Effects of selective endothelin ET(A) receptor antagonists on endothelin-1-induced potentiation of cancer pain.

In some diseases in which endothelin-1 production increases, e.g. prostate cancer, endothelin-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin ET(A) receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on the nociception potentiated by endothelin-1 in a cancer inoculation-induced pain model in mice, induced by inoculation of the androgen-independent human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency (SCID) mice. No pain responses were observed in the sham-operated mice, whereas monophasic pain responses were observed in the PPC-1-inoculated mice. Endothelin-1 (1 to 10 pmol/paw) but not sarafotoxin S6c potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3 to 3 mg/kg, p.o.) significantly inhibited the endothelin-1 (10 pmol/paw)-induced potentiation of nociception in a dose-dependent manner. These results suggest that selective endothelin ET(A) receptor antagonists might relieve pain in patients with various diseases in which endothelin-1 production is increased, e.g. prostate cancer.