Involvement of Endothelin and ETA Endothelin Receptor in Mechanical Allodynia in Mice Given Orthotopic Melanoma Inoculation

Abstract

Abstract. We investigated whether endothelin (ET) would be involved in skin cancer pain in mice. Orthotopic inoculation of B16-BL6 melanoma cells into the plantar region of the hind paw produced marked mechanical allodynia in C57BL/ 6 mice. Intraplantar injections of the ET Areceptor antagonist BQ-123 (0.3 -3 nmol/ site), but not the ET B -receptor antagonist BQ-788 (1 and 3 nmol/ site), inhibited mechanical allodynia in mice with grown melanoma. In naive mice, an intraplantar injection of tumor extract (1 and 3 mg/ site), which was prepared from the grown melanoma in the paw, produced mechanical allodynia, which was inhibited by BQ-123 and BQ-788 at doses of 3 and 10 nmol/ site. An intraplantar injection of ET-1 (1 and 10 pmol/ site) elicited licking behavior, which was increased in the melanoma-bearing hind paw. BQ-123 (3 and 10 nmol/ site) inhibited licking induced by ET-1 (10 pmol/ site). The level of mRNA of ET A , but not ET B , receptor, was significantly increased in the dorsal root ganglia on the inoculated side. Cultured B16-BL6 cells contained ET, and the melanoma mass increased the concentration of ET as it grew bigger. These results suggest that ET-1 and ET A receptor are at least partly involved in the induction of pain induced by melanoma cell inoculation.

Evidence for the endothelin system as an emerging therapeutic target for the treatment of chronic pain

“…Several types of cancer cells are known to produce ET-1 in culture or after injection into animal models, as indicated by increased ET-1 protein and/or mRNA levels 96,101–104. These high levels of ET-1 seem to correlate with increases in nociceptive behaviors, mechanical hyperalgesia, and mechanical allodynia, which are mediated by ET A receptors 72,101–104. In murine models of cancer pain, thermal hyperalgesia is significantly increased, which may be mediated by ET B receptors in the early stage and the ET A receptor in long-lasting hyperalgesia 96,105.…”

New perspectives on the endothelin axis in pain

“…Mechanical hyperalgesia of a significantly lower level was exhibited by mice with subcutaneous fibrosarcoma implants not involving bone [96]. Tactile allodynia also developed following inoculation into mouse plantar soft tissue of squamous cell carcinoma (SCC, HSC-3 cell line), melanoma (WM 164 cells) [97; 98], or highly invasive and metastatic murine melanoma (B16-BL6 cells) [99]. In all experimental models, the pain level (defined by the degree of tactile allodynia) correlated with tumor growth (volume).…”

“…Immunohistochemistry revealed high levels of ET-1 in cultured 2472 sarcoma cells, while ET-1 plasma levels increased about 5 times in sarcoma-bearing mice compared to sham controls (1.56±0.48 vs. 0.319±0.36 pg/ml) [30]. ET tissue content increased with the tumor mass over time after inoculation of metastatic murine melanoma into the plantar mouse hind paw [99]. A direct correlation was demonstrated between tactile allodynia and the ET-1 level produced by the melanoma tumors in the skin.…”

Effects of the Prostaglandin E1 Analog Limaprost on Mechanical Allodynia Caused by Chemotherapeutic Agents in Mice

“…Mechanical allodynia of the hind paw was assessed as described (9). After an acclimation period of at least 30 min, von Frey filament with the bending force of 0.69 mN was pressed perpendicularly against the plantar skin and was held for 1 -3 s with it slightly buckled.…”