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性疼痛发展的基础的细胞和分子机制。具体而言，该建议旨在评估周围代谢型谷氨酸受体5（MGLUR5）在炎症引起的疼痛和超敏反应中的作用。药理学研究的证据表明，MGLUR5在慢性疼痛的发展和维持中起着至关重要的作用。但是，MGLUR5激活诱导超敏反应的分子机制尚不清楚。此外，MGLUR5在整个神经系统中都表达，但是在外周伤害感官感觉神经元（伤害感受器）中表达的MGLUR5的特定作用尚不清楚。我将通过本提案中的实验解决这两个问题。首先，我将检验以下假设：炎症性疼痛的全部表达需要外周MGLUR5。为了检验该假设，我将评估仅在周围伤害感受器中缺少MGLUR5的一系列转基因敲除小鼠的疼痛与疼痛相关的行为。其次，我将解决MGLUR5诱导的超敏反应的分子机制。这些变化被认为是由于对周围伤害感受器表达的阳离子通道的调节所致。 MGLUR5和炎症介质Bradykinin激活了PLC耦合的细胞内信号级联。有趣的是，心动激肽激活导致伤害性阳离子通道瞬态受体电位A1（TRPA1）的激活。 Bradykinin受体和MGLUR5之间共有的常见PLC耦合细胞内信号传导级联反应表明MGLUR5可能会调节TRPA1。在此提案中，我将检验以下假设：MGLUR5激活可以调节伤害感受器中的TRPA1。我将利用原位杂交和钙成像来评估伤害感受器中MGLUR5和TRPA1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元中TRPA1介导的反应。最后，我将确定药理学MGLUR5活化是否会差异地影响TRPA1 KO小鼠的体内疼痛行为，而其野生型同窝仔。公共卫生相关性：该提案中的实验将为周围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的见解。对周围MGLUR5在炎症性疼痛中的作用以及MGLUR5诱导的超敏反应的信号传导机制的作用有了改进的了解，将直接指导未来的疼痛研究和治疗人类炎症性疼痛状况的治疗干预措施的发展。