Neural Mechanisms of Cancer Pain

描述：(摘自申请人的摘要) 癌症引起的疼痛深深地导致了皮肤的侵蚀。 尽管癌症疼痛通常得到有效控制，但患者的生活质量 对于毒品，与这些药物相关的许多不良副作用 药物限制了它们的使用。开发新的有效的治疗方法 因为癌症疼痛受制于对基础知识的匮乏。 癌症疼痛的神经生物学机制。我们已经参与了 发展一种癌症疼痛的动物模型，将使严格的 探索潜在的机制并检验特定的假说。在 建议的研究，使用行为学的多学科方法， 将使用电生理和形态学方法来研究 使用新开发的小鼠模型研究癌症疼痛的外周机制。我们的 初步研究表明，皮下种植后肿瘤生长 溶骨性纤维肉瘤细胞进入后爪导致机械性 同侧爪子有痛觉过敏。我们将研究肿瘤的影响 皮肤伤害性感受器的兴奋性和形态发育 覆盖在肿瘤上。在电生理记录中，我们将确定 伤害性感受器是否自发激活并对 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和神经生长因子在血管内皮细胞中的作用 它们被认为是从肿瘤中分泌出来的，在肿瘤引起的 伤害性和伤害性感受器的兴奋性。我们还将调查 纤维肉瘤是否增加了表皮的神经支配 肿瘤上覆盖的皮肤。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量化。由于表皮神经纤维包括 伤害性感受器、肿瘤诱导的增殖和增强的兴奋性 纤维可能会导致癌症疼痛。 这些研究将提供有关相互作用的新信息。 肿瘤和周围神经。结果可能会对未来产生直接影响 治疗癌症疼痛的外周作用的新型药物的开发 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.