Takao Taniguchi, Xin-Tian Fan, Ken Kitamura and Tetsuo Oka (*)
Department of Pharmacology, School of Medicine, Tokai University, Isehara
259-1193, Japan
(*) To whom correspondence should be addressed.
Abstract: The intra-third-ventricular (i.t.v.) administration
of [Met5]-enkephalin (enk) to rats pretreated i.t.v. with three
peptidase inhibitors (PIs), amastatin, 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 each. The enk-induced inhibition in rats pretreated
with any combination of two PIs, however, were markedly smaller than that
in rats pretreated with all three PIs, indicating that three kinds of enzymes
all played important roles in the inactivation of enk. The inhibitory effect
of enk on the tail-flick 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-nociceptive potencies of enk and morphine were similar
to the relative inhibitory potencies obtained previously with the isolated
guinea pig ileum pretreated with the three PIs, indicating that the hydrolysis
of the i.t.v. administered enk was largely prevented by the three PIs. However,
the magnitude 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 prevented by the s.c. administration of three PIs at doses up to
10 micromol each/kg.
Keywords: [Met5]-enkephalin, Anti-nociception, Amastatin,
Phosphoramidon, Captopril