Antinociceptive properties of inhibitors of endopeptidase 24.15.
Endopeptidase 24.15, a metalloendopeptidase active in brain, rapidly converts prodynorphin-derived peptides into leu-enkephalin. Inhibitors of this enzyme slow the degradation of these peptides in vivo and in vitro. The present study evaluated two inhibitors of endopeptidase 24.15, N-[1-(RS)-carboxy-3-phenyl-propyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-D-Ala-Phe-p-aminobenzoate (cFP-A(D)AF-pAB), for antinociception on the tail-flick and jump tests in rats following intracerebroventricular administration relative to an inhibitor of endopeptidase 24.11, N-(1-(RS)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (cFP-F-pAB). cFP-AAF-pAB, cFP-A(D)AF-pAB and cFP-F-pAB produced equipotent dose-dependent (25-250 nmol) and time-dependent (5-7 h) antinociception with larger effects on the jump (49-51% increase) relative to the tail-flick (28-41% increase) test. Naloxone (1 mg/kg, SC) significantly reduced antinociception elicited by all inhibitors on the jump test. Motor performance failed to be affected by inhibitor administration. The gradual appearance of antinociception and its naloxone sensitivity suggest that these effects are mediated through inhibition of opioid peptide degradation.
Department of Psychology, Queens College, CUNY, Flushing 11367.
B
B
Kest
M
M
Orlowski
C J
CJ
Molineaux
R J
RJ
Bodnar
D000818:Animals; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time; D012018:Reflex / Q000187:drug effects; D012684:Sensory Thresholds / Q000187:drug effects
D009842:Oligopeptides; C064939:N-(1-carboxy-3-phenylpropyl)-alanyl-alanyl-phenylalanine-4-aminobenzoate; D009270:Naloxone; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase