Pharmacological evaluation of analgesic effects of the cholecystokinin2 receptor antagonist Z-360 in mouse models of formalin- and cancer-induced pain.
Z-360, a novel cholecystokinin(2) (CCK(2)) receptor antagonist, has been developed as a therapeutic drug for pancreatic cancer and showed pain relief action in phase Ib/IIa clinical trial. This study was attempted to elucidate the analgesic efficacy of Z-360 in mice. Oral administration of Z-360 (30-300 mg/kg) showed a dose-dependent inhibitory effect on the late phase of nociceptive responses to formalin. YF476, another CCK(2) receptor antagonist, was without effects at 1 and 10 mg/kg. In contrast, the CCK(1) receptor antagonist devazepide inhibited the nociceptive responses to formalin. In a mouse model of cancer pain, significant anti-allodynic effect of Z-360 was observed after single and repeated oral administration of 100 and 300 mg/kg doses. Anti-allodynic effect was also observed after repeated administration of devazepide. Combined single treatment with morphine and Z-360 caused an increase inhibition of pain-related responses in the pain models produced by formalin and cancer. Although Z-360 has lower affinity for CCK(1) receptor than for CCK(2) receptor, Z-360 exhibited an inhibitory effect on sulfated CCK-8-induced gallbladder emptying, a CCK(1) receptor-mediated effect, at a dose of 100 mg/kg. These results suggest that Z-360 inhibits inflammatory and cancer pain probably through the blockade of CCK(1) receptors. Z-360 is expected to become a useful drug for the pancreatic cancer with analgesic effects as well as the prolongation of survival.
Yoshinaga
Koji
K
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., 2512-1 Numagami, Oshikiri, Kumagaya, Saitama 360-0111, Japan. kouji-yoshinaga@zeria.co.jp
Horii
Takayuki
T
Hamano
Hiroki
H
Eta
Runa
R
Ozaki
Tomoko
T
Orikawa
Yuki
Y
Yoshii
Kazuyoshi
K
Kawabata
Yoshihiro
Y
Hori
Yuko
Y
Seto
Koichi
K
Takei
Mineo
M
Kuraishi
Yasushi
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001570:Benzodiazepinones / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005557:Formaldehyde / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001570:Benzodiazepinones; D043887:Receptor, Cholecystokinin B; C528831:Z-360; D005557:Formaldehyde