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Pain in patients with metastatic cancer contributes to increased suffering in those already burdened by their advancing illness.The causes of this pain are unknown, but are likely to involve the action of tumor-associated mediators and their receptors.In recent years, several chemical mediators have increasingly come to the forefront in the pathophysiology of cancer pain.One such mediator, endothelin-1 (ET-1), is a peptide of 21 amino acids that was initially shown to be a potent vasoconstrictor.Extensive research has revealed that members of the ET family are indeed produced by several epithelial cancerous tumors, in which they act as anticrime and/or paracrine growth factors.Several preclinical and clinical studies of various malignancies have suggested that the ET axis may represent an interesting contributor to tumor progression.In addition, evidence is accumulating to suggest that ET-1 may contribute to pain states both in cancer and in non-malignant conditions.ET-1 both stimulates nociceptors and sensitizes them to painful stimuli.ET-1-induced pain-related behavior seems to be mediated either solely by one receptor type or via both endothelin-A receptors (ETAR) and endothelin-B receptors (ETBR).Whereas stimulation of ETAR on nociceptors always elicits a pain response, stimulation of ETBR may causc analgesia or elicit a pain response, depending on the eonditions.The administration of ETAR antagonists in the receptive fields of these nociceptors has been shown to ameliorate pain-related behaviors in animals, as well as in some patients with advanced metastatic prostate cancer.