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Mechanisms of Muscle Afferent Sensitization after Ischemia

缺血后肌肉传入敏化的机制

基本信息

批准号：
8631367
负责人：
Michael P Jankowski
金额：
$ 31.84万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631367
关键词：
ASIC channel Acute Affect Afferent Neurons Anatomy Animals Behavioral Biological Assay Cardiovascular Diseases Cardiovascular system Cells Complex Regional Pain Syndromes Cutaneous Data Development Disease Drug Formulations Esthesia Event Fatigue Fiber Gene Expression Genes Goals Health Heating Hematological Disease Homeostasis Human Individual Injury Ischemia Knowledge Lead Mechanics Mediating Modeling Molecular Mus Muscle Musculoskeletal Pain Myalgia Nerve Neurons Nociception Nociceptors Pain Patients Pattern Peripheral Peripheral Nerves Peripheral Vascular Diseases Phase Phenotype Physiological Play Population Preparation Property Purinoceptor Reflex action Reperfusion Therapy Reporting Reverse Transcriptase Polymerase Chain Reaction Role Running Sickle Cell Anemia Small Interfering RNA Spinal Cord Spinal Ganglia Stimulus Structure of ulnar nerve System Techniques Testing Therapeutic Studies Tissues United States Up-Regulation artery occlusion base behavior test brachial artery chronic pain experience grasp in vivo insight median nerve molecular phenotype neurochemistry novel pain behavior pain receptor prevent public health relevance receptor research study response sensor sickle cell crisis

项目摘要

ABSTRACT: Musculoskeletal pain resulting from tissue ischemia with reperfusion is a major health issue that affects millions of people in the United States. Peripheral ischemia/ reperfusion occurs in blood disorders like sickle cell disease, and in cardiovascular disorders such as peripheral vascular disease. Ischemia/ reperfusion is also thought to be the underlying cause of complex regional pain syndrome. While much is known about the functional properties and plasticity of cutaneous nociceptors following peripheral injuries and how these fibers contribute to pain, relatively little is known about the functional properties of group III and IV muscle afferents and their role in muscle pain development. The major goal of this proposal is to determine the molecular mechanisms of muscle afferent sensitization that may underlie muscle pain during ischemia and after tissue reperfusion. We hypothesize that these distinct phases cause differential changes in heat, mechanical and chemo-sensitivity in muscle afferents, which are mediated by upregulation of purinergic receptors during ischemia and acid sensing ion channels after reperfusion leading to muscle pain. In order to increase our knowledge of muscle afferents, we developed a novel ex vivo forepaw muscle, median & ulnar nerves, dorsal root ganglion (DRG), spinal cord recording preparation that enables us to comprehensively phenotype these afferents in mouse. We are also able to analyze the central anatomy, and the neurochemical or molecular phenotypes of these afferents using combinations of ex vivo recording with immunocytochemical and single cell RT-PCR analyses. In Specific Aim 1, we will determine if upregulation of purinergic receptors, P2Y1 and P2X5, regulate the observed changes in heat and chemosensitivity in muscle afferents, respectively during ischemia using in vivo siRNA-mediated knockdown of these genes in single peripheral nerves in conjunction with ex vivo recording preparations. Next, in Specific Aim 2, we will utilize a similar approach to SA1 except we will determine if upregulation of ASIC1 and ASIC3 regulate the novel changes in mechanical and metabolite responses in muscle afferents, respectively after transient ischemia with tissue reperfusion. Finally, in Specific Aim 3, we will determine if upregulation of P2Y1 and P2X5 regulate muscle pain during ischemia while upregulation of ASIC1 and ASIC3 regulate muscle pain after reperfusion by analyzing the effects of receptor knockdown on recognized muscle pain behavior tests between these two phases. This study will enable us to characterize the changes in both non-nociceptive and nociceptive muscle afferents after ischemia/ reperfusion and identify unique mechanisms associated with muscle afferent sensitization that underlie muscle pain development. This may lead to the formulation of more appropriate treatments for musculoskeletal pain associated with ischemia/ reperfusion that target the proper pain receptor(s) or primary afferent subpopulation(s).

摘要：组织缺血再灌注引起的肌肉骨骼疼痛是一个主要的健康问题