Angiotensin-converting enzyme inhibitors potentiate the analgesic activity of [Met]-enkephalin-Arg6-Phe7 by inhibiting its degradation in mouse brain.
The proteolytic degradation of the enkephalin-containing heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe (YGGFMRF) was investigated by incubating the peptide with synaptic membranes from mouse whole brain and characterizing the formed products. The degradation products were derivatized with 4-dimethylaminoazobenzene-4'-isothiocyanate and then analyzed by high pressure liquid chromatography and by amino-terminal analysis. The incubation of YGGFMRF with synaptic membranes yielded YGGFM and RF as the degradation products. The angiotensin-converting enzyme (ACE) inhibitors, MK-422 and captopril, potently inhibited the formation of YGGFM and RF with IC50 values of 8 nM and 95 nM, respectively. The "enkephalinase A" inhibitor, thiorphan, weakly inhibited this dipeptidyl carboxypeptidase activity with an IC50 greater than 1 microM. YGGFMRF, MK-422, captopril, and thiorphan all produced a dose-dependent analgesic response in the mouse hot plate test when administered intracerebroventricularly. However, when subanalgesic doses of inhibitors were co-administered with a subanalgesic dose of YGGFMRF, only the ACE inhibitors, MK-422 and captopril, potentiated the analgesic response of the peptide. These data provide in vitro and in vivo evidence that ACE is the primary enzyme involved in the proteolytic degradation of YGGFMRF in the mouse brain.
D000700:Analgesics / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002216:Captopril / Q000494:pharmacology; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology; D015773:Enalaprilat; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D013570:Synaptic Membranes / Q000378:metabolism; D015244:Thiorphan; D008625:Tiopronin / Q000031:analogs & derivatives / Q000494:pharmacology
D000700:Analgesics; D000806:Angiotensin-Converting Enzyme Inhibitors; D004744:Enkephalin, Methionine; D004656:Enalapril; C027511:enkephalin-Met, Arg(6)-Phe(7)-; D002216:Captopril; D015244:Thiorphan; D008625:Tiopronin; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat