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

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.
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项目成果

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JON DAVID LEVINE其他文献

JON DAVID LEVINE的其他文献

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{{ truncateString('JON DAVID LEVINE', 18)}}的其他基金

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:
    10558628
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress
慢性化疗周围神经病变:神经可塑性和压力的作用
  • 批准号:
    10472499
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
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:
    10091973
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress
慢性化疗周围神经病变:神经可塑性和压力的作用
  • 批准号:
    10229396
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
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:
    9750359
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress
慢性化疗周围神经病变:神经可塑性和压力的作用
  • 批准号:
    10013159
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress
慢性化疗周围神经病变:神经可塑性和压力的作用
  • 批准号:
    10701692
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress
慢性化疗周围神经病变:神经可塑性和压力的作用
  • 批准号:
    9986945
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 61.73万
  • 项目类别:
Nociceptor mechanisms in the transition from acute to chronic pain
从急性疼痛转变为慢性疼痛的伤害感受器机制
  • 批准号:
    8827433
  • 财政年份:
    2014
  • 资助金额:
    $ 61.73万
  • 项目类别:

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