Inhibitory Effects of a Selective Endothelin-A Receptor Antagonist YM598 on Endothelin-1-induced Potentiation of Nociception in Formalin-induced and Prostate Cancer-induced Pain Models in Mice

Abstract

In some diseases in which endothelin-1 (ET-1) production increases (e.g. prostate cancer), ET-1 is considered to be involved in the generation of pain. In the present study, we investigated the effects of a selective endothelin-A receptor antagonist, YM598, on the nociception potentiated by ET-1 in formalin-induced and cancer inoculation-induced pain models in mice. The formalin-induced pain model was prepared by intraplantar injection of 0.7% formalin into the hind paws of ICR mice, and the cancer pain model was prepared by inoculation of the human prostate cancer cell line PPC-1 into the hind paws of severe combined immunodeficiency mice. Formalin caused a biphasic pain response and paw edema in the mouse hind paw. ET-1 (10 pmol/paw) potentiated these responses, and single oral administration of YM598 (0.3-3 mg/kg) significantly inhibited this ET-1-induced potentiation of nociception and paw edema. ET-1 (10 pmol/paw) also potentiated the pain response in prostate cancer-inoculated mice. Both YM598 and atrasentan (0.3-3 mg/kg) significantly inhibited the ET-1-induced potentiation of nociception. These results suggest that selective endothelin-A receptor antagonists relieve pain in patients with various diseases in which ET-1 production increases (e.g. prostate cancer).

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

“…Pain is prevalent in about 70% of people with metastatic cancers such as prostate and breast cancer 97. Exogenous application of ET-1 in animal models of cancer has been found to potentiate cancer-induced nociception and sensitization of C-fibers to heat via activation of ET A receptors, a similar pathway as that seen in ET-1-induced potentiation of formalin- and capsaicin-induced nociception 98,99. It has been shown that the concentration of ET-1 has a more direct correlation to pain levels than the size of the tumor in mice,100 illustrating the importance of evaluating algogens released by cancerous tumors, such as ET-1, to identify novel therapeutic targets to treat cancer pain.…”

Validation of the University of California San Francisco Oral Cancer Pain Questionnaire

“…17-19 For example, endothelin (ET-1), a vasoactive peptide that is produced by a number of different malignancies, sensitizes peripheral afferent sensory nerve fibers and contributes to both soft tissue and bone cancer pain as well as pain due to oral squamous cell carcinoma. 7,16,19,20 We recently demonstrated that the site of action for ET-1 in producing cancer pain in a mouse model is in the periphery within the tumor microenvironment. 19 The finding that a peripheral nociceptive mediator is responsible for cancer pain supports our current finding in humans that surgical resection leads to a significant reduction in pain since the cellular source of the mediator would be removed.…”

Targeting Bone Metastasis in Prostate Cancer with Endothelin Receptor Antagonists

“…ET-1 enhances pain states in various models of acute chemicaland inflammation-induced pain and in chronic pain types such as neuropathic pain, where selective ET A inhibition shows preclinical efficacy (26). The key relevance of ET-1 and the effectiveness of ET A inhibition have also been shown in acute pain models, both irritant induced and prostate cancer related (27). In the latter experiments, ET-1 axis inhibition both with small-molecule inhibitors resulted in significant pain control.…”