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

描述（申请人提供）：胃促生长素是由胃内分泌细胞释放的一种肠道激素，是生长激素促分泌受体（GHS-R）的内源性配体。胃饥饿素循环水平升高与饥饿感、食物摄入和胃排空增加有关。由于术后胃肠梗阻的临床重要性和缺乏有效的促动力治疗，后一种功能引起了人们的兴趣。胃饥饿素加速胃排空的机制已经通过许多生理学方法进行了研究，并且迷走神经的重要作用已经被确定，但迄今为止还没有发表的研究直接研究胃饥饿素引起的迷走神经传出或单一单位传入活动，因此，对胃饥饿素的迷走神经信号反应的细节仍然不清楚。此外，我们实验室和其他人获得的初步数据与最初发表的假设相矛盾，即胃饥饿素的促动力学作用机制取决于迷走神经传入输入。本研究将使用我们最近开发的两种新技术：胃超声显微法监测胃运动，以及一种独特的双记录技术，允许同时监测单个单位迷走神经传出和传入活动，研究由全身胃饥饿素给药引起的内脏神经元信号传导的详细情况。实验将验证以下假设：1)全身性胃饥饿素通过中枢作用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迷走神经传出兴奋；3)全身性胃饥饿素通过尾侧脑干的GHS-R作用增加迷走神经传出输出；4)胃饥饿素引起的胃运动增加是通过迷走神经介导和迷走神经独立机制的结合发生的。这项工作将描述迷走神经传入和传出纤维类型的特定亚类，其活性被全身胃饥饿素修饰。这些技术的结合将允许区分传入和传出放电与离散胃区（包括括约肌）运动之间的时间关系，并将区分通过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成部分。本研究将直接揭示ghrelin对肠道运动影响的神经机制，并为理解迷走神经和内分泌信号在多种肠道激素调节肠道功能中的综合作用提供新的途径。

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.