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

• 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
• 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

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.

项目摘要/摘要 细胞外基质（ECM）在疼痛结缔组织疾病的病理生理学中起主要作用 以炎症和组织损伤为特征，例如关节炎和皮炎。高分子量 ECM的主要非蛋白质成分透明质酸（HMWH）被代谢为低分子量 在这些临床条件下的透明质酸（LMWH）。在初步研究中，我们表明LMWH敏感 滑膜和皮肤伤害感受器，并产生关节和皮肤的机械性痛觉过敏。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， 虽然当前的教条教导HMWH的镇痛特性是由于其粘弹性特性引起的，但 我们提出了一个新的假设，即HMWH诱导的镇痛/抗疗法和LMWH诱导的 机械性痛觉过敏均由其在同源透明质酸（HA）受体CD44中的作用产生 疼痛感觉神经元（伤害感受器）的质膜。为了检验这一假设，我们将：1） 全面研究这两种大小的HA类别的亲和抗伤害感性特性，以建立 LMWH的特性诱导疼痛（痛觉过敏）和HMWH，诱导镇痛（抗高质量）； 2） 使用体外贴片钳电生理学来确定HA直接作用于伤害感受器以敏化（LMWH） 或对伤害感受器兴奋性的反向敏化（HMWH），并确定伤害感受器种群 在功能受HA调节的每个人群中产生其效果和离子通道的作用； 3） 确认同源透明质酸受体CD44的作用及其下游第二信号信号 途径，在LMWH Hypergesia和HMWH镇痛中，CD44在伤害感受器中；和，4）使用 炎症，神经性和应激诱导的疼痛的临床前模型，以证明伤害感受器CD44为 这些综合征参与疼痛，HMWH可以用作抗高疗法/镇痛 治疗方式。提出的实验将洞悉有关该重要元素的作用 各种疼痛综合征的ECM，以及开发新的，更有效形式的HMWH来治疗的基本原理 疼痛。