Hyaluronan signaling to nociceptors in inflammatory pain

炎症性疼痛中透明质酸向伤害感受器发出信号

基本信息

批准号：
9908043
负责人：
JON DAVID LEVINE
金额：
$ 58.74万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2019-04-05 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908043
关键词：
Absence of pain sensation Acute Pain Affect Afferent Neurons Analgesics Applications Grants Arthritis Attenuated Binding Bradykinin CD44 Antigens CD44 gene Capsaicin Cell membrane Clinical Connective Tissue Diseases Cutaneous Degenerative polyarthritis Dermatitis Development Disease Dose Electrophysiology (science)Elements Extracellular Matrix Fiber Functional disorder Hyaluronan Hyperalgesia In Vitro Inflammation Inflammation Mediators Inflammatory Injury Intra-Articular Injections Ion Channel Joints Ligands Mechanics Mediating Methods Modality Molecular Weight Movement Nerve Nerve Endings Neurons Neuropathy Nociception Nociceptors Pain Pain Research Pain management Patients Play Population Pre-Clinical Model Property Publications Reactive Oxygen Species Reporting Research Role Second Messenger Systems Signal Pathway Signal Transduction Spinal Ganglia Stress Structure Supporting Cell Syndrome Synovial joint TRPV1 gene Testing Therapeutic Tissues Urate attenuation base chronic pain clinical pain design experimental study improved in vivo inflammatory pain insight joint inflammation knock-down mechanical force novel osteoarthritis pain pain model pain reduction patch clamp receptor sexual dimorphism tissue injury viscoelasticity voltage clamp

项目摘要

PROJECT SUMMARY/ABSTRACT The extracellular matrix (ECM) plays a major role in the pathophysiology of painful connective tissue diseases characterized by inflammation and tissue injury, such as arthritis and dermatitis. High molecular weight hyaluronan (HMWH), the major non-protein component of the ECM, is metabolized to low molecular weight hyaluronans (LMWH) in these clinical conditions. In preliminary studies we have shown that LMWH sensitizes synovial and cutaneous nociceptors, and produces articular and cutaneous mechanical hyperalgesia. In contrast, HMWH is currently used in the treatment of pain in patients with arthritis and other connective tissue diseases, and while current dogma teaches that the analgesic properties of HMWH are due to its viscoelastic properties, we propose the novel hypothesis that both HMWH-induced analgesia/anti-hyperalgesia, and LMWH-induced mechanical hyperalgesia are both generated by their action at the cognate hyaluronan (HA) receptor, CD44, in the plasma membrane of pain sensory neurons (nociceptors). To test this hypothesis, we will: 1) comprehensively study the pro- and anti-nociceptive properties of these two size classes of HA to establish the properties of LMWH that induce pain (hyperalgesia) and HMWH that induce analgesia (anti-hyperalgesia); 2) use in vitro patch-clamp electrophysiology to establish that HA acts directly on nociceptors to sensitize (LMWH) or reverse sensitization (HMWH) of nociceptor excitability, and determine the nociceptor populations upon which HAs act to produce their effects and the ion channels in each population whose function is modulated by HA; 3) confirm the role of the cognate hyaluronan receptor, CD44 and its downstream second messenger signaling pathways, in LMWH hyperalgesia and HMWH analgesia, and that the CD44 is in nociceptors; and, 4) use preclinical models of inflammatory, neuropathic and stress-induced pain to demonstrate that nociceptor CD44 is involved in the pain in with these syndromes, and that HMWH can be used as an anti-hyperalgesia/analgesia therapeutic modality. The proposed experiments will provide insight into the role of an important element of the ECM in diverse pain syndromes, and a rationale for developing new, more effective forms of HMWH to treat pain.

项目概要/摘要细胞外基质 (ECM) 在疼痛性结缔组织疾病的病理生理学中发挥着重要作用其特征是炎症和组织损伤，例如关节炎和皮炎。高分子量透明质酸 (HMWH) 是 ECM 的主要非蛋白质成分，被代谢为低分子量透明质酸（LMWH）在这些临床条件下。在初步研究中，我们已经表明 LMWH 可以使滑膜和皮肤伤害感受器，并产生关节和皮肤机械痛觉过敏。相比之下， HMWH 目前用于治疗关节炎和其他结缔组织疾病患者的疼痛，虽然当前的教条认为 HMWH 的镇痛特性是由于其粘弹性特性，我们提出了新的假设，即 HMWH 诱导的镇痛/抗痛觉过敏和 LMWH 诱导的镇痛/抗痛觉过敏机械性痛觉过敏都是通过作用于同源乙酰透明质酸 (HA) 受体 CD44 产生的，疼痛感觉神经元（伤害感受器）的质膜。为了检验这个假设，我们将：1) 全面研究这两个尺寸类别的 HA 的促伤害和抗伤害特性，以确定引起疼痛（痛觉过敏）的 LMWH 和引起镇痛（抗痛觉过敏）的 HMWH 的特性； 2）使用体外膜片钳电生理学来确定 HA 直接作用于伤害感受器来致敏 (LMWH) 或伤害感受器兴奋性的反向敏化（HMWH），并确定伤害感受器群体 HA 发挥作用以产生其作用，每个群体中的离子通道的功能受 HA 调节； 3）确认同源透明质酸受体 CD44 及其下游第二信使信号传导的作用 LMWH 痛觉过敏和 HMWH 镇痛中的途径，以及 CD44 存在于伤害感受器中；以及，4) 使用炎症、神经性和应激性疼痛的临床前模型证明伤害感受器 CD44 与这些综合征的疼痛有关，HMWH 可用作抗痛觉过敏/镇痛药治疗方式。所提出的实验将深入了解一个重要元素的作用 ECM 治疗多种疼痛综合征，以及开发新的、更有效的 HMWH 治疗形式的基本原理疼痛。