Neural Mechanisms of Cancer Pain

癌痛的神经机制

• 批准号: 7667445
• 负责人: Donald Simone
• 金额: $ 23.01万
• 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/7667445
• 关键词: ATP Receptors; Adverse effects; Agonist; Animal Model; Antibodies; Attenuated; Behavior; Behavioral; Biochemical Markers; C Fiber; Cell Culture Techniques; Cells; Chemicals; Coculture Techniques; 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; effective therapy; fibrosarcoma; implantation; in vivo; interdisciplinary approach; neoplastic cell; neurobiological mechanism; neuromechanism; neuronal excitability; novel; novel strategies; patch clamp; receptor; receptor function; release factor; response; 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（由申请人提供）：由癌症引起的疼痛，特别是转移至骨骼的癌症，通常是极其痛苦的，并且严重影响患者的生活质量。虽然癌症疼痛通常可以通过麻醉剂有效控制，但与这些药物相关的许多不良副作用限制了它们的使用。由于缺乏对癌痛的基本神经生物学机制的了解，阻碍了癌症疼痛新的有效治疗方法的开发。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机制并测试特定假设。该模型基于在跟骨内及其周围植入溶骨性纤维肉瘤细胞。这会产生自发性疼痛和痛觉过敏、肿瘤覆盖皮肤中 C 伤害感受器的敏化以及初级传入纤维的变性。研究发现，TNFa 和 ET-1 在肿瘤部位以高浓度存在，并有助于痛觉过敏和致敏。在拟议的研究中，将采用由相关行为以及体内和体外电生理学研究组成的多学科方法来进一步研究产生疼痛的肿瘤-神经相互作用。具体来说，我们将研究辣椒素受体、TRPV1 和 ATP 受体在肿瘤诱发的痛觉过敏和伤害感受器敏化中的作用。在行为研究中，将确定递送至肿瘤部位的受体选择性拮抗剂对痛觉过敏的影响。类似地，将从体内初级传入纤维进行记录，并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感受器敏化。最后，将从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，以识别癌细胞对神经元兴奋性以及通过 TRPV1 和 ATP 受体进行信号传导的直接影响。这些研究将提供有关肿瘤与周围神经之间功能相互作用的新信息。结果可能对未来开发作用于肿瘤/神经水平的外周癌症疼痛新药物产生直接影响。