Neural Mechanisms of Cancer Pain

癌痛的神经机制

• 批准号: 7490976
• 负责人: Donald Simone
• 金额: $ 22.39万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490976
• 关键词: ATP Receptors; Adverse effects; Agonist; Animal Model; Antibodies; Attenuated; Behavior; Behavioral; Biochemical Markers; C Fiber; Cells; Chemicals; Class; Coculture Techniques; Cultured Cells; Cutaneous; Development; Endothelin-1; Fiber; Future; Generations; Hyperalgesia; Implant; In Vitro; Injection of therapeutic agent; Knowledge; Label; Lead; Malignant Neoplasms; Measures; Mechanics; Methods; Modeling; Mus; Muscle; Narcotics; Neoplasm Metastasis; Nerve; Neuraxis; Neurons; Nociceptors; Osteolytic; P2X-receptor; Pain; Pain management; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Neoplasms; Pharmaceutical Preparations; Purinoceptor; Quality of life; Role; Signal Transduction; Site; Skin; Spinal Ganglia; Stimulus; System; TRPV1 gene; Testing; Withdrawal; base; bone; cancer cell; cancer pain; capsaicin receptor; fibrosarcoma; implantation; in vivo; interdisciplinary approach; neoplastic cell; neurobiological mechanism; neuromechanism; neuronal excitability; novel; novel strategies; patch clamp; receptor; receptor function; release factor; response; size; spontaneous pain; tumor; tumor growth

DESCRIPTION (provided by applicant): Pain resulting from cancer, particularly cancer that metastasizes to bone, is often extremely painful and profoundly contributes to the erosion of the patients,Ao quality of life. Although cancer pain is often managed effectively with narcotics, the many undesirable side effects associated with these medications limit their use. The development of new and effective treatments for cancer pain is hampered by a paucity of knowledge about the basic neurobiological mechanisms underlying cancer pain. We have been involved in the development of a murine model of cancer pain that allows rigorous exploration of underlying mechanisms and testing of specific hypotheses. The model is based on implantation of osteolytic fibrosarcoma cells in and around the calcaneous bone. This produces spontaneous pain and hyperalgesia, sensitization of C nociceptors in skin overlying the tumor, and degeneration of primary afferent fibers. It was found that TNFa and ET-1 are present in high concentrations at the tumor site and contribute to the hyperalgesia and sensitization. In the proposed studies, a multidisciplinary approach consisting of correlative behavioral, and in vivo and in vitro electrophysiological studies will be used to further investigate tumor-nerve interactions that produce pain. Specifically, we will investigate the role of the capsaicin receptor, TRPV1, and ATP receptors in tumor- evoked hyperalgesia and nociceptor sensitization. In behavioral studies, the effects of receptor selective antagonists delivered to the tumor site upon hyperalgesia will be determined. Similarly, recordings will be made from primary afferent fibers in vivo and antagonists will be used to determine whether these receptor systems contribute to tumor-evoked sensitization of nociceptors. Finally, patch clamp recordings will be made from DRG neurons that are cultured alone or with cancer cells to identify direct effects of the cancer cells on neuronal excitability and signaling via TRPV1 and ATP receptors. These studies will provide new information on functional interactions between tumors and peripheral nerve. Results may have a direct impact on the future development of novel medications for cancer pain that act peripherally at the tumor/nerve level.

描述(申请人提供)：癌症引起的疼痛，特别是转移到骨骼的癌症，往往是极其痛苦的，并深刻地导致患者的生活质量的侵蚀。尽管麻醉药通常能有效地控制癌症疼痛，但与这些药物相关的许多不良副作用限制了它们的使用。对癌症疼痛的基本神经生物学机制缺乏了解，阻碍了癌症疼痛新的有效治疗方法的发展。我们参与了癌症疼痛小鼠模型的开发，该模型允许严格探索潜在的机制并测试特定的假说。该模型是基于在跟骨及其周围植入溶骨性纤维肉瘤细胞。这会导致自发的疼痛和痛觉过敏，肿瘤周围皮肤的C伤害性感受器敏化，以及初级传入纤维的退化。研究发现，肿瘤组织中高浓度的TNFa和ET-1参与了痛觉过敏和增敏作用。在拟议的研究中，将采用多学科方法，包括相关的行为学、体内和体外电生理学研究，以进一步研究产生疼痛的肿瘤-神经相互作用。具体地说，我们将研究辣椒素受体、TRPV1和ATP受体在肿瘤引起的痛觉过敏和伤害性感受器敏化中的作用。在行为学研究中，将确定受体选择性拮抗剂对肿瘤部位痛觉过敏的影响。类似地，将在体内记录初级传入纤维，并将使用拮抗剂来确定这些受体系统是否有助于肿瘤诱发的伤害性感受器的敏化。最后，将对单独培养或与癌细胞一起培养的DRG神经元进行膜片钳记录，以确定癌细胞通过TRPV1和ATP受体对神经元兴奋性和信号传递的直接影响。这些研究将为肿瘤和周围神经之间的功能相互作用提供新的信息。结果可能会对未来癌症疼痛新药的开发产生直接影响，这些新药在肿瘤/神经水平上发挥外围作用。