权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defining the role of peripheral Adrb3 in chronic pain and inflammation

定义外周 Adrb3 在慢性疼痛和炎症中的作用

基本信息

批准号：
10216371
负责人：
Andrea G Nackley
金额：
$ 53.46万
依托单位：
DUKE 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：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10216371
关键词：
Adipocytes Adipose tissue Affect Animal Model Behavior Behavioral Biological Markers Blood C57BL/6 Mouse Catechol O-Methyltransferase Catecholamines Cells Chronic Clinical Corticosterone Data Development Down-Regulation Enzymes Exhibits Female Fibromyalgia Flow Cytometry Genotype Goals Healthcare Hindlimb Immune Immune response Immunohistochemistry Individual Inflammation Inflammatory Interleukin-6 Knowledge Lead Maintenance Measures Mediating Metabolism Methodology Methyltransferase Gene MicroRNAs Mitogen-Activated Protein Kinases Molecular Mus Muscle Nerve Neuroglia Neuronal Plasticity Neurons Nociceptors Pain Parents Pathway interactions Patients Pattern Peripheral Peripheral Nerves Persistent pain Pharmacology Phosphorylation Physiology Plasma Population Quality of life Receptors, Adrenergic, beta-3 Reporting Resolution Rodent Rodent Model Role Signal Transduction Site Skin Specificity Spinal Spinal Cord Spinal Ganglia Stress Stressful Event Swimming Syndrome Temporomandibular Joint Disorders Testing Time Tissues Tumor-infiltrating immune cells Up-Regulation Variant Volition Work adipokines behavioral phenotyping beta-adrenergic receptor calcium indicator cell type central sensitization chronic pain clinically relevant cytokine effective therapy genetic variant improved in vivo calcium imaging inhibitor/antagonist insight male molecular phenotype multiplex assay neuroinflammation new therapeutic target novel pain behavior prevent relating to nervous system side effect treatment strategy

项目摘要

ABSTRACT Functional pain syndromes affect over 100 million people, yet remain ineffectively treated because the causes are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to low activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated 66% of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that lead to low activity of the COMT enzyme. Individuals with the ‘low COMT activity’ genotype report greater pain at baseline and enhanced pain following stressful events that potentiate catecholamine release from sympathetic nerves. Consistent with clinical syndromes, our lab has shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites and enhances pain following repeated stress. In subsequent studies, we demonstrated that COMT-dependent pain is initiated by peripheral adrenergic receptor beta-3 (Adrb3) through the release of pro-inflammatory cytokines in local tissues. The pain is maintained by subsequent increases in pro-inflammatory cytokines in spinal tissues and activation of mitogen activated protein kinases (MAPKs) in the cell bodies and central terminals of pain-sensing nociceptors. Together, these data show that heightened catecholamine tone leads to chronic pain via peripheral Adrb3 and its downstream effectors. However, the cell types that express Adrb3 and mediate pain still need to be identified and the molecular mechanisms determined. We hypothesize that activation of Adrb3 on adipocytes (fat cells that surround peripheral nociceptor and sympathetic nerve terminals) drives chronic COMT-dependent pain via increases in cytokines and MAPKs that promote inflammation and nociceptor activation. Further, we hypothesize that stress-induced catecholamine release amplifies the effects of Adrb3 signaling on inflammation and pain. Preliminary data reveal that COMT-dependent increases in pro-inflammatory cytokines are mediated by Adrb3 located on adipocytes. Additional data reveal that sustained activation of Adrb3 leads to decreased levels of miR-133a, a microRNA expressed in adipocytes that is able to block MAPK signaling. The proposed studies will extend this work to directly determine 1) Adrb3 and miR-133a expression patterns in adipose vs other peripheral tissues over time and their relationship to COMT-dependent functional pain, 2) the role of peripheral Adrb3 and miR-133a in mediating COMT-dependent inflammation and neuroinflammation, 3) the role of peripheral Adrb3 and miR-133a in mediating COMT-dependent increases in the activity of mechosensitive and thermosensitive nociceptors, and 4) how these molecular and behavioral phenotypes are influenced by stress. Results from these studies will advance our knowledge about the mechanisms whereby peripheral Adrb3 drives chronic pain and elucidate new targets for the development of peripherally-restricted therapies with improved specificity and side-effect profiles for the treatment of functional pain syndromes.

Please try later.