CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence

CB2 大麻素抑制阿片类药物耐受性和依赖性的机制

基本信息

批准号：
10343812
负责人：
Andrea Grace Hohmann
金额：
$ 51.72万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343812
关键词：
Absence of pain sensation Acute Acute Pain Address Adenylate Cyclase Adverse effects Agonist Arrestins Attenuated Binding CB2 knockout CNR1 gene CNR2 gene Cannabinoids Cells Cessation of life Chronic Clinic Clinical Dependence Development Dose Epidemic Exhibits GTP-Binding Proteins Genetic Human Immune In Vitro Inositol Phosphates Kinetics Knockout Mice Laboratories Lead Ligands MAPK3 gene Measures Mechanics Mediating Mediation Microglia Modeling Molecular Morphine Mus Naloxone Neuraxis Nociception Nociceptors Opiate Addiction Opioid Opioid Analgesics Opioid Receptor Opioid agonist Overdose Pain Threshold Persons Pharmacology Phase I Clinical Trials Phase II Clinical Trials Physical Dependence Receptor Signaling Risk Signal Transduction Signaling Protein Site Testing Therapeutic Therapeutic Index Therapeutic Uses Toxic effect Translating Translations Treatment Efficacy United States Validation Ventilatory Depression Withdrawal Symptom abuse liability addiction base beta-arrestin cell type chronic pain chronic pain management clinically significant efficacy testing experimental study improved innovation morphine tolerance mu opioid receptors novel novel strategies opiate tolerance opioid use opioid withdrawal pain model painful neuropathy pre-clinical prescription opioid abuse prescription opioid misuse preservation prevent protein activation receptor binding recruit sexual dimorphism therapeutic opioid treatment response

项目摘要

Despite significant limitations, opioids remain a mainstay for the treatment of severe acute and chronic pain. Two clinically significant limitations that accompany the long-term therapeutic use of opioids are: (1) The development of tolerance (requiring escalating doses of opioid to maintain the desired therapeutic benefit or leading to diminished benefit with constant dose) and (2) Physical dependence (withdrawal symptoms on cessation of opioid use, which are very unpleasant, and seeking their avoidance may increase the risk for opioid addiction). Currently, there are no practical approaches for decreasing opioid tolerance or suppressing the development of physical dependence. However, in exploring potential interactions between CB2 cannabinoid receptor (CB2R) and mu opioid receptor (MOR) signaling, we made the exciting discovery that certain CB2 agonists effectively prevented the development of tolerance to opioid-induced anti-allodynic efficacy in a murine neuropathic pain model, while also blunting the physical dependence that accompanies chronic morphine exposure. These findings, if they can be translated to humans, hold the promise to significantly improve the clinical use of opioids. On the path to translating these findings, we will complete three specific aims to better understand how CB2 and mu opioid receptor agonists interact to suppress opioid tolerance and dependence: Aim 1: Identify the CB2-expressing cells engaged by LY28282360 to prevent opioid tolerance. We will delineate the cell types responsible for the ability of LY2828360 to block development of morphine tolerance and identify site of action using both pharmacological manipulations and a conditional deletion approach. Separate studies will target primary afferent nociceptors vs. microglia. Aim 2: Define the conditions under which CB2 agonists suppress opioid-induced physical dependence. We will delineate the cell types responsible for the effects of LY2828360 on opioid dependence, as measured using naloxone precipitated opioid withdrawal, using both pharmacological manipulations and a conditional deletion approach. Separate studies will target primary afferent nociceptors vs. microglia. Aim 3: Mechanistic characterization of CB2R/MOR interaction. We will characterize CB2 ligands for their G protein/arrestin signaling bias as well as their kinetics of G protein activation. We will also determine if the slow activation of G protein signaling by LY2828360 and related CB2 agonists is due to the kinetics of receptor binding. Finally, if the results of Aims 1 or 2 suggest that MOR and CB2R are interacting in the same cell, we will characterize the differences in CB2R/MOR crosstalk between slowly and rapidly signaling CB2 agonists. Completion of these aims will fully characterize interactions between CB2 and opioid receptors in preclinical and cell-based models. These studies will help define the clinical settings where CB2 agonists may be useful in countering two major limitations on the use of opioids in treating chronic pain.

尽管有很大的局限性，阿片类药物仍然是治疗严重急性和慢性疼痛的支柱。长期治疗使用阿片类药物伴随的两个临床显着限制是：（1）产生耐受性（需要增加阿片类药物的剂量以维持所需的治疗效果或导致恒定剂量的效果减弱）和（2）身体依赖性（戒断症状）停止使用阿片类药物，这是非常令人不愉快的，寻求避免可能会增加风险阿片类药物成瘾）。目前，尚无降低阿片类药物耐受性或抑制阿片类药物耐受性的实用方法。身体依赖性的发展。然而，在探索 CB2 之间的潜在相互作用时大麻素受体 (CB2R) 和 mu 阿片受体 (MOR) 信号传导，我们做出了令人兴奋的发现：某些 CB2 激动剂可有效防止对阿片类药物引起的抗异常性疼痛产生耐受性在小鼠神经病理性疼痛模型中的功效，同时还削弱了伴随而来的身体依赖性慢性吗啡暴露。如果这些发现能够转化为人类，那么它们有望显着改善阿片类药物的临床使用。在转化这些发现的过程中，我们将完成三个具体目标是为了更好地了解 CB2 和 mu 阿片受体激动剂如何相互作用来抑制阿片类药物耐受性和依赖性：目标 1：鉴定 LY28282360 参与的 CB2 表达细胞，以防止阿片类药物耐受。我们将描绘了 LY2828360 阻止吗啡耐受发展的能力的细胞类型并使用药理学操作和条件删除方法来确定作用位点。单独的研究将针对初级传入伤害感受器与小胶质细胞。目标 2：定义 CB2 激动剂抑制阿片类药物引起的身体依赖的条件。我们将描述 LY2828360 对阿片类药物依赖产生影响的细胞类型（如测量结果）使用纳洛酮促使阿片类药物戒断，同时使用药理学操作和有条件的删除方法。单独的研究将针对初级传入伤害感受器与小胶质细胞。目标 3：CB2R/MOR 相互作用的机制表征。我们将表征 CB2 配体的 G 蛋白/抑制蛋白信号偏向及其 G 蛋白激活动力学。我们还将确定速度是否缓慢 LY2828360 和相关 CB2 激动剂激活 G 蛋白信号传导是由于受体的动力学绑定。最后，如果目标 1 或 2 的结果表明 MOR 和 CB2R 在同一细胞中相互作用，我们将表征缓慢和快速信号传导的 CB2 激动剂之间 CB2R/MOR 串扰的差异。这些目标的完成将在临床前充分表征 CB2 和阿片受体之间的相互作用和基于细胞的模型。这些研究将有助于确定 CB2 激动剂可能有用的临床环境克服使用阿片类药物治疗慢性疼痛的两个主要限制。