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: 10339337
• 负责人: JON DAVID LEVINE
• 金额: $ 61.73万
• 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/10339337
• 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; Supporting Cell; Syndrome; Synovial joint; TRPV1 gene; Testing; Therapeutic; Tissues; Urate; attenuation; base; chronic pain; clinical pain; experimental study; improved; in vivo; inflammatory pain; insight; joint inflammation; knock-down; mechanical force; novel; osteoarthritis pain; pain model; pain reduction; patch clamp; rational design; 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.

项目总结/文摘