Pharmacological evaluation of analgesic effects of the cholecystokinin 2 receptor antagonist Z-360 in mouse models of formalin- and cancer-induced pain

Koji Yoshinaga, Takayuki Horii, Hiroki Hamano, Runa Eta, Tomoko Ozaki, Yuki Orikawa, Kazuyoshi Yoshii, Yoshihiro Kawabata, Yuko Hori, Koichi Seto, Mineo Takei, Yasushi Kuraishi

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Z-360, a novel cholecystokinin2 (CCK2) 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 CCK1 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 CCK1 receptor than for CCK2 receptor, Z-360 exhibited an inhibitory effect on sulfated CCK-8-induced gallbladder emptying, a CCK1 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 CCK1 receptors. Z-360 is expected to become a useful drug for the pancreatic cancer with analgesic effects as well as the prolongation of survival.

Original languageEnglish
Pages (from-to)244-248
Number of pages5
JournalBiological and Pharmaceutical Bulletin
Volume33
Issue number2
DOIs
Publication statusPublished - 02-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

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