Effects of peptidase inhibitors on the enkephalin-induced anti-nociceptionin rats

The intra-third-ventricular (i.t.v.) administration of [Met(5)]-enkephalin (enk) to rats pretreated i.t.v. with three peptidase inhibitors (PIs), amas tatin, captopril and phosphoramidon, inhibited the tail-flick response. The enk-induced inhibition was augmented by increasing the doses of the three PIs, with the maximum inhibition being attained at the doses of 10 nmol eac h. The enk-induced inhibition in rats pretreated with any combination of tw o PIs, however, were markedly smaller than that in rats pretreated with all three PIs, indicating that three kinds of enzymes all played important rol es in the inactivation of enk. The inhibitory effect of enk on the tail-fli ck response in rats pretreated with the three PIs at doses of 10 nmol each was approximately tenfold higher than that of morphine. The relative anti-n ociceptive potencies of enk and morphine were similar to the relative inhib itory potencies obtained previously with the isolated guinea pig ileum pret reated with the three PIs, indicating that the hydrolysis of the i.t.v. adm inistered enk was largely prevented by the three PIs. However, the magnitud e of the enk-induced inhibition in rats pretreated s.c. with the three PIs indicated that the hydrolysis of enk injected i.t.v. was not largely preven ted by the s.c. administration of three PIs at doses up to 10 mu mol each/k g.