Signaling balance and opioid dependence

信号平衡和阿片类药物依赖

• 批准号: 10708852
• 负责人: JENNIFER L WHISTLER
• 金额: $ 61.47万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/10708852
• 关键词: Abstinence; Acute; Agonist; Analgesics; Animals; Arrestins; Behavior; Behavioral; Biology; Brain; Cells; Characteristics; Clinical; Cognitive; Color; Data; Decision Making; Dependence; Derivation procedure; Diagnosis; Dissociation; Distress; Dopamine; Dopamine D2 Receptor; Dose; 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; Titrations; Ventral Tegmental Area; Weaning; Wild Type Mouse; Withdrawal; Work; addiction; dopaminergic neuron; drug abstinence; drug withdrawal; experimental study; flexibility; gamma-Aminobutyric Acid; mu opioid receptors; mutant; neural; neuroadaptation; neuromechanism; novel; opioid abuse; opioid epidemic; opioid use; pain relief; pre-clinical research; preclinical study; prevent; protein activation; receptor; recruit; response; sensor; side effect; tool

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基本药物，目前没有替代品可供使用。 术后和其他严重适应症。然而，长期使用阿片类药物会导致许多副作用， 以及物质使用障碍（SUD）的重大风险。SUD或“成瘾”是根据行为特征诊断的。 广泛表现为失去控制或“强迫性”吸毒和决策能力受损的特征 或“认知灵活性”，即使在数月或数年的禁欲之后。然而，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式，而不是药物滥用的长期变化。 行为的灵活性是人类SUD的基础。此外，SUD机制的临床前研究已被 仅限于比较服用或未服用药物的动物。这使得很难分离阿片类药物- 仅仅由于药物暴露而引起的生物学和行为变化， SUD的病理学我们已经开发了一种独特的工具来规避阿片类药物滥用中的这一重大混淆 research.具体来说，我们已经开发了一种基因敲入小鼠，它表达了一种修饰的μ阿片受体 (MOR)改变了信号特性莫尔在被其内源性配体内啡肽激活时， 脑啡肽参与G蛋白信号传导以控制神经元活动。G蛋白激活后， 内源性配体，大多数G蛋白偶联受体（GPCR），包括莫尔，然后迅速募集抑制蛋白 抑制G蛋白信号并促进受体内吞作用，以及莫尔的快速再循环。这 机制，从而仔细地以精确度和时间过程来调节G蛋白信号， 涉及以脉动方式释放的发射器。与此相反，吗啡激活的MORs及其 衍生物有效地参与G蛋白信号传导，但很少参与抑制蛋白。在目前的气相化学还原术语中， 药理学上，吗啡被称为“偏向性”激动剂，相对于抑制蛋白，优先向G蛋白发出信号，而 内啡肽是“平衡的”激动剂，与G蛋白和抑制蛋白结合。RMOR受体是 被设计成当被吗啡激活时有效地接合G蛋白和抑制蛋白，而不改变 响应于内源性递质的信号传导。重要的是，在我们以前广泛的工作中，我们发现 RMOR小鼠不会对吗啡产生耐受性或依赖性，也不会过渡到强迫性药物 在野生型（WT）小鼠的条件下寻找SUD模型。最近，我们发现， 吗啡在WT小鼠中引起认知灵活性的长期变化，这种作用在RMOR小鼠中也不存在。 在这里，我们将使用WT和RMOR小鼠来确定SUD的分子和突触机制。 所有小鼠接受药物，但只有WT显示病理性吗啡反应。我们建议，任何 两种基因型中发生的吗啡诱导的变化可能反映了对药物暴露的反应， 仅限于WT小鼠的变化可能导致SUD的病理学。