Vascular Pain Mechanisms

描述(申请人提供)：虽然许多疼痛综合征被认为与血管成分有关，但潜在的机制仍然难以捉摸。以前的研究已经提供了强有力的证据，证明血管内皮细胞可以释放出中介物质，但内皮细胞本身可以动态参与疼痛产生的机制还没有描述。我们最近发现了一种新的机制，它驱动血管内皮细胞对外周痛觉过敏做出积极贡献。这种现象被称为刺激依赖性痛觉过敏(SDH)，可由两种血管活性物质-内皮素-1(ET-1)和肾上腺素作用于它们在内皮细胞上的同源受体而产生一种状态，在这种状态下，机械刺激产生ATP释放，进而作用于感觉神经元上的P2X3受体。这一发现是因为我们对心血管和肾血管文献中两种独立的方法进行了创新性的调整，以削弱该部位的内皮细胞功能。 伤害性试验：使用辛基诺-9和蛋氨酸诱导的高同型半胱氨酸血症的治疗。这项拨款申请概述了研究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。在第一个具体目标中，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从内皮细胞释放的机制，3)参与SDH的内皮细胞的第二信使通路，以及4)哪些伤害性感受器介导SDH。与探讨血管内皮细胞主动参与SDH特定机制的细胞机制不同，第二个特定目标将更广泛地研究血管内皮细胞在具有血管成分的临床PAI综合征模型中的作用，而不限于SDH机制。这一目标还将评估血管内皮细胞作为现有血管疼痛综合征(例如，Triptans和�阻滞剂)治疗的可能靶点，其机制尚不完全清楚。此外，由于应激是临床疼痛状况的主要因素，血管被认为在其中起作用，我们将研究神经内分泌应激轴介体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作用，这些研究有可能为血管疼痛综合征的药物治疗的发展确定新的靶点。

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.