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Signaling balance and opioid dependence

信号平衡和阿片类药物依赖

基本信息

批准号：
10839725
负责人：
JENNIFER L WHISTLER
金额：
$ 6.09万
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/10839725
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

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基本药物，目前尚无替代品