Cancer Pain and Breast Tumor Metastasis to Bone

描述(由申请人提供)： 骨癌极大地降低了每年数百万癌症患者的生活质量。设计治疗这种慢性疼痛的新疗法的一个主要问题是，直到最近，还没有一个模型可以用来定义产生和维持骨癌疼痛的机制。这项建议的主要目的是使用一个本质上混合的大鼠肿瘤模型(因为它同时诱导骨形成和破坏)来定义引起骨癌疼痛的机制，这些疼痛是由乳腺或前列腺癌等混合肿瘤转移到骨骼时产生的。将稳定转染绿色荧光蛋白的大鼠乳腺癌细胞注射并限制在大鼠股骨髓内间隙。在28天的时间里，这些肿瘤细胞增殖并诱导骨形成、骨破坏、骨癌相关疼痛行为以及感觉神经元和脊髓神经元的一系列神经化学变化，这些变化似乎参与了骨癌疼痛的产生和维持。 利用这个模型，我们将定义：肿瘤生长、骨形成、骨破坏、破骨细胞形成和骨癌痛相关行为的时间进程和程度(目标1)：随着肿瘤填充髓内间隙、骨重塑和骨癌痛的发生，骨的感觉和交感神经支配如何变化(目标2)；随着肿瘤的生长，初级传入神经元、交感神经元、脊髓和背柱核发生的神经化学变化，肿瘤诱导的骨重建和骨癌痛的发生(目标3)；无论是全身或鞘内注射吗啡、COX-2抑制剂、加巴喷丁或内皮素A受体拮抗剂，都可以减少骨癌疼痛相关行为、肿瘤生长、骨重建、破骨细胞形成以及周围和中枢神经系统中发生的神经化学变化的特定方面(目标4)。来自这些研究的信息应该会扩大我们对骨癌疼痛产生和维持的机制的理解，并导致开发更有效的治疗骨癌疼痛的疗法。

DESCRIPTION (provided by applicant): Bone cancer significantly decreases the quality of life of millions of cancer patients each year. A major problem in designing new therapies to treat this chronic pain was that until recently there was not a model available to define the mechanisms that generate and maintain bone cancer pain. The major thrust of this proposal is to use a rat tumor model that is mixed in nature (in that it induces both bone formation and destruction) to define the mechanisms that give rise to bone cancer pain that arises from mixed tumors such as breast or prostate when they metastasize to bone. Rat mammary carcinoma cells, stably transfected with green fluorescent protein, will be injected and confined to the intramedullary space of the rat femur. Over a twenty eight day period these tumor cells proliferate and induce bone formation, bone destruction, bone cancer related pain behaviors and a set of neurochemical changes in both sensory and spinal cord neurons that appears to be involved in generating and maintaining bone cancer pain. Using this model we will define: the time course and extent of tumor growth, bone formation, bone destruction, osteoclastogenesis, and bone cancer pain related behaviors (Aim 1): how the sensory and sympathetic innervation of bone changes as the tumor fills the intramedullary space, the bone is remodeled and bone cancer pain develops (Aim 2); the neurochemical changes that occur in primary afferent sensory neurons, sympathetic neurons, the spinal cord and dorsal column nuclei as the tumor grows, tumor induced bone remodeling occurs and bone cancer pain develops (Aim 3); whether systemic or intrathecal administration of morphine, COX-2 inhibitor, gabapentin or endothelin A receptor antagonist reduce specific aspects of bone cancer pain related behaviors, tumor growth, bone remodeling, osteoclastogenesis and the neurochemical changes that occur in the peripheral and central nervous system (Aim 4). Information from these investigations should expand our understanding of the mechanisms that generate and maintain bone cancer pain and lead to the development of more effective therapies for treating bone cancer pain.