The Microbiome in opioid use and abuse

摘要 目前，我们面临着一个关于阿片类药物危机的重大难题。一方面，我们有 没有可行的替代方案来治疗手术后的严重疼痛和慢性疼痛。另一方面，服用这些药物的人 用于合法目的的药物正在以令人震惊的速度过渡到阿片类药物的过度使用和滥用。而当 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不谋而合，它仍然是 诚然，只有一小部分服用阿片类药物治疗疼痛的患者过渡到滥用。如果我们能确定 那些在阿片类药物治疗之前风险最大的疼痛患者，我们可能会阻止阿片类药物滥用的浪潮。一个 最近一些令人信服的研究表明，肠道微生物群的变化可以影响过多的肠道。 中枢神经系统紊乱，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，在阿片类药物处方增加的同时，也出现了 大量增加常规的、经常是不必要的口服抗生素的使用--这一趋势已经改变了肠道 整整一代人的微生物群。毫不奇怪，考虑到阿片受体在脑内的广泛表达 肠道，阿片类药物已被证明可以改变肠道微生物群。此外，微生物群中的变化已经被 表明阿片类药物可以改变阿片类药物的止痛和奖赏，这表明阿片类药物影响了肠道-脑轴。然而，为了 到目前为止，还没有研究检查肠道微生物群是否影响滥用倾向。在这里，我们将利用 强迫性寻药复吸小鼠模型的行为变异性和小鼠微生物组 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群是否共同作用于 变化(目标1)。我们还将检查“上瘾”小鼠或“非上瘾”小鼠的微生物组是否可以 使受试者倾向于或保护受试者免受强迫寻求毒品或复发(目标2)。本项目为双重委托人 调查员建议，利用两位专家在各自领域的互补专长， 一个是分子微生物学家，另一个是阿片类药剂学家。

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.