Effects of Sustained Opiates on Bone Metastasis and Pain

描述(申请人提供)：癌症转移到骨是导致恶性肿瘤患者疼痛的主要原因。这种疼痛是剧烈和持续的，并导致严重的活动受限和生活质量的急剧下降。阿片类药物是报告中度至重度疼痛的癌症患者疼痛管理的最常见治疗方法。癌症疼痛的慢性性质通常需要长期使用阿片类药物治疗。在幼稚的动物中，持续的鸦片类药物暴露诱导了意想不到的神经整形适应，这自相矛盾地加剧了疼痛。阿片类药物诱导的痛敏可能会潜在地加剧癌症疼痛的某些方面。阿片类药物持续给药对骨癌引起的疼痛、骨破坏、初级传入伤害性纤维和脊髓的表型变化以及疾病进展的影响知之甚少。这项建议使用了一种小鼠骨癌模型，在该模型中，肉瘤细胞被注射并封闭在股骨中，导致对肿瘤的解剖定位。这使得能够在严格控制的条件下分析持续阿片类药物对肿瘤生长和进展、骨形态变化、癌症诱导的疼痛以及背根节(DRG)和脊髓的表型特征的影响。这项建议验证了以下假设：阿片类药物持续给药增强肉瘤诱导的疼痛，改变肉瘤小鼠背根神经节和脊髓的表型特征，区别于肉瘤单独或阿片类药物单独暴露的小鼠，促进肿瘤生长，并通过u阿片受体特异性机制(目标2)以时间和剂量依赖的方式(目标1)增强骨破坏(目标1)。我们的目标是获得足够的初步数据，以便详细描述阿片剂诱导的癌症疼痛不良反应的机制，这将在随后的RO1应用中探索。我们对阿片类药物认识的增加有助于确定限制阿片类药物潜在有害作用的治疗方案，并改变这些药物用于治疗癌症引起的疼痛的方式。

DESCRIPTION (provided by applicant): Metastatis of cancer to bone is the leading cause of pain in patients with malignant tumors. Such pain is intense and unremitting, and results in severe limitation of activity and a drastic decrease in quality of life. Opiates are the most common treatment for pain management in cancer patients reporting moderate to severe pain. The chronic nature of cancer pain often requires prolonged treatment with opiates. In naive animals, sustained opiate exposure induces unexpected neuroplastic adaptations that paradoxically enhance pain. Opioid-induced hyperalgesia may potentially exacerbate some aspects of cancer pain. Little is known about the consequences of sustained opiate administration on bone cancer-induced pain, bone destruction, phenotypic changes in primary afferent nociceptive fibers and spinal cord, and disease progression. This proposal uses a murine bone cancer model in which sarcoma cells are injected and sealed into the femur, resulting in anatomical localization of the tumor. This allows for analysis of the effects of sustained opiates on tumor growth and progression, changes in bone morphology, cancer-induced pain, and phenotypic characteristics in the dorsal root ganglia (DRG) and spinal cord under closely controlled conditions. This proposal tests the hypothesis that sustained opiate administration enhances sarcoma-induced pain, alters the phenotypic characteristics of the DRG and spinal cord of sarcoma mice differentially from mice with sarcoma alone or opiate exposure alone, enhances tumor growth, and enhances bone destruction (Aim 1) in a time- and dosedependent manner (Aim 2) through a mu opioid receptor specific mechanism (Aim 3). Our goal is to obtain sufficient preliminary data to allow detailed characterization of mechanisms of opiate-induced adverse actions in cancer pain which would be explored in a subsequent RO1 application. Such increases in our understanding could help identify treatment options limiting the potentially deleterious actions of opiates, and changing the way these drugs are used to treat cancer-induced pain.