Alcohol, TRPV1 and Pancreatic Nerves in Pain and Inflammation

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不清楚。基于最近的文献和我们自己的初步发现，我们建议研究乙醇和神经过程之间的相互作用，这些过程可能导致局部组织损伤(神经源性炎症)，特别是香草素离子通道TRPV1的作用。我们的实验室发现了胃和胰腺之间的一种新的神经融合的证据，即初级伤害性神经元的二分形式，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，会导致胰腺的急性损伤。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，酒精可以增加已建立的胰腺炎动物的疼痛反应，这种效应可能是由TRPV1介导的。因此，我们的假设是，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TRPV1来调节的，这可以导致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：1.明确胃胰腺神经反射和TRPV1在介导酒精性急性胰腺损伤中的作用；2.明确胃胰腺神经和TRPV1在介导慢性胰腺炎酒精性疼痛加重中的作用。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，并可能导致发现治疗急性和慢性胰腺炎的新靶点。此外，如本文所述，对促炎性胃胰腺神经反射的阐明，代表着我们在理解口服摄入的物质(如乙醇)如何在没有直接暴露的情况下也会对内脏器官造成伤害方面的潜在突破。

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.