Nociceptive Mechanisms Underlying Sickle Cell Pain

镰状细胞疼痛背后的伤害机制

• 批准号: 8334025
• 负责人: Cheryl A Hillery
• 金额: $ 43.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334025
• 关键词: A Mouse; Abnormal Hemoglobins; Acute; Acute Pain; Adult; Adverse effects; Affect; Afferent Neurons; Agreement; Behavioral; Behavioral Assay; Biochemistry; Birth; Blood Vessels; Brain; C Fiber; Cell Adhesion; Child; Chronic; Complex; Cutaneous; Data; Development; Endothelium; Erythrocytes; Event; Exhibits; Experimental Models; Family; Fiber; Functional disorder; Genetic; Goals; Grant; Heating; Hematopoietic stem cells; Hemolysis; Hospitalization; Hypersensitivity; Hypoxia; Inborn Genetic Diseases; Individual; Injury; Ion Channel; Knockout Mice; Knowledge; Lead; Length of Stay; Life; Measures; Mechanics; Mediating; Methods; Modeling; Molecular Biology; Mus; Nerve; Neuraxis; Neurons; Nociception; Nociceptors; Opioid; Organ; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physicians; Physiological; Plague; Preparation; Prevention; Process; Property; Quality of life; Reporting; Role; Scientist; Sensory; Shapes; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Site; Skin; Spinal Cord; Stem cell transplant; Stimulus; Syndrome; TRPA1 Channel; TRPV1 gene; Testing; Translational Research; abstracting; afferent nerve; base; chronic pain; disability; experience; heat stimulus; human disease; improved; in vivo; insight; interdisciplinary approach; neurobiological mechanism; novel; novel therapeutic intervention; pain behavior; programs; receptor; response; sickling

Project Summary/Abstract: Sickle cell disease is accompanied by both chronic and severe episodic pain that is difficult to treat, and profoundly erodes the quality of life of those who suffer from it. Despite a detailed understanding of the genetics, molecular biology and biochemistry of sickle hemoglobin, the pathogenesis of the profound pain syndromes observed in sickle cell disease remain incompletely understood and likely involve complex and heterogeneous steps occurring in both the peripheral and central nervous systems. The goal of this proposal is to elucidate the mechanisms by which sickle cell disease results in pain, focusing on peripheral mechanisms in primary afferent nerve terminals. Using a murine model of severe sickle cell disease, the Berkeley Sickle Mice, we demonstrate that these mice exhibit marked hypersensitivity to mechanical, heat and cold peripheral stimuli. Furthermore, induction of acute sickling with hypoxia specifically exacerbates the ongoing mechanical hypersensitivity in sickle cell mice. In agreement, teased fiber recordings from skin-nerve preparations from these mice indicate that both myelinated A¿ fiber and unmyelinated C fiber nociceptors are sensitized to mechanical stimuli. These findings parallel the mechanical hypersensitivity and pain reported by patients with sickle cell disease. Thus, these sickle cell mice represent a novel model of long-lasting chronic pain hypersensitivity that is closely associated with a human disease. On the basis of these findings and our observations with sensory plasticity in other pain models, we hypothesize that sensitization of primary afferent terminals contributes to sickle cell pain and that this sensitization is mediated by increased function of Transient Receptor Potential ion channels. Therefore, the Specific Aims for this project are to 1) Characterize the sensitization state of primary afferent fibers to mechanical, heat and cold stimuli in mice with sickle cell disease. 2) Determine the contribution of the Transient Receptor Potential (TRP) Ion Channels TRPA1 and TRPV1 to both the behavioral hypersensitivity and the sensitization of primary afferent fibers in sickle cell disease. 3) Characterize how acute vaso-occlusion modulates mechanical hypersensitivity in sickle mice. We will use both ex vivo and in vivo electrophysiological recordings to characterize the sensitization state of primary afferent fibers in Berkeley sickle cell mice. Next, we will utilize both genetic (TRP channel null mice induced with sickle cell disease) and pharmacologic approaches (selective TRP channel antagonists) to determine the role of specific TRP-family ion channels in sickle cell-associated primary afferent sensitization and pain behavior. Finally, we will induce acute sickling crises by an experimental model of vaso-occlusion to study how vaso-occlusion modulates mechanical hypersensitivity in sickle mice. These interrelated Specific Aims provide a multifaceted, coordinated and tightly focused approach that will clarify the role of primary afferent neurons in the development of pain syndromes within the complex setting of sickle cell-induced vascular and organ pathologies, as well as provide insight into the potential value of targeted TRP antagonist therapies for sickle cell pain.

项目概要/摘要： 镰状细胞病伴有慢性和严重的发作性疼痛，难以治疗， 深刻地侵蚀了那些患有它的人的生活质量。尽管详细了解了 遗传学、分子生物学和生物化学的镰状血红蛋白，深刻的痛苦的发病机制 在镰状细胞病中观察到的综合征仍然不完全清楚，可能涉及复杂的， 在外周和中枢神经系统中发生的异质步骤。这项提案的目的是 阐明镰状细胞病导致疼痛的机制，重点是外周机制 初级传入神经末梢使用严重镰状细胞病的小鼠模型， 小鼠，我们证明，这些小鼠表现出显着的过敏性，机械，热和冷外周 刺激。此外，缺氧诱导急性镰状化特别加剧了正在进行的机械性 镰状细胞小鼠的超敏反应。与此一致，从皮肤神经制备物中提取的纤维记录， 这些小鼠表明，有髓A纤维和无髓C纤维伤害感受器都对 机械刺激这些发现与以下患者报告的机械性超敏反应和疼痛平行： 镰状细胞病。因此，这些镰状细胞小鼠代表了一种新的长期慢性疼痛模型 与人类疾病密切相关的超敏反应。根据这些发现和我们的 在其他疼痛模型中观察到感觉可塑性，我们假设初级传入神经的敏化 终末有助于镰状细胞疼痛，这种敏化是由增加的功能介导的。 瞬时受体电位离子通道。因此，本项目的具体目标是：1）表征 镰状细胞病小鼠初级传入纤维对机械、热和冷刺激敏感状态 疾病2)确定瞬时受体电位（TRP）离子通道TRPA 1和 TRPV 1对镰状细胞行为超敏反应和初级传入纤维的敏化作用 疾病3)描述急性血管闭塞如何调节镰状小鼠的机械超敏反应。我们 将使用离体和体内电生理记录来表征 伯克利镰状细胞小鼠的初级传入纤维。接下来，我们将利用两种遗传（TRP通道无效小鼠 镰状细胞病诱导）和药理学方法（选择性TRP通道拮抗剂）， 确定特异性TRP家族离子通道在镰状细胞相关初级传入敏化中的作用 和疼痛行为。最后，我们将通过血管阻塞的实验模型诱导急性镰状危象， 研究血管阻塞如何调节镰状小鼠的机械超敏反应。这些相互关联的具体 目标提供了一个多方面、协调一致和重点突出的方法， 在镰状细胞诱导的复杂环境中，传入神经元在疼痛综合征的发展中的作用 血管和器官病理学，以及提供深入了解靶向TRP拮抗剂的潜在价值 镰状细胞疼痛的疗法。