Functional interactions between tumor and peripheral nerve: Morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain

被引:176
作者
Wacnik, PW
Eikmeier, LJ
Ruggles, TR
Ramnaraine, ML
Walcheck, BK
Beitz, AJ
Wilcox, GL
机构
[1] Univ Minnesota, Sch Med, Dept Neurosci, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Sch Med, Dept Vet Pathobiol, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Sch Med, Dept Orthoped Surg, Minneapolis, MN 55455 USA
[4] Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA
[5] Univ Minnesota, Sch Vet Med, Dept Pharmacol, Minneapolis, MN 55455 USA
[6] Univ Minnesota, Sch Vet Med, Dept Vet Pathobiol, Minneapolis, MN 55455 USA
[7] Univ Minnesota, Sch Vet Med, Dept Orthoped Surg, Minneapolis, MN 55455 USA
[8] Univ Minnesota, Sch Vet Med, Dept Neurosci, Minneapolis, MN 55455 USA
关键词
hyperalgesia; primary afferent fibers; tumor nociception; endothelin; cancer pain; tumor microperfusion;
D O I
10.1523/JNEUROSCI.21-23-09355.2001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
This paper describes a model of tumor-induced bone destruction and hyperalgesia produced by implantation of fibrosarcoma cells into the mouse calcaneus bone. Histological examination indicates that tumor cells adhere to the bone edge as early as post-implantation day (PID) 3, but osteolysis does not begin until PID 6, correlating with the development of hyperalgesia. C3H/He mice exhibit a reproducible hyperalgesia to mechanical and cold stimuli between PID 6 and 16. These behaviors are present but significantly reduced with subcutaneous implantation that does not involve bone. Systemic administration of morphine (ED50 9.0 mg/kg) dose-dependently attenuated the mechanical hyperalgesia. In contrast, bone destruction and hypersensitivity were not evident in mice implanted with melanoma tumors or a paraffin mass of similar size. A novel microperfusion technique was used to identify elevated levels of the putative algogen endothelin (ET) in perfusates collected from the tumor sites of hyperalgesic mice between PID 7 and 12. Increased ET was evident in microperfusates from fibrosarcoma tumor-implanted mice but not from melanoma tumor-implanted mice, which are not hyperalgesic. Intraplantar injection of ET-1 in naive and, to a greater extent, fibrosarcoma tumor-bearing mice produced spontaneous pain behaviors, suggesting that ET-1 activates primary afferent fibers. Intraplantar but not systemic injection of the ET-A receptor antagonist BQ-123 partially blocked tumor-associated mechanical hyperalgesia, indicating that ET-1 contributes to tumor-induced nociception. This model provides a unique approach for quantifying the behavioral, biochemical, and electrophysiological consequences of tumor-nerve interactions.
引用
收藏
页码:9355 / 9366
页数:12
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