Role of CB1 Receptors in Opioid Tolerance During Pain

CB1 受体在疼痛期间阿片类药物耐受性中的作用

• 批准号: 10585037
• 负责人: Adrianne Rae Wilson-Poe
• 金额: $ 8.4万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585037
• 关键词: 8 year old; Absence of pain sensation; Address; Agonist; Analgesics; Animal Model; Animals; Area; Attenuated; Award; Botanicals; Brain; CNR1 gene; COVID-19 pandemic; Cannabinoids; Cannabis; Child; Clinical; Clinical Research; Complex; Consumption; Data; Development; Dose; Funding; GTP-Binding Proteins; Geographic state; Goals; Harm Reduction; Health; Human; Hyperalgesia; Hypersensitivity; Inhalation; Intraperitoneal Injections; Legal; Literature; Mediating; Medical Marijuana; Membrane; Mentors; Midbrain structure; Morphine; Mothers; Motivation; Neurons; Opioid; Opioid Analgesics; Overdose; Pain; Pain Threshold; Pathway interactions; Peer Review; Pharmaceutical Preparations; Pharmacology; Phase; Physical Dependence; Plant Extracts; Plants; Policies; Prevalence; Property; Protocols documentation; Publications; Research; Rewards; Role; Route; Self Administration; Signaling Protein; Smoke; System; Testing; Therapeutic; Time; Translations; Work; abuse liability; attenuation; base; career; caregiving; chronic pain; chronic pain management; chronic pain patient; clinically relevant; endogenous cannabinoid system; endogenous opioids; inflammatory pain; insight; midbrain central gray substance; morphine tolerance; mu opioid receptors; novel therapeutics; opiate tolerance; opioid abuse; opioid sparing; opioid use; pain reduction; pain relief; painful neuropathy; parent grant; pre-clinical; prevent; primary caregiver; protective effect; receptor; recruit; side effect; tool; vapor

PROJECT SUMMARY The goal of this research is to characterize the interaction between the mu-opioid and CB1-cannabinoid receptors during pain. The analgesic properties of opioids are well known, and because of the recent legalization of medicinal cannabis in many US states, cannabis is increasingly being utilized as an analgesic. A growing body of evidence suggests that the cannabinoid and opioid systems interact in several ways that could be of significant therapeutic utility. However, the mechanisms of cannabinoid/opioid interactions, and the abuse potential of combined cannabinoid/opioid administration have yet to be elucidated. Therefore, we propose to characterize the interaction between opioids and cannabinoids in conditions during which these drugs might be used for their analgesic properties; specifically, in inflammatory and neuropathic pain. This five-year, Pathway to Independence project has three Specific Aims. The first Aim, to characterize pain- induced adaptations in the CB1 receptor system, was addressed during the mentored phase of this award. The independent Aims (during the R00 phase) characterized the effects of vaporized low-THC whole-plant cannabis extract (WPE). We found that WPE is not able to reverse hypersensitivity in animals with neuropathic pain, it does not attenuate morphine tolerance, however it does reduce the abuse liability of opioids. Although the modulation of opioid reward is a promising finding, vaporized WPE lacks clinical utility in the context of chronic pain, given its lack of efficacy for anti-hyperalgesia. Based upon our previous findings, we hypothesize that unlike low-THC, high-THC whole-plant cannabis extract (THC-WPE) will reduce pain and morphine tolerance in animals with neuropathic pain, while simultaneously reducing the abuse liability of opioids. The proposed studies have immense clinical relevance, given the prevalence of THC consumption by chronic pain patients. The studies in this Supplement do not deviate from those proposed in the original Application. The completion of the proposed studies will allow me to accomplish my immediate goals of further characterizing opioid/cannabinoid interactions, and focus on therapeutic protocols which have the greatest clinical implications. In doing so, my work will more directly benefit human health, which is in line with my long-term goal of identifying novel therapies that maximize analgesia while minimizing negative side effects. These studies represent a critical stepping-stone whereby I might engage in collaborative clinical studies that are informed by my findings at the bench. As a single mother and the primary caregiver of an 8-year old child, this Supplement will also provide bridge funding at a critical and vulnerable time of my career, as I compete for my first R01 funding. The proposed studies will undoubtedly result in peer-reviewed publications which will help me re-gain momentum lost due to caregiving responsibilities during the COVID-19 pandemic.

项目摘要 本研究的目的是表征μ-阿片和CB 1-大麻素之间的相互作用 感受器在疼痛中阿片类药物的镇痛特性是众所周知的，并且由于最近的 随着美国许多州将药用大麻合法化，大麻越来越多地被用作止痛剂。 越来越多的证据表明，大麻素和阿片系统以多种方式相互作用， 可能具有显著的治疗效用。然而，大麻素/阿片类药物相互作用的机制， 大麻素/阿片样物质联合给药滥用可能性尚待阐明。所以我们 建议描述阿片类药物和大麻素之间的相互作用，在此期间， 药物可因其镇痛特性而使用;特别是用于炎性和神经性疼痛。这 五年，独立之路项目有三个具体目标。第一个目标，描述疼痛的特征- 在CB 1受体系统中诱导适应，在该奖项的指导阶段得到了解决。 独立的目标（在R 00阶段）的特点是蒸发的低THC整株植物的影响， 大麻提取物（WPE）。我们发现WPE不能逆转神经病理性动物的超敏反应， 疼痛，它不会减弱吗啡耐受性，但它确实减少了阿片类药物的滥用倾向。虽然 阿片样物质奖赏的调节是一个有希望的发现，蒸发的WPE在以下情况下缺乏临床实用性： 慢性疼痛，因为它缺乏抗痛觉过敏的功效。基于我们之前的发现，我们假设 与低THC不同，高THC全植物大麻提取物（THC-WPE）将减少疼痛和吗啡 在患有神经性疼痛的动物中的耐受性，同时减少阿片类药物的滥用倾向。的 考虑到慢性疼痛患者THC消耗的普遍性，拟议的研究具有巨大的临床相关性。 患者本补充中的研究不偏离原始申请中提出的研究。的 完成拟议的研究将使我能够实现我的直接目标，进一步表征 阿片类药物/大麻素相互作用，并专注于具有最大临床价值的治疗方案 含义。这样做，我的工作将更直接地有益于人类健康，这符合我的长期目标。 目标是确定新的治疗方法，最大限度地提高镇痛效果，同时尽量减少负面影响。这些 研究是一个关键的垫脚石，我可以借此参与合作临床研究， 根据我在法官席上的发现作为一个单身母亲和一个8岁孩子的主要照顾者， 在我职业生涯的关键和脆弱时期，当我参加竞争时，这个补充基金也将提供过渡资金 我的第一笔R 01资金拟议的研究无疑将产生同行评审的出版物， 帮助我重新获得因在COVID-19大流行期间承担更多责任而失去的动力。