The Microbiome in opioid use and abuse

总结 目前，我们在阿片类药物危机方面面临着一个重大难题。一方面， 没有治疗严重术后和慢性疼痛的可行替代方案。另一方面，服用这些药物的人 用于合法目的的药物正以惊人的速度过渡到类阿片过度使用和滥用。而 阿片类药物滥用的急剧增加与阿片类药物处方的大量报道相吻合，但它仍然是 的确，只有一小部分因疼痛而服用阿片类药物的患者过渡到滥用。如果我们能找出 这些疼痛患者在阿片类药物治疗之前最有风险，我们可能会阻止阿片类药物滥用的浪潮。一 最近，一些令人信服的研究表明，肠道微生物组的改变可以影响过多的 中枢神经系统疾病，导致肠道微生物组的概念被广泛接受- 脑轴我们发现令人信服的是，与阿片类药物处方的增加同时， 大量增加的日常和经常不必要的使用口服避孕药-一种趋势，这已经改变了肠道 微生物组的一个完整的一代。毫不奇怪，考虑到阿片受体在大脑中的广泛表达， 肠道，阿片类药物已被证明可以改变肠道微生物组。此外，微生物组的改变已经被 结果表明，阿片类药物可以改变阿片类药物的镇痛和奖励，这表明阿片类药物影响肠-脑轴。但要 迄今为止，还没有研究检查肠道微生物组是否会影响滥用倾向。在这里，我们将利用 在强迫性药物寻求和复发的小鼠模型中的行为变异性，以及小鼠微生物组 变异性，包括先天的和对吗啡的反应，以确定滥用倾向和微生物组是否共同作用。 变化（目标1）。我们还将研究来自“成瘾”小鼠或“非成瘾”小鼠的微生物组是否可以 使受试者易患或保护受试者免于强迫性药物寻求或复发（目的2）。该项目是一个双重的主要 利用两名专家在各自领域的互补专长的调查员提案， 一个是分子微生物学家另一个是阿片类药物学家

Summary Currently we are faced with a significant conundrum with regard to the opioid crises. On the one hand, we have no viable alternative for treating severe post-surgical and chronic pain. On the other hand, people taking these drugs for legitimate purposes are transitioning at an alarming rate to opioid overuse and abuse. While the dramatic increase in opioid abuse has coincided with the much-reported increase in opioid prescriptions, it is still true that only a fraction of patients who are prescribed opioids for pain transition to abuse. If we could identify those pain patients most at risk prior to opioid treatment, we could potentially stem the tide of opioid abuse. A number of compelling studies have recently shown that alterations in the gut microbiome can influence a plethora of central nervous systems disorders, leading to widespread acceptance of the concept of a gut-microbiome- brain axis. We find it compelling that, coincident with the increase in opioid prescriptions, there has also been a large increase in the routine and often unnecessary use of oral antibiotics—a trend that that has altered the gut microbiome of an entire generation. Not surprisingly, given the widespread expression of opioid receptors in the gut, opioids have been shown to alter the gut microbiome. Furthermore, alterations in the microbiome have been shown to alter opioid analgesia and reward, suggesting that opioids influence the gut-brain axis. However, to date, no studies have examined whether the gut microbiome influences abuse liability. Here we will capitalize on both behavioral variability in a mouse model of compulsive drug seeking and relapse, and mouse microbiome variability, both innate and in response to morphine, to determine whether abuse liability and the microbiome co- vary (Aim 1). We will also examine whether the microbiome from an “addict” mouse or “non-addict” mouse can predispose to or protect subjects from compulsive drug seeking or relapse (Aim 2). This project is a dual Principal Investigator proposal that capitalizes on the complementary expertise of two experts in their respective fields, one a molecular microbiologist the other an opioid pharmacologist.