Degradation of kyotorphin by a purified membrane-bound-aminopeptidase from monkey brain: potentiation of kyotorphin-induced analgesia by a highly effective inhibitor, bestatin.
Kyotorphin (Tyr-Arg) was rapidly degraded in rat brain homogenates and the Vmax and Km were 29.4 nmol/mg protein/min and 16.6 microM, respectively. This degradation was effectively inhibited by bestatin (IC 50; 0.08 microM) and p-chloromercuribenzoate (IC 50; 0.70 microM). Kyotorphin was also degraded by a membrane-bound aminopeptidase from monkey brains. The Vmax and Km of kyotorphin degradation by the aminopeptidase were 20.0 nmol/mg protein/min and 29.2 microM, respectively. The degradation of kyotorphin was also inhibited effectively by bestatin (KI; 0.4 microM). Co-administration with bestatin 50 micrograms (i.cist.) potentiated the analgesic effects of kyotorphin (i.cist.) by 4.8 times, and these effects were abolished by pretreatment with naloxone 0.5 mg/kg s.c. These results suggest that potentiation of analgesia by bestatin may be due to the protection against the degradation of kyotorphin and released enkephalin by a membrane-bound aminopeptidase.
D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D004357:Drug Synergism; D004723:Endorphins / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008566:Membranes / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D000700:Analgesics; D004723:Endorphins; C019448:kyotorphin; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex