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) (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 CCK2 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.