Effects of Sustained Opiates on Bone Metastasis and Pain

持续阿片类药物对骨转移和疼痛的影响

• 批准号: 6953942
• 负责人: TAMARA E KING
• 金额: $ 22.59万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953942
• 关键词: analgesia; bone neoplasms; cancer pain; drug administration rate /duration; hyperalgesia; laboratory mouse; metastasis; neoplastic growth; opiate alkaloid; opioid receptor; pharmacokinetics; sarcoma; spinal ganglion

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.

描述（申请人提供）：癌症骨转移是恶性肿瘤患者疼痛的主要原因。这种疼痛是剧烈且持续的，导致活动严重受限和生活质量急剧下降。阿片类药物是治疗中度至重度疼痛的癌症患者最常见的疼痛治疗方法。癌症疼痛的慢性性质通常需要长期使用阿片类药物治疗。在幼稚动物中，持续接触阿片类药物会引起意想不到的神经塑性适应，从而反而加剧疼痛。阿片类药物引起的痛觉过敏可能会加剧癌症疼痛的某些方面。关于持续服用阿片类药物对骨癌引起的疼痛、骨质破坏、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。该提案使用小鼠骨癌模型，将肉瘤细胞注射并密封到股骨中，从而实现肿瘤的解剖定位。这样可以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、癌症引起的疼痛以及背根神经节 (DRG) 和脊髓表型特征的影响。该提案测试了以下假设：持续给予阿片类药物会增强肉瘤引起的疼痛，改变肉瘤小鼠的 DRG 和脊髓的表型特征（与单独肉瘤或单独阿片类药物暴露的小鼠不同），增强肿瘤生长，并通过 mu 阿片受体特异性机制（目标 3）以时间和剂量依赖性方式增强骨质破坏（目标 1）（目标 2）。我们的目标是获得足够的初步数据，以便详细描述阿片类药物引起的癌症疼痛不良反应的机制，这将在后续的 RO1 应用中进行探索。我们了解的增加可能有助于确定限制阿片类药物潜在有害作用的治疗方案，并改变这些药物治疗癌症引起的疼痛的方式。