Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV.
The tetrapeptide, endomorphin-2 (Tyr-Pro-Phe-PheNH2) possesses high affinity for mu opioid receptors, and produces potent analgesia in mice. Its structure appears to satisfy the substrate requirements of the proteinase, dipeptidyl peptidase IV which removes dipeptides from the amino terminus of peptides containing proline as the penultimate amino acid. A potent, stable and specific inhibitor of this enzyme, Ala-Pyrrolidonyl-2-nitrile, has been described which should potentiate endomorphin-2-induced analgesia. Further, since dipeptidyl peptidase IV has an absolute requirement for l-Pro, a more metabolically-stable d-Pro2-endomorphin-2 analog should produce longer analgesic actions at lower doses. The present study found that endomorphin-2 was degraded approximately twice as fast than the chromogenic substrate, Ala-Pro-2naphthylamide, by dipeptidyl peptidase IV, whereas d-Pro2-endomorphin-2 was totally resistant to this enzyme's action. d-Pro2-endomorphin-2 (ED50=0.05 microg) was more potent than endomorphin-2 (ED50=30 microg) in significantly increasing tail-flick latencies with longer durations of action. Both the peptide and analogue were equipotent (ED50=0.5 microg) in significantly increasing jump thresholds. Ala-Pyrrolidonyl-2-nitrile (10-75 nmol) elicited a dose-dependent analgesia, and potentiated the analgesic actions of endomorphin-2, particularly on the tail-flick test. Whereas systemic naltrexone (2.5, 10 mg/kg) dose-dependently eliminated each of the three forms of analgesia on the jump test as well as the peak (15 min) effect on the tail-flick test, analgesia elicited by either endomorphin-2, d-Pro2-endomorphin-2 or Ala-Pyrrolidonyl-2-nitrile returned after 30-60 min in naltrexone-treated rats on the tail-flick test. These data strongly suggest that dipeptidyl peptidase IV plays a role in the inactivation of endomorphin-2 in vivo, and thereby modulates its central analgesic actions.
Shane
R
R
Neuropsychology Doctoral Subprogram, Queens College, CUNY, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
Wilk
S
S
Bodnar
R J
RJ
D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage; D009842:Oligopeptides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D009271:Naltrexone; D018819:Dipeptidyl Peptidase 4