Gastrointestinal Core

胃肠核心

• 批准号: 10604273
• 负责人: HAMID I AKBARALI
• 金额: $ 25.03万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604273
• 关键词: Affect; Afferent Neurons; Anxiety; Awareness; Bacterial Translocation; Bathing; Behavioral; Biological Assay; Central Nervous System; Chronic; Cocaine; Collaborations; Colon; Complement; Constipation; Development; Drug Evaluation; Drug Modulation; Drug abuse; Drug usage; Dyes; Endocannabinoids; Enteral; Enteric Nervous System; Epithelium; Evaluation; Functional disorder; Funding; Gastrointestinal Motility; Gastrointestinal Physiology; Gastrointestinal Transit; Gastrointestinal tract structure; Goals; Gram-Positive Bacteria; HIV-1; In Vitro; Ion Channel; Laboratories; Ligands; Mediating; Methodology; Modeling; Moods; Morphine; Mus; Muscle; Myenteric Plexus; National Institute of Drug Abuse; Neurons; Neurotransmitters; Nicotinic Agonists; Opioid; Oral; Organ; Oxycodone; Pain; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Research; Research Personnel; Resources; Role; Scientist; Spinal Ganglia; System; Techniques; Training; Transgenic Mice; United States National Institutes of Health; Vancomycin; Virginia; antinociception; cytokine; drug of abuse; gastrointestinal; gastrointestinal epithelium; gastrointestinal function; gut bacteria; gut microbiome; gut-brain axis; ileum; in vitro Assay; in vivo; innovation; microbiome; microbiome alteration; mu receptors; opiate tolerance; opioid sparing; pain relief; patch clamp; pharmacologic; prevent; receptor; side effect; stem

Project Summary – Gastrointestinal Core The Gastrointestinal Core will provide the resources and innovative expertise to evaluate the bi-directional interaction between the gastrointestinal tract and central effects of drugs of abuse. The major impetus for this new core stems from the growing need for the evaluation of new compounds and pharmacological approaches to treat pain that are devoid of side-effects, particularly those associated with the gastrointestinal tract. Recent evidence that alterations in the gut microbiome affects several aspects of CNS functions, including those related to drug-induced anxiety and mood, suggests that understanding gastrointestinal effects for drugs of abuse is important and necessary. In particular, opioid-mediated gastrointestinal dysfunction represents a major effect that significantly limits their use for pain relief. Additionally, the complement of neurotransmitters, receptors and ion channels within the enteric nervous system are similar to those in the central neurons, and thus the gut also provides a useful model to examine the functional effects of drugs of abuse. Recent studies have further established that the gut-brain axis is bidirectional in which alterations of gut physiology can modulate central effects of drugs of abuse. The specific aims of the GI Core are to a) provide the resources to evaluate the effects of drugs of abuse on GI function, including in vivo and in vitro assays, and b) to evaluate the role of the microbiome on the central/peripheral effects of drugs of abuse. We will also utilize our recently developed methodologies to isolate and record from identified enteric neurons from transgenic mice and extrinsic sensory neurons from the dorsal root ganglia, to evaluate the mechanisms by which drugs of abuse affect ionic conductances and determine the role of the microbiome in the behavioral effects of drugs of abuse. Over the last decade, NIDA-funded investigators at VCU have recognized the need to evaluate various drugs of abuse in the gastrointestinal tract. Through collaboration with the Akbarali laboratory, their research has been expanded to investigate opioid sparing effects of endocannabinoids, mu receptor biased ligands, the effects of nicotinic agonists in reversal of opioid-induced constipation, and the interaction of HIV-1 Tat and morphine in enteric neurons, as well as developed the hypothesis defining the role of the gut microbiome in the development of opioid tolerance. Thus, this core enables young and established investigators to delve into an important physiological system relevant to drug abuse and provides training in this emerging field for drug abuse research.

项目摘要 - 胃肠道核心 胃肠道核心将提供评估双向的资源和创新专业知识 胃肠道和滥用药物的中心作用之间的相互作用。为此的主要动力 新的核心源于对新化合物和药品方法评估的需求日益增长的需求 治疗没有副作用的疼痛，尤其是与胃肠道相关的疼痛。最近的 肠道微生物组的改变会影响中枢神经系统功能的几个方面，包括相关的证据 对于药物引起的焦虑和情绪，表明了解滥用药物的胃肠道影响是 重要和必要的。特别是，阿片类药物介导的胃肠道功能障碍代表了主要效果 这大大限制了它们缓解疼痛的用途。此外，神经递质，接收器和 肠神经系统内的离子通道与中央神经元中的离子通道相似，因此肠道也 提供了一个有用的模型来检查滥用药物的功能影响。最近的研究进一步 确定肠道轴是双向的，其中肠道生理的改变可以调节中心 滥用药物的影响。 GI核心的具体目的是A）提供评估效果的资源 在胃肠道功能方面的滥用药物，包括体内和体外测定，b）评估 微生物组对滥用药物的中心/外围作用。我们还将利用我们最近开发的 从转基因小鼠和外部感觉中隔离和记录鉴定出的肠神经元和记录的方法 从背根神经节中的神经元评估滥用药物影响离子的机制 电导并确定微生物组在滥用药物的行为影响中的作用。在 最近十年，NIDA资助的VCU调查人员已经意识到有必要评估各种滥用药物 胃肠道。通过与Akbarali实验室的合作，他们的研究已扩大 为了研究内源性大麻素的阿片类药物稀疏作用，MU受体偏置配体，烟碱的作用 反向阿片类药物引起的便秘的激动剂，以及HIV-1 TAT和吗啡的相互作用 神经元，并提出了定义肠道微生物组在发展中的作用的假设 阿片类药物耐受性。这是，该核心使年轻和成熟的调查人员能够深入研究重要 与药物滥用相关的生理系统，并在这个新兴领域提供毒品滥用研究的培训。