The kappa-opioid receptor agonist U50,488H induces acute physical dependence in guinea-pigs

The present study was undertaken to determine whether acute physical dependence occurred in guinea-pigs in vivo and guinea-pig isolated ileum following a single dose of the kappa-opioid receptor agonist U50,488H. 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 increased locomotor activity accompanied by behavioural responses which differed from those previously found in this species with morphine withdrawal. Nor-binaltorphimine, 10 mg/kg s.c., given 1 h after administration of U50,488H, 10 mg/kg s.c., produced a small but significant increase in locomotor activity but no other withdrawal behaviours. The morphine withdrawal response was not significantly affected by U50,488H, 1 or 10 mg/kg s.c. On the guinea-pig isolated ileum, nor-binaltorphimine, 1 microM, produced a withdrawal contracture following 2 min contact of the ileum with U50,488H 1 microM. U50,488H, 1 microM, abolished the [Met5]enkephalin withdrawal response of the ileum. It is concluded that dependence 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.