Vascular Pain Mechanisms

血管疼痛机制

• 批准号: 9096900
• 负责人: JON DAVID LEVINE
• 金额: $ 45.58万
• 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/9096900
• 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; 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; innovation; kidney vascular structure; novel; peripheral pain; pre-clinical; receptor; research study; second messenger; triptans

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 �-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，之前的研究已经为血管腔内皮细胞释放的介质的作用提供了有力的证据。 ，但内皮细胞本身动态参与疼痛产生的机制尚未被描述，我们最近发现了一种驱动血管内皮细胞积极参与外周痛觉过敏的新机制。称为刺激依赖性痛觉过敏 (SDH) 可由两种血管活性化合物、内皮素-1 (ET-1) 和肾上腺素引起，作用于内皮细胞上的同源受体，产生一种状态，在这种状态下，机械刺激现在会释放ATP 反过来作用于感觉神经元上的 P2X3 受体，这一发现是通过我们创新性地采用心血管和肾血管文献中的两种独立方法来减弱内皮细胞而实现的。该位点的细胞功能 伤害性测试：用 octoxynol-9 和蛋氨酸诱导的高同型半胱氨酸血症进行治疗。该资助申请概述了研究 SDH 的细胞机制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的实验。 ，我们将研究SDH的机制，包括：1）内皮细胞在SDH中的作用，2）参与SDH的内皮细胞介质及其机制它们是从内皮细胞释放的，3) 参与 SDH 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。 SDH，第二个具体目标将更广泛地检查内皮细胞在具有血管成分的临床 Pai 综合征模型中的作用，而不仅限于 SDH 机制。评估内皮细胞作为现有治疗血管疼痛综合征（例如曲坦类和β受体阻滞剂）的可能目标，其机制尚未完全了解此外，因为压力是血管疼痛的临床疼痛状况的主要因素。我们将研究神经内分泌应激轴介质对此类综合征中内皮依赖性疼痛的影响，通过阐明内皮细胞对疼痛的贡献，这些研究有可能确定新的靶点。开发血管疼痛综合征的药物治疗。