Cancer Pain and Breast Tumor Metastasis to Bone

描述（由申请人提供）： 骨癌每年显著降低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，直到最近才有一个模型来定义产生和维持骨癌疼痛的机制。该提案的主要目的是使用本质上混合的大鼠肿瘤模型（因为它诱导骨形成和破坏）来定义引起骨癌疼痛的机制，骨癌疼痛是由混合肿瘤（如乳腺癌或前列腺癌）转移到骨时引起的。将用绿色荧光蛋白稳定转染的大鼠乳腺癌细胞注射并限制在大鼠股骨的髓内空间中。在28天的时间内，这些肿瘤细胞增殖并诱导骨形成、骨破坏、骨癌相关的疼痛行为以及感觉和脊髓神经元中的一组神经化学变化，其似乎参与产生和维持骨癌疼痛。 使用该模型，我们将定义：肿瘤生长、骨形成、骨破坏、破骨细胞生成和骨癌疼痛相关行为的时间过程和程度（目的1）：当肿瘤填充髓内空间、骨重塑和骨癌疼痛发展时，骨的感觉和交感神经支配如何变化（目的2）;随着肿瘤生长、肿瘤诱导的骨重建发生和骨癌疼痛的发展，初级传入感觉神经元、交感神经元、脊髓和背柱核中发生的神经化学变化（目标3）;无论是全身还是鞘内施用吗啡、考克斯-2抑制剂、加巴喷丁或内皮素A受体拮抗剂，都能减少骨癌疼痛相关行为、肿瘤生长、骨重塑、破骨细胞生成和外周和中枢神经系统中发生的神经化学变化的特定方面（目的4）。这些调查的信息应该扩大我们对产生和维持骨癌疼痛的机制的理解，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.