Targeting Gut-Brain Axis Signaling to Treat Opioid Induced Hyperalgesia and Tolerance in Mice with Chronic Trigeminal Neuropathic Pain

项目概要/摘要： 慢性疼痛在美国是一个严重的健康问题，治疗方法有限 可用的选项。阿片类药物通常用于治疗慢性疼痛，但严重 副作用如痛觉过敏（对疼痛刺激的敏感性增加）和耐受性。这两个副作用 限制阿片类药物缓解疼痛能力的有效性，并使患者更容易过量。 以前的研究表明阿片类药物会改变肠道微生物群。改变的微生物群的下游影响 包括增加肠道炎症、胆汁酸失调以及迷走神经和皮质活动的变化。 初步数据显示，长期使用阿片类药物会改变肠道中短链脂肪酸（SCFA）的产生， 通过生酮饮食调节肠道微生物组抑制了阿片诱导的维持， 痛觉过敏和耐受。从肠道到大脑的直接联系是通过迷走神经。最近的工作 已经表明迷走神经刺激可以调节边缘系统中的神经元活动，包括前额叶， 扣带皮层（ACC）是参与慢性疼痛处理的关键脑结构。综合起来看， 这些发现导致了一个中心假设，即长期使用阿片类药物会导致肠道微生物群的变化， 通过改变ACC中的神经元活性直接有助于阿片诱导的痛觉过敏和耐受 通过迷走神经，外周（生酮饮食）或中枢（神经调节）靶向 治疗方式可用于治疗阿片样物质诱导的痛觉过敏和耐受。两个目标是 建议测试这一中心假设，并证明肠脑轴的调制由饮食或 神经调节方法可以作为潜在的治疗选择。 目的1：确定肠道微生物群在特殊饮食（生酮饮食）对芬太尼的治疗作用中的作用 通过a）分析微生物群的变化B）改变微生物群， c）测量SCFA和胆汁酸 以检测由于长期芬太尼治疗而改变的微生物群的功能后果。 目的2：确定神经元活动改变对芬太尼诱导的痛觉过敏和耐受的影响。 慢性疼痛通过a）测量慢性疼痛和阿片样物质治疗期间的迷走神经活动B）检查 改变迷走神经活动对芬太尼诱导的痛觉过敏和耐受性的影响 调节ACC神经元活性可以治疗芬太尼诱导的痛觉过敏和耐受。完成本 一个拟议的项目将提供新的见解，改变肠脑信号如何导致行为变化 以及如何将肠-脑轴的调节用作芬太尼诱导的痛觉过敏的治疗策略 和宽容。

Project Summary/Abstract: Chronic pain is a significant health problem in the United States and in which there are limited treatment options available. Opioid drugs are commonly used in the treatment of chronic pain but carry with them serious side effects such as hyperalgesia (increased sensitivity to painful stimuli) and tolerance. These two side effects limit the effectiveness of opioids pain relieving ability and make the patient more susceptible to overdose. Previous research has shown opioids alter the gut microbiota. Downstream effects of an altered microbiota include increased gut inflammation, bile acid dysregulation, and change in vagal nerve and cortical activity. Preliminary data show that chronic opioid use alters short-chain fatty acid (SCFA) production in the gut and that modulating the gut microbiome through the ketogenic diet inhibits the maintenance of opioid induced hyperalgesia and tolerance. The direct link from the gut to the brain is through the vagal nerve. Recent work has shown that vagal nerve stimulation can modulate neuronal activity in the limbic system, including anterior cingulate cortex (ACC), a critical brain structure to be involved in chronic pain processing. Taken together, these findings lead to a central hypothesis that chronic opioid use causes microbiota changes in the gut which directly contributes to opioid induced hyperalgesia and tolerance by altering neuronal activity in the ACC through the vagal nerve, and that peripherally (ketogenic diet) or centrally (neuromodulation) targeted treatment modalities may be used to treat the opioid induced hyperalgesia and tolerance. Two aims are proposed to test this central hypothesis and to demonstrate that modulation of gut-brain axis by a dietary or neuromodulation approach can serve as potential therapeutic options. Aim 1: Establish the role of gut microbiota in the therapeutic effect of a special diet (ketogenic diet) on fentanyl induced hyperalgesia and tolerance under chronic pain by a) analyzing microbiota changes b) altering the microbiota with fecal microbiota transplantation or antibiotic administration c) measuring SCFAs and bile acids to detect the functional consequences of an altered microbiota due to chronic fentanyl treatment. Aim 2: Determine the effect of altered neuronal activity on fentanyl induced hyperalgesia and tolerance under chronic pain by a) measuring vagal nerve activity during chronic pain and opioid treatment b) examining the effect of altering vagal nerve activity on fentanyl induced hyperalgesia and tolerance c) investigating whether modulating ACC neuronal activity can treat fentanyl induced hyperalgesia and tolerance. Completion of this proposed project will provide new insight into how altered gut-brain signaling can lead to behavioral changes and how modulation of gut-brain axis can be used as a treatment strategy for fentanyl induced hyperalgesia and tolerance.