Neural Mechanisms of Cancer Pain

描述（由申请人提供）：癌症引起的疼痛，特别是转移到骨的癌症，通常非常疼痛，并严重影响患者的侵蚀和生活质量。虽然癌症疼痛通常可以用麻醉剂有效地控制，但与这些药物相关的许多不良副作用限制了它们的使用。由于对癌痛的基本神经生物学机制缺乏了解，阻碍了新的有效的癌痛治疗方法的发展。我们参与了癌症疼痛小鼠模型的开发，该模型允许对潜在机制进行严格探索并测试特定假设。该模型是基于在跟骨内和周围植入溶骨性纤维肉瘤细胞。这产生自发性疼痛和痛觉过敏，肿瘤上皮肤中C伤害感受器的敏化，以及初级传入纤维的变性。发现TNF α和ET-1以高浓度存在于肿瘤部位，并有助于痛觉过敏和敏化。在拟议的研究中，将采用多学科方法，包括相关的行为，以及体内和体外电生理研究，以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，TRPV 1，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，将在体内从初级传入纤维进行记录，并且将使用拮抗剂来确定这些受体系统是否有助于伤害感受器的肿瘤诱发的敏化。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，以鉴定癌细胞对神经元兴奋性和通过TRPV 1和ATP受体的信号传导的直接影响。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。结果可能对未来开发在肿瘤/神经水平外周发挥作用的新型癌痛药物产生直接影响。

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.