Opioid and cannabinoid interactions in pain and reward

摘要 慢性疼痛是一个重大的公共卫生问题，每年给社会造成数十亿美元的损失，并导致巨大的 无数人都在受苦。阿片类药物是治疗各种形式的癌症的最常用的药物之一 慢性疼痛是目前阿片类药物流行的原因。最近，大麻和大麻素化合物(例如， Δ，9-四氢大麻酚(Thc)和大麻二酚(Cbd))被描述为具有止痛作用。 属性。虽然这些大麻素，特别是精神活性较低的变体CBD，可能会提供替代 对于疼痛的阿片类药物治疗，很少有良好的对照研究显示出止痛效果，特别是对CBD。而当 目前还不清楚大麻素是否是治疗疼痛的好的单独选择，大麻素可能有用 阿片类药物，考虑到阿片和大麻素受体在奖赏方面的大量重叠-以及 疼痛相关的通路。我们提议的项目将专注于一种启发式方法，该方法结合了基本的 药理学、疼痛的新的可操作性行为分析和功能神经成像。的长期目标是 这项研究计划旨在通过最大化止痛效果来建立治疗慢性疼痛的新方法。 并将滥用责任降至最低。这项提案的目标，体现了迈向这一漫长目标的第一步- 术语目标是确定CBD如何改变羟考酮(Oxy)的效果，羟考酮是一种常见的处方阿片类药物 止痛药，在慢性疼痛和阿片类药物自我给药的情况下。我们最重要的假设是 CBD和Oxy将协同作用产生增强的止痛作用，而CBD将减弱这种作用 Oxy自我给药带来的痛苦。将调查两个主要的具体目标：(1)确定CBD如何 与Oxy相互作用以减少慢性操作性疼痛行为；以及(2)确定相互作用的效果 治疗慢性疼痛，奥昔洛韦自我给药，以及CBD止痛，强化和依赖。我们会 评估预先存在的疼痛对Oxy自我管理的影响，以及预先存在的Oxy自我管理的影响 对疼痛的管理。后一个目标是该提案的一个特别创新的方面。CBD-调节效应 关于疼痛和Oxy自我给药将在这两种情况下进行评估。神经成像将被用于 绘制和量化大脑奖赏和疼痛中心的神经连接变化的实验 在各种药物治疗(CBD、Oxy)和疼痛状态(急性、慢性)之后。此外，我们将在临床上使用 重要和创新的疼痛抑郁行为评估，准确地模拟人类受试者的疼痛。 完成这些研究的基本原理是，通过确定CBD和Oxy如何相互作用来影响疼痛和 物质使用，我们将为未来开发有效的镇痛剂奠定必要的基础 减少滥用责任。我们相信我们特别适合承接这个项目，因为我们有 统一的(并且已经在协作的)多学科团队，在行为方面具有互补的专业知识 神经科学、药理学和神经成像。

Abstract Chronic pain is a significant public health problem that costs society billions of dollars per year and causes great suffering in countless individuals. Opioid-based medications are among the most prescribed for various forms of chronic pain contributing to the current opioid epidemic. Recently, cannabis and cannabinoid compounds (e.g., Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been described as having pain-alleviating properties. While these cannabinoids, particularly the less psychoactive variant, CBD, may offer alternatives to opioid treatments for pain, few well-controlled studies demonstrate analgesic efficacy, especially for CBD. While it is still unclear if cannabinoids are good stand-alone options for treating pain, cannabinoids may act as useful opioid-sparing drugs, given the substantial overlap between opioid and cannabinoid receptors in reward- and pain-related pathways. Our proposed project will focus on a heuristic approach that incorporates fundamental pharmacology, novel operant behavioral assays of pain, and functional neuroimaging. The long-term goal of this research program is to establish novel approaches to treat chronic pain by maximizing analgesic efficacy and minimizing abuse liability. The objective of this proposal, which embodies the first step toward this long- term goal, is to determine how CBD modifies the effects of oxycodone (OXY), a commonly prescribed opioid analgesic, in the contexts of chronic pain and opioid self-administration. Our overarching hypothesis is that CBD and OXY will act synergistically to yield enhanced analgesic effects, and that CBD will attenuate the effects of pain on OXY self-administration. Two major specific aims will be investigated: (1) to determine how CBD interacts with OXY to reduce chronic operant pain behaviors; and (2) to determine the interacting effects of chronic pain, OXY self-administration, and CBD on analgesia, reinforcement, and dependence. We will assess the effects of preexisting pain on OXY self-administration, as well as the effects of preexisting OXY self- administration on pain. The latter goal is a particularly innovative aspect of this proposal. CBD-modulatory effects on pain and OXY self-administration will be evaluated under both conditions. Neuroimaging will be used across experiments to map and quantify changes in neural connectivity across reward and pain centers of the brain following the various drug treatments (CBD, OXY) and pain states (acute, chronic). Further, we will use clinically important and innovative pain-depressed behavioral assessments that accurately model pain in human subjects. The rationale for completing these studies is that by determining how CBD and OXY interact to affect pain and substance use, we will establish the necessary foundation for future efforts to develop effective analgesics with reduced abuse liability. We believe we are particularly well suited to undertake this project because we have a unified (and already collaborating) multidisciplinary team with complementary expertise in behavioral neuroscience, pharmacology, and neuroimaging.