Functional Interactions between Cancer Cells and Sensory Neurons

癌细胞和感觉神经元之间的功能相互作用

• 批准号: 8207959
• 负责人: Donald Simone
• 金额: $ 5.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207959
• 关键词: Absence of pain sensation; Accounting; Adenosine; Adult; Adverse effects; Afferent Neurons; Agonist; Analgesics; Behavioral; Bone remodeling; Calcium Signaling; Cancer Model; Cancer Pain Management; Cells; Child; Coculture Techniques; Collaborations; Development; Diagnosis; Dose; Effectiveness; Electrophysiology (science); Fiber; Grant; Hyperalgesia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Institutes; Lead; Ligands; Malignant Bone Neoplasm; Malignant Neoplasms; Mechanics; Methods; Modeling; Morphine; Mus; National Cancer Institute; Neoplasm Metastasis; Nerve Degeneration; Nerve Endings; Neuraxis; Neurons; Neuropathy; Nociception; Nociceptors; Opioid; Opioid Receptor; P2X-receptor; Pain; Pain management; Patients; Peripheral; Physiology; Public Health; Quality of life; Relative (related person); Reporting; Research; Resistance; Sensory; Signal Transduction; Spinal Cord; Spinal Ganglia; TRPV1 gene; Therapeutic; Therapeutic Uses; Ukraine; United States; United States National Institutes of Health; World Health Organization; bone; cancer cell; cancer pain; chronic pain; experience; fibrosarcoma; improved; in vitro Model; in vivo; injured; neuronal excitability; novel; novel strategies; patch clamp; public health relevance; receptor; receptor function; release factor; response; tripolyphosphate; tumor; tumor growth

DESCRIPTION (provided by applicant): Pain from cancer, particularly cancer that metastasizes to bone, is often severe, difficult to manage, and contributes significantly to the patients' poor quality of life. Although opioids remain the primary treatment for managing severe cancer pain, the relative resistance of cancer pain to opioids requires increased doses, which limit their use because of the many undesirable side effects associated with actions in the central nervous system. It is important to understand the mechanisms by which opioids become less effective in treating cancer pain. The mechanisms that drive cancer pain are multi-factorial and include bone remodeling, inflammatory responses, neurodegeneration, and release of algesic substances from the cancer cells that excite or sensitize nociceptors on primary afferent fibers. ATP is one of the known algesic substances that cancer cells contain and release during tumor growth. ATP activates peripheral P2X receptors which are located on nociceptive nerve endings. Previous behavioral studies from our group indicated that ATP contributes to the development of hyperalgesia in a murine model of bone cancer. Moreover, opioids modulate signaling at P2X receptors. Opioids such as morphine decrease ATP-evoked currents that occur through P2X receptors. We hypothesize that this opioid modulation of signaling through the P2X receptor is diminished by cancer cells, and that this may contribute to the decreased effect of opioids in cancer pain. In the proposed project, we will use an in vivo and a new in vitro co-culture method to determine the effect of cancer cells on ATP-evoked responses of dorsal root ganglion (DRG) neurons, how those responses are modulated by 5- and 4-opioid receptor agonists, and whether cancer cells promote a change in the expression of opioid receptors in DRG neurons. We will determine the effect of fibrosarcoma cells on P2X- dependent activation of mouse DRG neurons, changes in opioid modulation of P2X currents produced by cancer cells, and alterations in expression of 5- and 4-opioid receptors. Also, we will compare changes that occur in vivo (in tumor-bearing mice) to changes that occur in our co-culture model in vitro. The proposed studies will be done in Ukraine (Kiev) at the Bogomoletz Institute of Physiology in collaboration with Dr. Oleg A. Krishtal, who is an expert in patch clamp electrophysiology and P2X receptor function. This study is an extension of our ongoing project, NIH Grant CA091007, in which we are examining the contribution of peripheral P2X and TRPV1 receptors in cancer pain and nociceptor sensitization Results from these studies will provide new information on the mechanisms by which ATP contributes to cancer pain, and how opioids modulate ATP-evoked responses during tumor growth. Understanding how opioids can modulate cancer-related changes in responses of sensory neurons may lead to the development of novel approaches for managing cancer pain. PUBLIC HEALTH RELEVANCE: It is estimated by the National Cancer Institute that more than 1.4 million new cases of cancer were diagnosed in the United States in 2007, and the World Health Organization estimates that up to 15 million new cases of cancer may be diagnosed world-wide in 2020. Approximately 85% of adult patients with terminal cancer report intolerable pain and up to 75% of children with cancer experience pain. Understanding the mechanisms that drive cancer pain so that new and improved therapeutic approaches for pain management can be developed is a relevant public health issue.

