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

项目摘要/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 可用选项。阿片类药物常用于治疗慢性疼痛，但会带来严重的后果 副作用，例如痛觉过敏（对疼痛刺激的敏感性增加）和耐受性。这两个副作用 限制阿片类药物止痛能力的有效性，并使患者更容易服用过量。 先前的研究表明阿片类药物会改变肠道微生物群。微生物群改变的下游影响 包括肠道炎症增加、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群可抑制阿片类药物诱导的维持 痛觉过敏和耐受性。从肠道到大脑的直接联系是通过迷走神经。最近的工作 研究表明，迷走神经刺激可以调节边缘系统的神经元活动，包括前部 扣带皮层（ACC）是参与慢性疼痛处理的关键大脑结构。综合起来， 这些发现得出了一个中心假设，即长期使用阿片类药物会导致肠道微生物群发生变化，从而导致肠道菌群发生变化。 通过改变 ACC 中的神经元活动直接导致阿片类药物引起的痛觉过敏和耐受 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引起的痛觉过敏和耐受。两个目标是 建议测试这一中心假设并证明饮食或饮食对肠脑轴的调节 神经调节方法可以作为潜在的治疗选择。 目标 1：建立肠道微生物群在特殊饮食（生酮饮食）对芬太尼治疗效果中的作用 通过 a) 分析微生物群变化 b) 改变慢性疼痛下的痛觉过敏和耐受性 粪便微生物群移植或抗生素给药的微生物群 c) 测量 SCFA 和胆汁酸 检测因长期芬太尼治疗而改变的微生物群的功能后果。 目标 2：确定改变的神经元活动对芬太尼诱导的痛觉过敏和耐受性的影响 通过 a) 测量慢性疼痛和阿片类药物治疗期间的迷走神经活动 b) 检查慢性疼痛 改变迷走神经活动对芬太尼引起的痛觉过敏和耐受性的影响 c) 研究是否 调节 ACC 神经元活动可以治疗芬太尼引起的痛觉过敏和耐受。完成此 拟议的项目将为改变肠脑信号传导如何导致行为改变提供新的见解 以及如何将肠脑轴调节用作芬太尼引起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.