Neural Mechanisms of Cancer Pain

描述：（来自申请人摘要） 癌症引起的疼痛深刻地促进了 患者的生活质量，虽然癌症疼痛往往是有效的管理 与麻醉剂，许多不良的副作用与这些 药物限制其使用。开发新的有效治疗方法 对于癌症疼痛，由于缺乏关于基本的 癌症疼痛的神经生物学机制我们已经参与了 开发癌症疼痛的动物模型， 探索潜在的机制和测试特定的假设。在 建议的研究，一个多学科的方法，使用行为， 电生理和形态学方法将被用来研究 使用新开发的小鼠模型研究癌症疼痛的外周机制。我们 初步研究表明皮下植入后的肿瘤生长 骨溶解性纤维肉瘤细胞进入后爪导致机械 同侧爪的痛觉过敏。我们将研究肿瘤的影响 生长对皮肤伤害感受器兴奋性和形态学的影响 覆盖肿瘤。在电生理记录中，我们将确定 伤害感受器是否自发地活跃， 自然刺激（机械、热和冷）。此外，我们将确定 肿瘤坏死因子、内皮素-1和神经生长因子的作用 假设是由肿瘤分泌的， 伤害感受器的兴奋性。我们亦会研究 纤维肉瘤肿瘤是否增加了表皮的神经支配， 肿瘤上的皮肤免疫染色和共聚焦显微镜将用于 对表皮神经支配进行成像和定量。由于表皮神经纤维包括 伤害感受器，肿瘤诱发的增殖和这些的兴奋性增强 纤维可能导致癌症疼痛。 这些研究将提供新的信息功能之间的相互作用 肿瘤和周围神经。结果可能对未来产生直接影响 开发用于癌痛的新型药物， 肿瘤/神经水平。

DESCRIPTION:(from applicant's abstract) Pain resulting from cancer profoundly contributes to the erosion of the patients' 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 an animal model of cancer pain that will allow rigorous exploration of underlying mechanisms and testing of specific hypotheses. In the proposed studies, a multidisciplinary approach using behavioral, electrophysiological and morphological methods will be used to investigate peripheral mechanisms of cancer pain using a newly developed murine model. Our preliminary studies show that tumor growth following subcutaneous implantation of osteolytic fibrosarcoma cells into the hindpaw results in mechanical hyperalgesia on the ipsilateral paw. We will investigate effects of tumor growth on excitability and morphoiogy of cutaneous nociceptors in skin overlying the tumor. In electrophysiological recordings, we will determine whether nociceptors are spontaneously active and exhibit greater responses to natural stimuli (mechanical, heat and cold). In addition, we will determine the role of tumor necrosis factor, endothelin-1 and nerve growth factor each of which are hypothesized to be secreted from the tumor, on tumor-evoked nociception and on excitability of nociceptors. We will also investigate whether the fibrosarcoma tumor increases neural innervation of the epidermis in skin overlying the tumor. Immunostainingand confocal microscopy will be used to image and quantify epidermal innervation. Since epidermal nerve fibers include nociceptors, tumor-evoked proliferation and enhanced excitability of these fibers may contribute to cancer pain. 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.