Hyaluronan signaling to nociceptors in inflammatory 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中起着重要作用 其特征在于炎症和组织损伤，例如关节炎和皮炎。高分子量 透明质酸（HMWH）是ECM的主要非蛋白质组分，被代谢成低分子量 透明质酸（LMWH）在这些临床条件。在初步研究中，我们已经表明，LMWH敏化 滑膜和皮肤伤害感受器，并产生关节和皮肤机械痛觉过敏。与此相反， HMWH目前用于治疗关节炎和其他结缔组织疾病患者的疼痛， 虽然目前的教条教导HMWH的镇痛性质是由于其粘弹性， 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它们对同源透明质酸（HA）受体CD 44的作用而产生的， 痛觉神经元（伤害感受器）的质膜。为了验证这个假设，我们将：1） 全面研究这两种尺寸级别的HA的促伤害性和抗伤害性特性，以确定 LMWH诱导疼痛（痛觉过敏）和HMWH诱导镇痛（抗痛觉过敏）的性质; 2） 使用体外膜片钳电生理学确定HA直接作用于伤害感受器致敏（LMWH） 或伤害感受器兴奋性的反向致敏（HMWH），并确定伤害感受器群体， HA发挥作用以产生其效应，并且每个群体中的离子通道的功能由HA调节; 3） 证实同源透明质酸受体CD 44及其下游第二信使信号传导的作用 途径，在LMWH痛觉过敏和HMWH镇痛中，并且CD 44在伤害感受器中;以及，4）使用 炎性、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CD 44是 参与这些综合征的疼痛，HMWH可用作抗痛觉过敏/镇痛 治疗方式拟议的实验将提供深入了解的一个重要因素的作用， ECM在不同疼痛综合征中的作用，以及开发新的，更有效的HMWH治疗形式的基本原理 痛苦

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.