描述（由申请人提供）：癌症引起的疼痛，尤其是转移至骨骼的癌症，通常很严重，难以控制，并且会严重影响患者的生活质量。尽管阿片类药物仍然是治疗严重癌症疼痛的主要治疗方法，但癌症疼痛对阿片类药物的相对抵抗力需要增加剂量，这限制了它们的使用，因为与中枢神经系统的作用相关的许多不良副作用。了解阿片类药物在治疗癌症疼痛方面效果减弱的机制非常重要。 驱动癌性疼痛的机制是多因素的，包括骨重塑、炎症反应、神经变性以及癌细胞释放痛觉物质，刺激初级传入纤维上的伤害感受器或使其敏感。 ATP 是癌细胞在肿瘤生长过程中含有和释放的已知止痛物质之一。 ATP 激活位于伤害性神经末梢的外周 P2X 受体。我们小组之前的行为研究表明，ATP 有助于骨癌小鼠模型中痛觉过敏的发生。此外，阿片类药物还可调节 P2X 受体的信号传导。吗啡等阿片类药物可减少通过 P2X 受体产生的 ATP 诱发电流。我们假设癌细胞通过 P2X 受体减弱阿片类药物对信号传导的调节，这可能导致阿片类药物在癌症疼痛中的作用减弱。 在拟议的项目中，我们将使用体内和新的体外共培养方法来确定癌细胞对背根神经节（DRG）神经元ATP诱发反应的影响，这些反应如何被5-和4-阿片受体激动剂调节，以及癌细胞是否促进DRG神经元中阿片受体表达的变化。我们将确定纤维肉瘤细胞对小鼠 DRG 神经元 P2X 依赖性激活、癌细胞产生的 P2X 电流的阿片类药物调节的变化以及 5- 和 4- 阿片类受体表达的改变的影响。此外，我们还将比较体内（荷瘤小鼠）发生的变化与体外共培养模型中发生的变化。 拟议的研究将在乌克兰（基辅）Bogomoletz 生理学研究所与膜片钳电生理学和 P2X 受体功能专家 Oleg A. Krishtal 博士合作进行。这项研究是我们正在进行的项目 NIH Grant CA091007 的延伸，在该项目中，我们正在研究外周 P2X 和 TRPV1 受体在癌症疼痛和伤害感受器敏化中的作用。这些研究的结果将提供有关 ATP 导致癌症疼痛的机制以及阿片类药物如何在肿瘤生长过程中调节 ATP 诱发反应的新信息。了解阿片类药物如何调节与癌症相关的感觉神经元反应变化可能会导致治疗癌症疼痛的新方法的开发。 公共健康相关性：据美国国家癌症研究所估计，2007 年美国新诊断出超过 140 万例癌症病例，世界卫生组织估计，2020 年全球可能诊断出多达 1500 万例新发癌症病例。约 85% 的晚期癌症成年患者报告难以忍受的疼痛，高达 75% 的癌症儿童经历疼痛。了解导致癌症疼痛的机制，以便开发新的和改进的疼痛管理治疗方法是一个相关的公共卫生问题。