In Vivo Implications of Agonist Selective Activation of Delta Opioid Receptor

Delta 阿片受体激动剂选择性激活的体内影响

基本信息

批准号：
8092465
负责人：
Amynah Amir Ali Pradhan
金额：
$ 15.85万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8092465
关键词：
Absence of pain sensation Accounting Acute Adult Adverse effects Affect Agonist Analgesics Animals Anxiety Arrestins Behavior Behavioral Binding Biological Assay California Chronic Chronic Disease Clinical Collaborations Complex Convulsions Core Facility Coupling DNA Microarray Chip Development Educational process of instructing Electrophysiology (science)Emotional Faculty Fentanyl G-Protein-Coupled Receptors GTP-Binding Proteins Gene Activation Gene Expression Genes Goals In Vitro Institution Ion Channel Knock-out Knockout Mice Laboratories Learning Ligands Ligation Los Angeles Mediating Mediator of activation protein Mental Depression Mentors Modeling Morphine Mus Mutant Strains Mice Neurons Opioid Opioid Receptor Pain Pharmacology Pharmacotherapy Phase Phosphoproteins Positioning Attribute Postdoctoral Fellow Primary Cell Cultures Property Proteins RNA Interference Receptor Activation Receptor Down-Regulation Receptor Inhibition Receptor Signaling Research Research Personnel Role Seizures Signal Transduction Signaling Protein Site Spinal Ganglia Structure Technical Expertise Techniques Therapeutic Time Universities Validation Work addiction arrestin 1 arrestin 2 brain tissue cell type chronic pain delta opioid receptor desensitization experience in vivo in vivo Model inflammatory pain inhibitor/antagonist interest knowledge base novel receptor receptor binding receptor internalization response skills trafficking

项目摘要

DESCRIPTION (provided by applicant): I am currently a senior level postdoctoral fellow with a primary research focus in opioid receptor pharmacology. I intend to transition to a junior faculty position in the next two years, and my current mentored position has been structured to accomplish this goal. I have a wide-range of experience with in vivo models of pain and addiction, as well as extensive experience with techniques to assess receptor binding, function, and localization ex vivo. I am currently working in the laboratory of Dr. Christopher Evans, a prominent opioid researcher, at the University of California Los Angeles (UCLA). During my time at UCLA, I will enhance my skill set by learning new techniques in primary cell culture, electrophysiology, and arrays. My mentor and I have also planned several strategies to facilitate my transition to a faculty position, including budgetary responsibility, teaching, and course work. UCLA is a renowned institution with a number of high profile researchers, and during this mentored phase I will develop important collaborations that I hope to sustain into my independence. In addition, the university also has several state-of-the-art core facilities through which I will enhance my research opportunities. My research focus is on the in vivo consequences of ligand directed signaling at the delta (4) opioid receptor. Agonists for this receptor are being developed for clinical use, as activation of 4 receptors relieves pain, and reduces anxiety and depression. However, a major limitation to the clinical use of these compounds is that a subset of 4 agonists also produce convulsions, the mechanism of which is unknown. This agonist-selective behavior could be due to differential trafficking and signaling of the 4 receptor, and my recent work shows that the internalizing agonist, SNC80, produces convulsions which are not observed with the non-internalizing agonist, ARM390. 2-arrestins are major mediators of receptor internalization, and also mediate subsequent receptor signaling. One of the aims of this proposal is to determine the role of 2-arrestins in SNC80 and ARM390-induced behaviors, using 2-arrestin 1 and 2 knockout mice. In addition, to characterize the different signaling mechanisms regulating this functional selectivity, the distinct signaling complexes formed by SNC80 and ARM390 will be determined using proximity ligation assays and phosphoprotein arrays. Furthermore, I have found that repeated use of these agonists in an inflammatory pain model also results in differential tolerance. SNC80 produces receptor down regulation and generalized tolerance to all agonist-induced effects. In contrast, ARM390-tolerant animals show intact 4 receptors, and analgesic tolerance only - the mechanism of which is unknown. A further aim of this application is to characterize this differential tolerance, by looking for changes in receptor-ion channel coupling within the dorsal root ganglia following chronic use. I will also examine the role of 2-arrestins in these two types of tolerance, and explore possible mechanisms underlying these differences using DNA microarrays. This work has important therapeutic implications, and will enhance our understanding of in vivo opioid receptor trafficking and signaling. PUBLIC HEALTH RELEVANCE: Delta opioid receptor activation produces pain-relief, and reduces anxiety and depression; and for this reason agonist to this receptor are being developed for clinical use. However, a deterrent to the development of these compounds is that some delta agonists also produce convulsions, and at the moment there is no way to predict whether a novel agonist will have this property. The goal of this proposal is to determine the mechanism that accounts for this difference between agonists that bind to the same receptor. Ultimately, this work would increase the potential for the delta opioid receptor as a novel drug therapy.