Alcohol, TRPV1 and Pancreatic Nerves in Pain and Inflammation

酒精、TRPV1 和胰神经在疼痛和炎症中的作用

• 批准号: 7936067
• 负责人: PANKAJ J PASRICHA
• 金额: $ 20.18万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936067
• 关键词: Acute; Affect; Alcohols; Animals; Behavioral; Cells; Communication; Data; Ethanol; Event; Heavy Drinking; Immune; In Vitro; Inflammation; Inflammatory; Injury; Ion Channel; Laboratories; Lead; Literature; Mediating; Methods; Nerve; Neurogenic Inflammation; Neurons; Nociception; Oral; Organ; Pain; Pancreas; Pancreatic Diseases; Pancreatic Injury; Pancreatitis; Pathway interactions; Patients; Pattern; Physiological; Play; Process; Publishing; Reflex action; Reporting; Research; Role; Signal Transduction; Spinal; Stimulus; Stomach; TRPV1 gene; Tissues; Transducers; Up-Regulation; Vanilloid; Visceral; alcohol effect; base; chronic pancreatitis; drinking; experience; in vivo; innovation; nerve supply; new therapeutic target; novel; relating to nervous system; response

DESCRIPTION (provided by applicant): The mechanisms by which alcohol mediates either inflammation or pain in pancreatitis remain relatively obscure. Based on recent literature and our own preliminary findings, we propose to examine the interaction between ethanol and neural processes that can contribute to local tissue injury (neurogenic inflammation), focusing in particular on the role of the vanilloid ion channel, TRPV1. Our laboratory has discovered evidence of a novel neural convergence between the stomach and pancreas in the form of dichotomizing primary nociceptive neurons, which we have termed gastropancreatic nerves. We have also demonstrated that these neurons participate in a novel cross-talk between these organs. This communication involves TRPV1 and if activated, results in acute injury to the pancreas. We have shown that ethanol is able to sensitize this pathway. Further, we provide evidence that alcohol can increase the pain response in animals with established pancreatitis, an effect possibly mediated by TRPV1. Our hypothesis for this application is therefore that the effects on alcohol on the pancreas are mediated in part via TRPV1 expressed by a unique set of gastropancreatic nerves and this can result in both neurogenic inflammation acutely and upregulation of pain signaling chronically. To prove this, we propose the following specific aims: Specific Aim 1: To determine the role of gastropancreatic neuronal reflexes and TRPV1 in mediating alcohol-induced acute pancreatic injury Specific Aim 2: To determine the role of gastropancreatic nerves and TRPV1 in mediating alcohol-induced exacerbation of pain in chronic pancreatitis e will use a variety of physiological, pharmacological and behavioral methods to accomplish these aims. The data from these exploratory studies will provide important information as to the mechanisms of alcohol-mediated pancreatic injury and pain and may lead to the discovery of novel therapeutic targets for the management of both acute and chronic pancreatitis. In addition, elucidation of a pro-inflammatory gastropancreatic neural reflex, as described here, represents a potential breakthrough in our understanding of how orally ingested substances such as ethanol can cause injury to visceral organs even in the absence of direct exposure.

描述（由申请人提供）：酒精介导胰腺炎炎症或疼痛的机制仍然相对模糊。基于最近的文献和我们自己的初步研究结果，我们建议研究乙醇和神经过程之间的相互作用，可以有助于局部组织损伤（神经源性炎症），特别是香草酸离子通道，TRPV1的作用。我们的实验室已经发现了胃和胰腺之间的一种新的神经会聚的证据，其形式为二分的初级伤害性神经元，我们称之为胃胰腺神经。我们还证明了这些神经元参与了这些器官之间的一种新的串扰。这种通讯涉及TRPV1，如果被激活，会导致胰腺急性损伤。我们已经证明，乙醇能够敏化这一途径。此外，我们提供的证据表明，酒精可以增加胰腺炎动物的疼痛反应，这种作用可能是由TRPV1介导的。因此，我们对此应用的假设是，酒精对胰腺的影响部分是通过一组独特的胃胰腺神经表达的TRPV 1介导的，这可能会导致急性神经源性炎症和慢性疼痛信号的上调。为了证明这一点，我们提出了以下具体目标：具体目标1：确定胃胰神经反射和TRPV1在介导酒精诱导的急性胰腺损伤中的作用具体目标2：确定胃胰神经和TRPV1在介导慢性胰腺炎中酒精诱导的疼痛加重中的作用，我们将使用各种生理学，药理学和行为学方法来实现这些目标。这些探索性研究的数据将为酒精介导的胰腺损伤和疼痛的机制提供重要信息，并可能导致发现新的治疗靶点，用于急性和慢性胰腺炎的管理。此外，如本文所述，阐明促炎性胃胰腺神经反射代表了我们对口服摄入物质（如乙醇）如何导致内脏器官损伤（即使在没有直接暴露的情况下）的理解的潜在突破。