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: 7140204
• 负责人: TAMARA E KING
• 金额: $ 18.43万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140204
• 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（由申请人提供）：癌症骨转移是恶性肿瘤患者疼痛的主要原因。这种疼痛是强烈且持续的，会导致活动严重受限和生活质量急剧下降。阿片类药物是报告中度至重度疼痛的癌症患者中最常见的疼痛管理治疗。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，持续的阿片类药物暴露诱导了意想不到的神经可塑性适应，矛盾地增强了疼痛。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。关于持续给予阿片类药物对骨癌引起的疼痛、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，人们知之甚少。该提议使用了一种小鼠骨癌模型，其中肉瘤细胞被注射并密封到股骨中，导致肿瘤的解剖定位。这允许分析持续阿片类药物对肿瘤生长和进展的影响，骨形态学的变化，癌症引起的疼痛，以及在严格控制的条件下背根神经节（DRG）和脊髓的表型特征。该提案检验了以下假设：持续给予阿片类药物可增强肉瘤诱导的疼痛，改变肉瘤小鼠DRG和脊髓的表型特征，与单独肉瘤或单独暴露阿片类药物的小鼠不同，可增强肿瘤生长，并通过μ阿片受体特异性机制（目的3）以时间和剂量依赖性方式（目的2）增强骨破坏（目的1）。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诱导的癌症疼痛不良反应的机制，这将在随后的RO1应用程序中进行探索。这种认识的增加可以帮助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。