在该通路对呕吐的调控及机制，目的是补充和完善呕吐中枢调控理论，为化疗性呕吐防治提供新的策略和靶点。

呕吐是临床常见症状之一，严重呕吐（如化疗性呕吐等）不但使病情加重，且影响治疗效果，其发病机制复杂。下丘脑在调控延髓呕吐中枢方面具有重要作用，且脑肠肽增食欲素（Orexin）可通过影响胃肠动力参与呕吐调控。本课题焦点是探讨弓状核（ARC）–背侧迷走复合体（DVC）Orexin神经/功能通路的构成，以及Orexin在该通路对呕吐的调控及机制，目的是补充和完善呕吐中枢调控理论，为化疗性呕吐防治提供新的策略和靶点。. 研究发现，ARC-DVC间存在Orexin神经通路和功能通路，其参与化疗呕吐的发病过程。顺铂可使大鼠高岭土摄入增加，食物摄入减少，血浆中Orexin-A水平下降，且呈量效依赖关系。DVC中孤束核（NTS）微量注射Orexin-A可促进化疗性呕吐大鼠胃运动和胃排空。ARC注射 Orexin-A可有效抑制呕吐模型组大鼠高岭土摄入量，并可改善顺铂对胃运动的抑制，该效应可通过Orexin-A受体发挥作用。Orexin-A受体拮抗剂SB-408124可部分阻断电刺激ARC对NTS内Orexin-A反应的GD神经元的兴奋作用。电刺激ARC 可使大鼠胃运动幅度和频率均显著增强，DVC预先注射SB-408124可部分阻断这种作用。研究还发现，ARC Orexin-A调控呕吐作用可能与下游NPY1受体信号传导有关。. 研究成果在国际SCI期刊发表论文11篇，国内核心期刊发表论文3篇，并在国内外会议上交流，得到同行专家的关注和认可。该研究不仅为脑肠肽的基础研究奠定了基础，还为化疗性呕吐的防治提供了实验依据。本项目协助培养1位博士研究生和3位硕士研究生。.