Opioid and cannabinoid interactions in pain and reward

摘要 慢性疼痛是一个重要的公共卫生问题，每年花费社会数十亿美元，并造成严重的疾病。 无数人的痛苦。基于阿片类药物的药物是各种形式的最常见的处方之一。 导致目前阿片类药物流行的慢性疼痛。最近，大麻和大麻素化合物（例如， Δ9-四氢大麻酚（THC）和大麻二酚（CBD））已被描述为具有缓解疼痛的作用。 特性.虽然这些大麻素，特别是精神活性较低的大麻素，CBD，可能提供替代品， 阿片类药物治疗疼痛，很少有对照良好的研究表明镇痛效果，特别是CBD。而 目前还不清楚大麻素是否是治疗疼痛的好的独立选择，大麻素可能是有用的， 考虑到阿片类药物和大麻素受体在奖赏方面的大量重叠， 疼痛相关的通路我们提出的项目将集中在一个启发式的方法，结合基本 药理学、疼痛的新型操作性行为测定和功能性神经成像。的长期目标 这项研究计划是建立新的方法来治疗慢性疼痛，最大限度地提高止痛效果 最大限度地减少滥用责任。这一提案的目标是实现这一长期目标的第一步- 长期目标是确定CBD如何改变羟考酮（OXY）的作用，OXY是一种常用的阿片类药物 镇痛剂，在慢性疼痛和阿片类自我给药的情况下。我们的首要假设是 CBD和OXY将协同作用以产生增强的镇痛作用，并且CBD将减弱这种作用。 OXY自我给药的疼痛。将研究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;（2）确定相互作用效应 慢性疼痛，OXY自我管理，和CBD对镇痛，强化和依赖性。我们将 评估既存疼痛对OXY自我给药的影响，以及既存OXY自我给药的影响。 疼痛的管理。后一个目标是这项建议的一个特别创新的方面。CBD调节效应 将在两种条件下评价疼痛和OXY自我给药。神经成像将用于 绘制和量化大脑奖励和疼痛中心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制行为评估，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， 我们将为今后开发有效的止痛药奠定必要的基础， 减少滥用责任。我们相信我们特别适合承担这个项目，因为我们有一个 统一的（并且已经合作的）多学科团队，在行为方面具有互补的专业知识 神经科学、药理学和神经影像学。

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.