Neural Mechanisms of Cancer Pain

描述（由申请人提供）：癌症引起的疼痛，特别是转移到骨骼的癌症，通常是非常痛苦的，并且深刻地导致患者的侵蚀，影响生活质量。虽然癌症疼痛通常可以通过麻醉药有效地控制，但与这些药物相关的许多不良副作用限制了它们的使用。由于缺乏对癌症疼痛的基本神经生物学机制的了解，癌症疼痛的新有效治疗方法的发展受到阻碍。我们参与了一种小鼠癌症疼痛模型的开发，该模型可以对潜在机制进行严格的探索，并对特定假设进行测试。该模型是基于骨溶解纤维肉瘤细胞植入和周围的跟骨。这会产生自发的疼痛和痛觉过敏，肿瘤上皮肤C伤害感受器的致敏，以及原发性传入纤维的变性。我们发现TNFa和ET-1在肿瘤部位高浓度存在，并有助于痛觉过敏和致敏。在拟议的研究中，包括相关行为，体内和体外电生理研究在内的多学科方法将用于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受体在肿瘤引起的痛觉过敏和伤害感受器致敏中的作用。在行为学研究中，受体选择性拮抗剂递送到肿瘤部位对痛觉过敏的影响将被确定。同样地，将对体内的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致敏。最后，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，以确定癌细胞对神经元兴奋性和通过TRPV1和ATP受体传递信号的直接影响。这些研究将为肿瘤与周围神经之间的功能相互作用提供新的信息。这一结果可能会对未来在肿瘤/神经水平外周作用的治疗癌症疼痛的新型药物的开发产生直接影响。

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.