Chronic Cannabinoids, Tumor Growth and Hyperalgesia

慢性大麻素、肿瘤生长和痛觉过敏

• 批准号: 6811644
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6811644
• 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）：患有晚期癌症的患者经常会经历疼痛，而当前的治疗方法可能难以管理。最近开发的癌症疼痛模型开始揭示肿瘤细胞与可能是这种疼痛的神经系统之间相互作用的机制。我们的初步研究表明，植入小鼠后爪的溶裂性纤维肉瘤的神经和血管化随着肿瘤生长而降低。随着该模型中的疼痛行为的增加，这些变化发生。我们的目标是开发更有效的方法来治疗癌症疼痛。一种潜在的方法是使用大麻素。我们使用鼠类疼痛的鼠模型的研究表明，急性给药大麻素减弱了肿瘤诱发的疼痛行为。但是，长期给药大麻素可以产生耐受性。这已经显示出大麻素在急性疼痛模型中的抗伤害感受性作用。尚未报道慢性大麻素的长期给药是有效的还是导致慢性疼痛模型中耐受性的发展。大麻素会减少某些肿瘤细胞系的增殖并减少体内肿瘤的生长。在某些肿瘤细胞系中，大麻素会诱导凋亡。因此，长期给药大麻素也可能减少肿瘤的生长，从而与肿瘤生长和肿瘤诱发的疼痛相关的神经和血管形态的形态变化。我们将使用行为分析，计算机建模，免疫组织化学，共聚焦显微镜和立体学方法来确定大麻素激动剂的慢性给药是否会减弱肿瘤诱发的机械痛觉过敏的发展，肿瘤诱发的机械杀伤症，肿瘤的生长，神经性，神经性和血管生长和血管生长和癌症模型的血管生成。这些研究的积极结果表明，大麻素可能对治疗癌症疼痛有用。