Alcohol, TRPV1 and Pancreatic Nerves in Pain and Inflammation

点击翻译按钮获取中文摘要

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.