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和机械感受机制在胃动力的调节中发挥着重要作用。 摄入膳食后，食糜进入十二指肠，渗透压和机械扩张的刺激可能会激活粘膜中的迷走神经传入纤维，导致胃松弛和胃运动抑制。 该神经通路的异常可能是功能性消化不良的原因。目前，人们对负责这些迷走神经反射的神经回路知之甚少。 根据我们的初步研究，我们假设高渗食糜和机械扩张会刺激肠道 EC 细胞释放血清素 (5-HT)，而肠道 EC 细胞充当管腔刺激的传感器。 5-HT 反过来激活迷走神经传入纤维，释放 P 物质或 CGRP，然后刺激孤束核 (NTS) 中的中间神经元。 与迷走神经背运动核 (DMNV) 相互作用的两组 NTSA 神经元将受到刺激：(i) GABA 能神经元的激活将抑制与胃内胆碱能神经元突触的 DMNV 胆碱能神经元，(ii) 谷氨酰胺能神经元的刺激将激活这些 DMNV 神经元其突触与胃内一氧化氮神经元。 以这种方式，迷走神经传入神经可以同时兴奋和抑制迷走神经传出神经传递，从而产生胆碱能障碍和NANC输入到胃的激活以优化胃松弛。 为了检验这一假设，我们将检查十二指肠扩张和高渗溶液刺激所利用的神经通路，以介导胃松弛。 将研究 5-HT 在介导这些十二指肠刺激迷走神经感觉纤维激活中的作用。 我们将通过细胞内记录和标记技术来表征化学编码。 将使用髓质切片对 NTS 和 DMNV 突触关系进行体外电生理分析。 将评估谷氨酸和 GABA 作为兴奋性和抑制性神经递质在血清素或十二指肠刺激激活期间打开和关闭 DMNV 中神经元群的可能性。 这些研究将提供十二指肠扩张和高渗溶液激活的迷走神经回路神经成分的详细特征，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开发。