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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：
9914099
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/9914099
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 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 addiction base beta-arrestin cell type chronic pain 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 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.

尽管存在重大限制，阿片类药物仍然是治疗严重急性和慢性疼痛的主要药物。