Duodenal Regulation of Gastric Motility

胃动力的十二指肠调节

• 批准号: 6653126
• 负责人: CHUNG OWYANG
• 金额: $ 32.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-20 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653126
• 关键词: GABA receptor; NMDA receptors; afferent nerve; body fluid osmolarity; calcitonin gene related peptide; capsaicin; duodenum; electrophysiology; gamma aminobutyrate; gastric mucosa; gastrointestinal pharmacology; glutamates; immunocytochemistry; laboratory rat; muscle relaxation; neuroregulation; serotonin; stomach motility /pressure; vagus nerve

Chemoreceptive and mechanoreceptive mechanisms in the duodenum play an important role in the regulation of gastric motility. Following ingestion of a meal as chyme enters the duodenum, stimulation by osmolarity and mechanical distension may activate vagal affrent fibers in the mucosa resulting in gastric relaxation and inhibition of gastric motility. Abnormalities in this neural pathway may be a cause of functional dyspepsia. Currently little is known about the neural circuits responsible for these vago-vagal reflexes. Based on our preliminary studies, we hypothesize that hyperosmolar chyme and mechanical distension stimulate the release of serotonin (5-HT) from intestinal EC cells which act as a sensor for luminal stimuli. 5-HT in turn activates vagal afferent fibers releasing substance P or CGRP which then stimulates interneurons in the nucleus tractus solitarius (NTS). Two groups of NTSA neurons interacting with the dorsal vagal motor nucleus (DMNV) will be stimulated: (i) activation of GABAergic neurons will inhibit DMNV cholinergic neurons which synapse with intragastric cholinergic neurons and (ii) stimulation of glutaminergic neurons will activate those DMNV neurons which synapse with intragastric nitric oxide neurons. In this manner the vagal afferents may concurrently excite and inhibit vagal efferent transmission producing dysfacilitation of cholinergic and activation of NANC input to the stomach to optimize gastric relaxation. To test this hypothesis, we will examine the neural pathways utilized by duodenal distension and stimulation by hyperosmolar solutions to mediate gastric relaxation. The role of 5-HT in the mediation of activation of vagal sensory fibers by these duodenal stimuli will be investigated. We will characterize the chemical codings by intracellular recording and labeling techniques. In vitro electrophysiological analysis of the NTS and DMNV synaptic relationship will be performed using medullary slices. The possibility of glutamate and GABA as excitatory and inhibitory neurotransmitters to turn on and off populations of neurons in the DMNV during activation by serotonin or duodenal stimulation will be assessed. These studies will provide a detailed characterization of the neural components of the vago-vagal circuit activated by duodenal distension and hyperosmolar solution to mediate gastric relaxation. This information may help to elucidate the pathophysiology of functional dyspepsia and lead to the development of novel therapies.

十二指肠中的化学感受性和机械受体机制在调节胃运动中起重要作用。 摄入餐随着Chyme进入十二指肠的摄入后，渗透性和机械延伸的刺激可能会在粘膜中激活迷走神经纤维纤维，从而导致胃松弛和抑制胃运动。 该神经途径中的异常可能是功能性消化不良的原因。目前，对负责这些Vago-Vagal反射的神经回路知之甚少。 基于我们的初步研究，我们假设高摩尔的CHYME和机械延伸刺激了从肠道EC细胞中释放的5-羟色胺（5-HT），这些细胞充当腔刺激的传感器。 5-HT反过来激活了释放物质P或CGRP的迷走神经传入纤维，然后刺激soltractus solitarius（NTS）中的中间神经元。 Two groups of NTSA neurons interacting with the dorsal vagal motor nucleus (DMNV) will be stimulated: (i) activation of GABAergic neurons will inhibit DMNV cholinergic neurons which synapse with intragastric cholinergic neurons and (ii) stimulation of glutaminergic neurons will activate those DMNV neurons which synapse with intragastric一氧化氮神经元。 通过这种方式，迷走神经传入可能会同时激发和抑制迷走神经传播的传播，从而产生胆碱能和胃输入的动力障碍，以优化胃松弛。 为了检验这一假设，我们将检查通过十二指肠延伸和高渗溶液刺激使用的神经途径，以介导胃松弛。 将研究5-HT在这些十二指肠刺激中的迷走传感纤维激活中的作用。 我们将通过细胞内记录和标记技术来表征化学编码。 NTS和DMNV突触关系的体外电生理分析将使用髓切片进行。 将评估谷氨酸和GABA作为兴奋性和抑制性神经递质在通过5-羟色胺或十二指肠刺激激活期间开启和关闭神经元种群的兴奋性和抑制性神经递质的可能性。 这些研究将提供通过十二指肠延伸和高摩尔溶液激活的流浪性电路的神经成分的详细表征，以介导胃松弛。 这些信息可能有助于阐明功能性消化不良的病理生理学，并导致新疗法的发展。