The role of peripheral metabotropic glutamate receptor 5 in inflammatory pain

外周代谢型谷氨酸受体5在炎性疼痛中的作用

• 批准号: 8049104
• 负责人: MICHAEL MONTANA
• 金额: $ 2.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049104
• 关键词: Absence of pain sensation; Address; Adverse effects; Affect; Afferent Neurons; Animal Model; Animals; Asses; BDKRB2 gene; Behavior; Behavioral; Biochemistry; Bradykinin; Bradykinin Receptor; Calcium; Capsaicin; Cations; Cell Culture Techniques; Chemicals; Chronic; Chronic inflammatory pain; Clinical; Contralateral; Coupled; Data; Development; Exhibits; Formalin; Formalin Tests; Functional disorder; Future; Genetic; Genetic Models; Glutamates; Goals; Health; Human; Hypersensitivity; Image; In Situ Hybridization; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Investigation; Ion Channel; Ipsilateral; Irritants; Knock-out; Knockout Mice; Maintenance; Mechanics; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Biology; Molecular Target; Montana; Mus; Nervous system structure; Neuraxis; Neurons; Nociception; Pain; Pain Research; Patients; Peripheral; Peripheral Nerves; Phospholipase C; Play; Reporting; Role; Signal Pathway; Signal Transduction; Site; Spinal Ganglia; Stimulus; Testing; Therapeutic; Therapeutic Intervention; Training; behavior test; chronic pain; design; effective therapy; experience; improved; in vivo; inflammatory pain; insight; metabotropic glutamate receptor 5; novel; pain behavior; receptor; research and development; research study; response

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the cellular and molecular mechanisms that underlie the development of chronic inflammatory pain. Specifically, this proposal is designed to assess the role that peripheral metabotropic glutamate receptor 5 (mGluR5) plays in inflammation-induced pain and hypersensitization. Evidence from pharmacological studies indicates that mGluR5 plays a critical role in the development and maintenance of chronic pain. However, the molecular mechanisms through which mGluR5 activation induces hypersensitivity are unclear. In addition, mGluR5 is expressed throughout the nervous system, but the specific role of mGluR5 expressed in peripheral nociceptive sensory neurons (nociceptors) is unknown. I will address both of these issues through the experiments in this proposal. First, I will test the hypothesis that peripheral mGluR5 is required for the full expression of inflammatory pain. To test this hypothesis I will asses the pain related behaviors of a line of genetically modified knockout mice that lack mGluR5 only in peripheral nociceptors. Second, I will address the molecular mechanisms underlying mGluR5-induced hypersensitivity. These changes have been suggested to be due to the modulation of cation channels expressed on peripheral nociceptors. Both mGluR5 and the inflammatory mediator bradykinin activate PLC-coupled intracellular signaling cascades. Interestingly bradykinin activation results in the activation of the nociceptive cation channel Transient Receptor Potential A1 (TRPA1). The common PLC-coupled intracellular signaling cascade shared between bradykinin receptor and mGluR5 suggests that mGluR5 may modulate TRPA1. In this proposal I will test the hypothesis that mGluR5 activation can modulate TRPA1 in nociceptors. I will utilize in situ hybridization and calcium imaging to assess for mGluR5 and TRPA1 colocalization in nociceptors. Then I will assess whether mGluR5 activation can modulate TRPA1 mediated responses in dorsal root ganglia neurons in vitro. Finally I will determine whether pharmacological mGluR5 activation differentially affects the in vivo pain behaviors of TRPA1 KO mice as compared to their wildtype littermates. PUBLIC HEALTH RELEVANCE: The experiments in this proposal will provide critical insight into the role of peripheral mGluR5 in chronic pain and the molecular mechanisms through which mGluR5 activation results in hypersensitivity. An improved understanding of both the role of peripheral mGluR5 in inflammatory pain, and the signaling mechanisms underlying mGluR5-induced hypersensitivity, will directly guide both future pain research and the development of therapeutic interventions for the treatment of human inflammatory pain conditions.

描述（由申请人提供）： 该提案的长期目标是了解慢性炎症疼痛发展的细胞和分子机制。具体来说，该提案旨在评估外周代谢型谷氨酸受体 5 (mGluR5) 在炎症引起的疼痛和过敏中所起的作用。药理学研究证据表明，mGluR5 在慢性疼痛的发生和维持中发挥着关键作用。然而，mGluR5 激活诱发超敏反应的分子机制尚不清楚。此外，mGluR5在整个神经系统中表达，但在外周伤害感受神经元（伤害感受器）中表达的mGluR5的具体作用尚不清楚。我将通过本提案中的实验来解决这两个问题。首先，我将检验以下假设：外周 mGluR5 是炎性疼痛充分表达所必需的。为了检验这一假设，我将评估一系列仅在外周伤害感受器中缺乏 mGluR5 的转基因敲除小鼠的疼痛相关行为。其次，我将阐述 mGluR5 诱导的超敏反应的分子机制。这些变化被认为是由于外周伤害感受器上表达的阳离子通道的调节所致。 mGluR5 和炎症介质缓激肽均可激活 PLC 耦合的细胞内信号级联。有趣的是，缓激肽激活会导致伤害性阳离子通道瞬时受体电位 A1 (TRPA1) 的激活。缓激肽受体和 mGluR5 之间共有的常见 PLC 耦合细胞内信号级联表明 mGluR5 可能调节 TRPA1。在本提案中，我将测试 mGluR5 激活可以调节伤害感受器中的 TRPA1 的假设。我将利用原位杂交和钙成像来评估伤害感受器中 mGluR5 和 TRPA1 的共定位。然后我将评估 mGluR5 激活是否可以在体外调节背根神经节神经元中 TRPA1 介导的反应。最后，我将确定与野生型同窝小鼠相比，药理学 mGluR5 激活是否对 TRPA1 KO 小鼠的体内疼痛行为产生差异性影响。公共健康相关性：本提案中的实验将为外周 mGluR5 在慢性疼痛中的作用以及 mGluR5 激活导致超敏反应的分子机制提供重要见解。更好地了解外周 mGluR5 在炎性疼痛中的作用以及 mGluR5 诱导的超敏反应背后的信号机制，将直接指导未来的疼痛研究和治疗人类炎性疼痛病症的治疗干预措施的开发。