Pharmacological evaluation of analgesic effects of the cholecystokinin2 receptor antagonist Z-360 in mouse models of formalin- and cancer-induced pain

Biol Pharm Bull. 2010;33(2):244-8. doi: 10.1248/bpb.33.244.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Benzodiazepinones / pharmacology*
  • Benzodiazepinones / therapeutic use
  • Cell Line, Tumor
  • Disease Models, Animal*
  • Drug Evaluation, Preclinical / methods
  • Formaldehyde / toxicity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Neoplasms / complications
  • Neoplasms / drug therapy*
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain / etiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin B / antagonists & inhibitors*
  • Receptor, Cholecystokinin B / physiology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzodiazepinones
  • Receptor, Cholecystokinin B
  • Z-360
  • Formaldehyde