Vascular Pain Mechanisms

血管疼痛机制

• 批准号: 9317549
• 负责人: JON DAVID LEVINE
• 金额: $ 44.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317549
• 关键词: Afferent Neurons; Applications Grants; Attenuated; Blood Vessels; Cardiovascular system; Cell physiology; Cells; Clinical; Development; Endothelial Cells; Endothelin; Endothelin-1; Epinephrine; Generations; Health; Hyperalgesia; Hyperhomocysteinemia; Individual; Inflammatory; Knowledge; Literature; Mechanical Stimulation; Mediating; Mediator of activation protein; Methionine; Methods; Migraine; Modeling; Nerve Fibers; Nerve Pain; Neurosecretory Systems; Nociception; Nociceptors; Pain; Pathway interactions; Patients; Peptides; Peripheral; Pharmacological Treatment; Play; Pre-Clinical Model; Role; Second Messenger Systems; Signal Transduction; Site; Stimulus; Stress; Syndrome; Testing; Vascular Diseases; Vascular Endothelial Cell; Work; afferent nerve; experimental study; innovation; kidney vascular structure; novel; peripheral pain; pre-clinical; public health relevance; receptor; triptans; vascular contributions

DESCRIPTION (provided by applicant): While many pain syndromes are thought to have a vascular component, the underlying mechanisms remain elusive. Previous studies have provided strong evidence for a role of mediators that can be released by endothelial cells which line the lumen of blood vessels, but mechanisms by which endothelial cells themselves could dynamically participate in pain generation have not been described. We recently discovered a novel mechanism which drives an active contribution of vascular endothelial cells to peripheral hyperalgesia. This phenomenon, referred to as stimulus-dependent hyperalgesia (SDH) can be elicited by two vasoactive compounds, endothelin-1 (ET-1) and epinephrine, acting at their cognate receptors on the endothelial cell to produce a state in which mechanical stimulation now produces release of ATP that, in turn, acts on P2X3 receptors on sensory neurons. This discovery was made possible by our innovative adaptation of two independent methods from the cardiovascular and renal vascular literature to attenuate endothelial cell function at the site of nociceptive testing: treatment with octoxynol-9 and methionine-induced hyperhomocysteinemia. This grant application outlines experiments to investigate the cellular mechanisms of SDH and to explore the potential role of this or other endothelial cell mechanisms in vascular pain syndromes. In the first Specific Aim, we will investigate mechanisms of SDH including: 1) the role of the endothelial cell in SDH, 2) endothelial cell mediators involved in SDH and mechanisms by which they are released from the endothelial cell, 3) second messenger pathways in endothelial cells involved in SDH, and 4) which nociceptors mediate SDH. In contrast to Specific Aim 1 which probes cellular mechanisms by which vascular endothelial cells actively participate in particular mechanism of SDH, the second Specific Aim will more generally examine the role of the endothelial cell in models of clinical pai syndromes with a vascular component, not limited to the SDH mechanism. This aim will also evaluate the endothelial cell as a possible target of existing treatments for vascular pain syndromes (e.g., triptans and ß-blockers) the mechanisms of which are not fully understood. Furthermore, since stress is a major factor in clinical pain conditions in which blood vessels are thought to play a role, we will study the impact of neuroendocrine stress axis mediators on endothelialdependent pain in such syndromes. By elucidating the endothelial cell contribution to pain, these studies have the potential to identify novel targets for the development of pharmacological treatments of vascular pain syndromes.

描述（由申请人提供）：虽然许多疼痛综合征被认为具有血管成分，但其潜在机制仍然难以捉摸。以前的研究提供了强有力的证据，介质的作用，可以释放的内皮细胞内衬的血管腔，但机制，内皮细胞本身可以动态参与疼痛的产生还没有被描述。我们最近发现了一种新的机制，驱动血管内皮细胞的积极贡献外周痛觉过敏。这种现象被称为刺激依赖性痛觉过敏（SDH），可以由两种血管活性化合物内皮素-1（ET-1）和肾上腺素引起，其作用于内皮细胞上的同源受体以产生一种状态，其中机械刺激现在产生ATP的释放，ATP又作用于感觉神经元上的P2 X3受体。这一发现是通过我们对心血管和肾血管文献中两种独立方法的创新适应来实现的，以减弱伤害性试验部位的内皮细胞功能：用辛苯聚醇-9和甲硫氨酸诱导的高同型半胱氨酸血症治疗。这项资助申请概述了研究SDH细胞机制的实验，并探索这种或其他内皮细胞机制在血管疼痛综合征中的潜在作用。在第一个具体目标中，我们将研究SDH的机制，包括：1）SDH中内皮细胞的作用，2）SDH中涉及的内皮细胞介质及其从内皮细胞释放的机制，3）SDH中涉及的内皮细胞中的第二信使途径，以及4）哪些伤害感受器介导SDH。与探测血管内皮细胞积极参与SDH特定机制的细胞机制的特定目的1相比，第二个特定目的将更普遍地检查内皮细胞在具有血管成分的临床派综合征模型中的作用，而不限于SDH机制。该目的还将评估内皮细胞作为血管疼痛综合征的现有治疗的可能靶标（例如，曲坦类和β-受体阻滞剂），其机制尚未完全了解。此外，由于压力是临床疼痛的一个主要因素，其中血管被认为发挥了作用，我们将研究神经内分泌应激轴介质对内皮依赖性疼痛的影响，在这样的综合征。通过阐明内皮细胞对疼痛的贡献，这些研究有可能为血管疼痛综合征的药物治疗开发确定新的靶点。