Neural Mechanisms of Cancer Pain

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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.