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：
10009478
负责人：
Andrea G Nackley
金额：
$ 52.47万
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/10009478
关键词：
Adipocytes Adipose tissue Affect Animal Model Behavior Behavioral Biological Assay 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 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.

抽象的功能性疼痛综合症影响着超过 1 亿人，但由于其原因而仍未得到有效治疗越来越多的证据表明，这些综合症在很大程度上是由于低水平造成的。儿茶酚-O-甲基转移酶 (COMT) 的活性，一种代谢儿茶酚胺的酶。 66% 患有功能性疼痛综合征（例如纤维肌痛）的患者具有 COMT 基因变异，导致 COMT 酶活性低，具有“低 COMT 活性”基因型的个体报告疼痛更严重。基线时疼痛加剧，应激事件后疼痛加剧，从而增强儿茶酚胺的释放与临床综合征一致，我们的实验室表明药物抑制。 COMT 在啮齿类动物体内产生多个身体部位的疼痛，并在反复应激后加剧疼痛。随后的研究，我们证明COMT依赖性疼痛是由外周肾上腺素受体引发的 beta-3 (Adrb3) 通过在局部组织中释放促炎细胞因子来维持疼痛。随后脊髓组织中促炎细胞因子的增加和丝裂原的激活细胞体中的蛋白激酶 (MAPK) 和痛觉伤害感受器的中央末端共同作用。数据显示，儿茶酚胺音通过外周Adrb3及其下游导致慢性疼痛然而，表达 Adrb3 并介导疼痛的细胞类型仍需确定。我们研究了 Adrb3 对脂肪细胞（脂肪细胞）的激活作用。周围的伤害感受器和交感神经末梢）通过以下方式驱动慢性 COMT 依赖性疼痛促进炎症和伤害感受器激活的细胞因子和 MAPK 的增加。压力诱导的儿茶酚胺释放放大了 Adrb3 信号传导对炎症的影响初步数据表明，COMT 依赖性促炎细胞因子的增加是介导的。其他数据表明，Adrb3 的持续激活会导致脂肪细胞减少。 miR-133a 的水平，这是一种在脂肪细胞中表达的 microRNA，能够阻断 MAPK 信号传导。研究将扩展这项工作以直接确定 1) Adrb3 和 miR-133a 在脂肪与随着时间的推移，其他外周组织及其与 COMT 依赖性功能性疼痛的关系，2) 外周 Adrb3 和 miR-133a 介导 COMT 依赖性炎症和神经炎症，3) 外周 Adrb3 和 miR-133a 在介导 COMT 依赖性活性增加中的作用力敏和热敏伤害感受器，以及 4) 这些分子和行为表型是如何发生的这些研究的结果将增进我们对其机制的了解。外周 Adrb3 驱动慢性疼痛并阐明外周限制性药物开发的新靶点用于治疗功能性疼痛的具有改善特异性和副作用综合征特征的疗法。