Chronic Cannabinoids, Tumor Growth and Hyperalgesia

慢性大麻素、肿瘤生长和痛觉过敏

• 批准号: 6921862
• 负责人: DARRYL T HAMAMOTO
• 金额: $ 7.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921862
• 关键词: analgesia; apoptosis; cancer pain; cannabinoids; cell proliferation; computer simulation; confocal scanning microscopy; drug administration rate /duration; drug tolerance; genetically modified animals; hyperalgesia; immunocytochemistry; innervation; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplastic cell; neoplastic growth; therapy design /development

DESCRIPTION (provided by applicant): Patients with advanced stages of cancer frequently experience pain that can be difficult to manage with current therapeutic approaches. Recently developed models of cancer pain are beginning to unravel the mechanisms underlying interactions between tumor cells and the nervous system that may underlie this pain. Our preliminary studies show that innervation and vascularization of an osteolytic fibrosarcoma implanted into the hind paws of mice decrease with tumor growth. These changes occur as pain behaviors increase in this model. Our goal is to develop more effective approaches to treat cancer pain. One potential approach is the use of cannabinoids. Our studies using murine models of cancer pain suggest that acute administration cannabinoids attenuate tumor-evoked pain behaviors. However, chronic administration of cannabinoids can produce tolerance. This has been shown for the antinociceptive effects of cannabinoids in animal models of acute pain. Whether chronic administration of cannabinoids is effective or results in the development of tolerance in models of chronic pain has not been reported. Cannabinoids reduce proliferation of some tumor cell lines and decrease tumor growth in vivo. In some tumor cell lines, cannabinoids induce apoptosis. Therefore, chronic administration of cannabinoids may also decrease tumor growth and thereby the morphological changes in innervation and vascularization associated with tumor growth and tumor-evoked pain. We will use behavioral assays, computer modeling, immunohistochemistry, confocal microscopy, and stereological methods to determine whether chronic administration of the cannabinoid agonist, CP 55, 940, attenuates the development of tumor-evoked mechanical hyperalgesia, tumor growth, innervation and vascularization in a murine model of cancer pain. Positive results from these studies would suggest that cannabinoids could be useful for the treatment of cancer pain.

描述（由申请人提供）：晚期癌症患者经常会经历目前的治疗方法难以控制的疼痛。最近开发的癌症疼痛模型开始揭示肿瘤细胞与神经系统之间相互作用的机制，而神经系统可能是这种疼痛的根源。我们的初步研究表明，植入小鼠后爪的溶骨性纤维肉瘤的神经支配和血管化随着肿瘤的生长而减少。这些变化随着该模型中疼痛行为的增加而发生。我们的目标是开发更有效的方法来治疗癌症疼痛。一种可能的方法是使用大麻素。我们使用小鼠癌症疼痛模型进行的研究表明，急性施用大麻素可以减轻肿瘤引起的疼痛行为。然而，长期服用大麻素会产生耐受性。大麻素在急性疼痛动物模型中的抗伤害作用已证明这一点。长期服用大麻素是否有效或是否会导致慢性疼痛模型产生耐受性尚未有报道。大麻素可减少某些肿瘤细胞系的增殖并减少体内肿瘤的生长。在一些肿瘤细胞系中，大麻素诱导细胞凋亡。因此，长期施用大麻素也可能减少肿瘤生长，从而减少与肿瘤生长和肿瘤诱发的疼痛相关的神经支配和血管化的形态变化。我们将使用行为测定、计算机建模、免疫组织化学、共聚焦显微镜和体视学方法来确定长期施用大麻素激动剂 CP 55、940 是否会减弱肿瘤诱发的机械性痛觉过敏、肿瘤生长、神经支配和血管化的发展。癌症疼痛的小鼠模型。这些研究的积极结果表明大麻素可用于治疗癌症疼痛。