Vascular Pain Mechanisms

血管疼痛机制

• 批准号: 8760194
• 负责人: JON DAVID LEVINE
• 金额: $ 47.16万
• 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/8760194
• 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; pre-clinical; public health relevance; 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与血管有关，但其潜在机制仍然难以捉摸。先前的研究已经提供了强有力的证据，证明血管腔内内皮细胞可以释放介质的作用，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新的机制，它驱动血管内皮细胞对周围性痛觉过敏的积极贡献。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引起，内皮素-1 （ET-1）和肾上腺素，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，机械刺激现在产生ATP的释放，进而作用于感觉神经元上的P2X3受体。这一发现是通过我们创新地适应心血管和肾血管文献中的两种独立方法来减弱该部位的内皮细胞功能而成为可能的