Signaling balance and opioid dependence

信号平衡和阿片类药物依赖

基本信息

批准号：
10503891
负责人：
JENNIFER L WHISTLER
金额：
$ 66.36万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10503891
关键词：
Abstinence Acute Agonist Analgesics Animals Arrestins Behavior Behavioral Biology Brain Cells Characteristics Clinical Cognitive Color Data Decision Making Dependence Diagnosis Distress Dopamine Dopamine D2 Receptor Down-Regulation Drug Exposure Drug Modelings Drug abuse Endocytosis Endorphins Engineering Enkephalins Equilibrium Essential Drugs Exposure to Failure G-Protein-Coupled Receptors GABA Receptor GTP-Binding Proteins Genotype Goals Human Impairment Knock-in Mouse Lateral Ligands Link Medial Modeling Molecular Monitor Morphine Morphine Dependence Mus Naloxone Neurons Nucleus Accumbens Opiate Addiction Opioid Pain Pathologic Pathology Patients Pharmaceutical Preparations Pharmacology Phenotype Physical Dependence Positioning Attribute Pre-Clinical Model Prefrontal Cortex Probability Property Recycling Regimen Relapse Research Rewards Risk Role Self Administration Signal Transduction Signaling Protein Study models Substance Use Disorder Synapses Time Ventral Tegmental Area Weaning Wild Type Mouse Withdrawal Work addiction base dopaminergic neuron drug abstinence drug withdrawal experimental study flexibility gamma-Aminobutyric Acid mu opioid receptors mutant neuroadaptation neuromechanism novel opioid abuse opioid epidemic opioid use pain relief pre-clinical research preclinical study prevent protein activation receptor recruit relating to nervous system response sensor side effect tool

项目摘要

Opioid drugs are essential medications for the relief of serious pain, with no substitutes currently available for postsurgical and other severe indications. Long term use of opioids, however, leads to numerous side effects, and to substantial risk of substance use disorder (SUD). SUD or “addiction” is diagnosed based on behavioral characteristics that manifest broadly as loss of control or “compulsive” drug seeking and impaired decision making or “cognitive flexibility” even after months to years of abstinence. However, the majority of preclinical research of drug abuse focuses on models of drug-taking and reward-seeking rather than on the long-lasting changes in behavioral flexibility that underlie human SUDs. In addition, preclinical studies of SUD mechanism have been limited to comparing animals that have or have not taken drug. This has made it difficult to dissociate opioid- induced changes in biology and behavior that occur merely due to drug exposure from those that actually underlie the pathology of a SUD. We have developed a unique tool to circumvent this significant confound in opioid abuse research. Specifically, we have developed a knock-in mouse that expresses a modified mu opioid receptor (MOR) with altered signaling properties. The MOR when activated by its endogenous ligands, endorphins and enkephalins, engages G protein signaling to control neuronal activity. Following G protein activation by endogenous ligand, most G protein coupled receptors (GPCR), including the MOR, then rapidly recruit arrestins that silence the G protein signal and promote receptor endocytosis and, for the MOR, rapid recycling. This mechanism thereby carefully titrates G protein signal with a precision and time course ideally suited to respond to transmitters that are released in a pulsatile manner. In contrast, MORs activated by morphine and all its derivates effectively engage G protein signaling but poorly engage arrestins. In the current vernacular of GPCR pharmacology, morphine is termed a “biased” agonist, signaling preferentially to G protein over arrestins while endorphins are “balanced” agonists, engaging both G proteins and arrestins. The RMOR receptor was engineered to effectively engage both G protein and arrestin when activated by morphine without altering signaling in response to endogenous transmitters. Importantly, in our extensive previous work, we have found that RMOR mice do not develop tolerance or dependence to morphine nor do they transition to compulsive drug seeking in a model of SUD under conditions where wild type (WT) mice do. More recently, we have found while morphine causes long-lasting changes in cognitive flexibility in WT mice, this effect is also absent in RMOR mice. Here we will use WT and RMOR mice to pinpoint molecular and synaptic mechanisms that underlie SUDs in a paradigm where all mice receive drug but only WT show pathologic morphine responses. We propose that any morphine-induced changes that occur in both genotypes is likely to reflect a response to drug exposure, whereas changes confined to WT mice likely contribute to the pathology of SUDs.

阿片类药物是缓解严重疼痛的必不可少的药物，目前没有替代品术后和其他严重的适应症。但是，长期使用阿片类药物会导致许多副作用，并出现物质使用障碍的重大风险（SUD）。根据行为诊断出SUD或“成瘾” 广泛表现为失去控制或“强迫性”毒品的特征，决策和损害或几个月到几年的禁欲后，“认知灵活性”。但是，大多数临床前研究药物滥用的重点是吸毒和寻求奖励的模型，而不是持续的变化人类泡沫的基础的行为灵活性。另外，SUD机制的临床前研究已经仅限于比较尚未服用药物的动物。这使得分离阿片类药物很难诱发的生物学和行为变化仅是由于药物暴露于实际上的药物 SUD的病理。我们已经开发了一种独特的工具来规避阿片类药物滥用的这种重大混乱研究。具体而言，我们已经开发了一种表达修改后的阿片类药物接收器的敲门鼠标（MOR）具有改变信号的特性。 MOR被内源配体，内啡肽和 Enkephalins，参与G蛋白信号传导以控制神经元活性。遵循G蛋白激活内源配体，大多数G蛋白偶联受体（GPCR），包括MOR，然后迅速募集抑制蛋白静音G蛋白信号并促进受体内吞作用，并为MOR快速回收。这机制因此，以精确和时间过程为理想地响应G蛋白信号的机制仔细滴定G蛋白信号以脉动方式释放的发射器。相比之下，莫尔斯被吗啡及其所有有效地引入G蛋白信号传导，但吸收不良。在当前GPCR的白话药理学，吗啡被称为“有偏见”的激动剂，优先向G蛋白发出信号，而不是停滞蛋白内啡肽是“平衡”的激动剂，吸引了G蛋白和逮捕蛋白。 RMOR受体是设计为有效地接合G蛋白和逮捕蛋白，而被吗啡激活而无需更改响应内源性发射器的信号传导。重要的是，在我们以前的广泛工作中，我们发现 RMOR小鼠不会产生耐受性或对吗啡的依赖性，也不会过渡到强迫性药物在野生类型（WT）小鼠的条件下寻求SUD模型。最近，我们发现吗啡会导致WT小鼠认知灵活性的长期变化，在RMOR小鼠中也没有这种作用。在这里，我们将使用wt和rmor小鼠来查明分子和合成机制，这些机制是suds的基础所有小鼠都接受药物但仅WT显示病理吗啡反应的范式。我们建议任何吗啡诱导的两种基因型中发生的变化可能反映了对药物暴露的反应，而局限于WT小鼠的变化可能有助于SUD的病理。