Hyaluronan signaling to nociceptors in inflammatory pain

项目摘要/摘要 细胞外基质(ECM)在痛性结缔组织病的病理生理学中起重要作用。 以炎症和组织损伤为特征的，如关节炎和皮炎。高分子量 透明质酸(HMWH)是细胞外基质的主要非蛋白质成分，被代谢成低分子量 透明质酸(LMWH)在这些临床条件下。在初步研究中，我们已经表明低分子肝素能敏化 滑膜和皮肤伤害性感受器，并产生关节和皮肤机械性痛觉过敏。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， 虽然目前的教条教导说，HMWH的止痛特性是由于其粘弹性特性， 我们提出了一个新的假设，即高分子肝素诱导的镇痛/抗痛觉过敏和低分子肝素诱导的 机械性痛敏都是由它们在同源透明质酸(HA)受体CD44上的作用而产生的。 痛觉神经元(伤害性感受器)的质膜。为了检验这一假设，我们将：1) 综合研究这两种粒径HA的促痛和抗伤害性，以建立 低分子肝素引起疼痛(痛敏)和高分子肝素诱导止痛(抗痛觉过敏)的特性；2) 利用体外膜片钳电生理学证实HA直接作用于伤害性感受器敏化(LMWH) 或伤害性感受器兴奋性的反向敏化(HMWH)，并确定其上的伤害性感受器种群 有作用产生它们的作用和每个群体中的离子通道，其功能受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的作用 低分子肝素痛敏和高分子肝素镇痛中的通路，以及CD44在伤害性感受器中的作用；以及，4)使用 炎症、神经病理性和应激性疼痛的临床前模型证明伤害性感受器CD44是 与这些症状有关的疼痛，HMWH可用作抗痛觉过敏/止痛 治疗方式。拟议的实验将使我们深入了解 不同疼痛综合征中的ECM，以及开发新的、更有效的HMWH治疗形式的理论基础 疼痛。

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.