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.
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).
Yuyama
Hironori
H
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Tsukuba-shi, Ibaraki, Japan. yuyama@yamanouchi.co.jp
Koakutsu
Akiko
A
Fujiyasu
Noriko
N
Fujimori
Akira
A
Sato
Shuichi
S
Shibasaki
Kumiko
K
Tanaka
Shohei
S
Sudoh
Katsumi
K
Sasamata
Masao
M
Miyata
Keiji
K
D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005557:Formaldehyde; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010146:Pain / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D010147:Pain Measurement; D011471:Prostatic Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D005557:Formaldehyde