THE KAPPA-OPIOID RECEPTOR AGONIST U50,488H INDUCES ACUTE PHYSICAL-DEPENDENCE IN GUINEA-PIGS

The present study was undertaken to determine whether acute physical d ependence occurred in guinea-pigs in vivo and guinea-pig isolated ileu m following a single dose of the kappa-opioid receptor agonist U50,488 H. Administration of naloxone hydrochloride, 15 and 30 mg/kg s.c., to guinea-pigs treated 1 h before with U50,488H, 10 mg/kg s.c., induced i ncreased locomotor activity accompanied by behavioural responses which differed from those previously found in this species with morphine wi thdrawal. Nor-binaltorphimine, 10 mg/kg s.c., given 1 h after administ ration of U50,488H, 10 mg/kg s.c., produced a small but significant in crease in locomotor activity but no other withdrawal behaviours. The m orphine withdrawal response was not significantly affected by U50,488H , 1 or 10 mg/kg s.c. On the guinea-pig isolated ileum, nor-binaltorphi mine, 1 muM, produced a withdrawal contracture following 2 min contact of the ileum with U50,488H 1 muM. U50,488H, 1 muM, abolished the [Met 5]enkephalin withdrawal response of the ileum. It is concluded that de pendence occurs following activation Of kappa-opioid receptors, which is largely non-morphine-like in the central nervous system, but which is morphine-like in the enteric nervous system.