Novel direct vago-vagal recording of i.v. ghrelin action

描述（由申请人提供）：胃内分泌细胞释放肠道激素ghrelin，作为生长激素促分泌素受体（GHS-R）的内源性配体。胃饥饿素循环水平的增加与饥饿感、食物摄入和胃排空的增加相关。由于术后胃梗阻的临床重要性和缺乏有效的促动力治疗，后者的功能是令人感兴趣的。生长激素释放肽加速胃排空的机制已经使用许多生理学方法进行了研究，并且已经确定了迷走神经的重要作用，但是迄今为止没有发表的研究直接研究了由生长激素释放肽引起的迷走传出或单个单位传入活动，因此，响应于生长激素释放肽的迷走信号传导的细节仍然不清楚。此外，我们实验室和其他实验室获得的初步数据与最初发表的假设相矛盾，即ghrelin的促动力作用机制取决于迷走神经传入输入。拟议的工作将调查详细的内脏神经元信号引起的系统生长激素释放肽管理，使用我们最近开发的两种新技术的组合：胃超声显微镜监测运动，和一个独特的双记录技术，允许同时监测单个单位迷走神经传出和传入活动。实验将检验以下假设：1）系统性生长激素释放肽中枢作用以增加迷走神经传出活动，2）不需要迷走神经或内脏传入输入来介导这种迷走神经传出兴奋，3）系统性生长激素释放肽作用于尾侧脑干中的GHS-R以增加迷走神经传出流出，和4）通过迷走神经介导的和迷走神经非依赖性机制的组合发生由生长素释放肽诱发的增加的胃运动。这项工作将表征迷走神经传入和传出纤维类型的特定亚类，其活性被系统性生长激素释放肽修饰。技术的组合将允许辨别传入和传出放电与离散胃区域（包括括约肌）中的运动之间的时间关系，并且将区分经由迷走神经依赖性和非依赖性途径介导的胃区域和括约肌运动的组分。这项工作将直接解决介导ghrelin对运动的影响的神经机制，并提供了一个新的方法来理解迷走神经和内分泌信号在肠道功能的调制广泛的肠道激素的综合作用的基础。

DESCRIPTION (provided by applicant): The gut hormone ghrelin is released by gastric endocrine cells and acts as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Increased circulating levels of ghrelin are associated with increased hunger, food intake, and gastric emptying. This latter function is of interest due to the clinical importance of postoperative gastric ileus and the lack of effective prokinetic therapies. The mechanisms by which ghrelin accelerates gastric emptying have been investigated using a number of physiological approaches, and an important role for the vagus nerve has been identified, but no published study to date has directly investigated vagal efferent nor single unit afferent activity evoked by ghrelin, and thus, details of vagal signaling in response to ghrelin remain obscure. Moreover, preliminary data obtained by our laboratory and others contradict the initial published hypothesis that the mechanism of ghrelin's prokinetic action depends on vagal afferent input. The proposed work will investigate the detailed visceral neuronal signaling evoked by systemic ghrelin administration, using a combination of two novel techniques we have recently developed: gastric ultrasonomicrometry to monitor motility, and a unique dual recording technique allowing simultaneous monitoring of single unit vagal efferent and afferent activity. The experiments will test the hypotheses that 1) systemic ghrelin acts centrally to increase vagal efferent activity, 2) that neither vagal nor splanchnic afferent input is required to mediate this vagal efferent excitation, 3) that systemic ghrelin acts at GHS-R in the caudal brainstem to increase vagal efferent outflow, and 4) that increased gastric motility evoked by ghrelin occurs via a combination of vagally-mediated and vagal-independent mechanisms. The work will characterize the particular subclasses of vagal afferent and efferent fiber types whose activity is modified by systemic ghrelin. The combination of techniques will allow discrimination of temporal relationships between afferent and efferent discharge and motility in discrete gastric regions, including sphincters, and will distinguish the components of gastric regional and sphincter motility mediated via vagal- dependent and -independent pathways. This work will directly address the neural mechanisms mediating ghrelin's effects on motility, and provide a foundation for a new approach to understanding the integrated role of vagal and endocrine signaling in the modulation of gut function by a wide range of gut hormones.