Pharmacological Evaluation of Analgesic Effects of the Cholecystokinin2Receptor Antagonist Z-360 in Mouse Models of Formalin- andCancer-Induced Pain

摘要

Z-360, a novel cholecystokinin2 (CCK2) receptor antagonist, has been developed as a therapeutic drug forpancreatic cancer and showed pain relief action in phase Ib/Ha clinical trial. This study was attempted to eluci-date the analgesic efficacy of Z-360 in mice. Oral administration of Z-360 (30-300 mg/kg) showed a dose-de-pendent inhibitory effect on the late phase of nociceptive responses to formalin. YF476, another CCK2 receptorantagonist, was without effects at 1 and 10 mg/kg. In contrast, the CCK1 receptor antagonist devazepide inhib-ited 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 effectwas also observed after repeated administration of devazepide. Combined single treatment with morphine andZ-360 caused an increase inhibition of pain-related responses in the pain models produced by formalin and can-cer. Although Z-360 has lower affinity for CCK1 receptor than for CCK2receptor, Z-360 exhibited an inhibitoryeffect on sulfated CCK-8-induced gallbladder emptying, a CCK1 receptor-mediated effect, at a dose of100 mg/kg. These results suggest that Z-360 inhibits inflammatory and cancer pain probably through the block-ade of CCK1 receptors. Z-360 is expected to become a useful drug for the pancreatic cancer with analgesic effectsas well as the prolongation of survival.