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

P. W. Wacnik, L. J. Eikmeier, T. R. Ruggles, M. L. Ramnaraine, B. K. Walcheck, A. J. Beitz, G. L. Wilcox

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9355-9366
Number of pages12
JournalJournal of Neuroscience
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2001

Keywords

  • Cancer pain
  • Endothelin
  • Hyperalgesia
  • Primary afferent fibers
  • Tumor microperfusion
  • Tumor nociception

Fingerprint

Dive into the research topics of 'Functional interactions between tumor and peripheral nerve: Morphology, algogen identification, and behavioral characterization of a new murine model of cancer pain'. Together they form a unique fingerprint.

Cite this