Abstract
Whereas endopeptidase 24.11 cleaves the Gly-Phe bond in both Met- and Leu-enkephalin, endopeptidase 24.15 rapidly converts dynorphin A1–8, alpha and beta-neoendorphin into Leu-enkephalin, and Met-enkephalin-Arg6-Gly7-Leu8 (MERGL) into Met-enkephalin. Inhibitors of both endopeptidase 24.11 and endopeptidase 24.15 each produce antinociception, and inhibitors of endopeptidase 24.11 increase the magnitude of enkephalin antinociception. The present study compared the central antinociceptive effect of an inhibitor of endopeptidase 24.15, N-[1-(R-S)-carboxy-3-phenyl-propyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB) with one of endopeptidase 24.11 N-[1-(RS)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (cFP-F-pAB) upon central opioid antinociception induced by MERGL, met-enkephalin and dynorphin A1–8. cFP-AAF-pAB, but not cFP-F-pAB increased MERGL antinociception on the tail-flick and jump tests. In contrast, cFP-F-pAB, but not cFP-AAF-pAB increased met-enkephalin antinociception. Whereas central dynorphin A1–8 failed to induce antinociception itself, co-administration of cFP-AAF-pAB and dynorphin A1–8 increased nociceptive thresholds. This effect was not accompanied by motor dysfunction, but was blocked by systemic pretreatment with naloxone or central pretreatment with naltrexone or nor-binaltorphamine, but not beta-funaltrexamine. These data indicate that endopeptidase 24.15 may be responsible for the degradation of specific opioid peptides (e.g., MERGL, dynorphin), and that this process may prevent the full expression of their antinociceptive properties.
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Acker GR, Molineaux CJ, Orlowski M (1987) Synaptosomal membrane-bound form of endopeptidase 24.15 generates leu-enkephalin from dynorphin A1–8 alpha-and beta-neoendorphin, and met-enkephalin from met-enkephalin-arg6-gly7-leu8. J Neurochem 48:284–292
Almenoff J, Wilk S, Orlowski M (1981) Membrane-bound pituitary metalloendopeptidase: apparent identity to enkephalinase. Biochem Biophys Res Commun 102:206–214
Belluzzi JD, Grant N, Garsky V, Sarantakis D, Wise CD, Stein L (1976) Analgesia induced in vivo by central administration of enkephalin in rat. Nature 260:625–626
Chaillet PH, Marcais-Collado H, Costetin J, Yi CC, DeLaBaume S, Schwartz JC (1983) Inhibition of enkephalin metabolism by, and antinociceptive activity of, bestatin, an aminopeptidase inhibitor. Eur J Pharmacol 86:329–342
Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa receptor. Science 215:413–415
Chipkin RE, Latranyi MB, Iorio LC, Barnett A (1982) Potentiation of d-ala2-enkephalinamide analgesia by thiorphan. Eur J Pharmacol 83:283–288
Chipkin RE, Berger JG, Billard W, Iorio LC, Chapman R, Barnett A (1988) Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. J Pharmacol Exp Ther 245:829–838
Chou J, Tang J, DelRio J, Yang HYT, Costa E (1984) Action of peptidase inhibitors on met-enkephalin-Arg-Phe and met-enkephalin metabolism and on electroacupuncture antinociception. J Pharmacol Exp Ther 230:349–352
Chu TG, Orlowski M (1984) Active-site directed N-carboxymethyl peptide inhibitors of a soluble metalloendopeptidase from rat brain. Biochemistry 23:3598–3603
Chu TG, Orlowski M (1985) Soluble metalloendopeptidase from rat brain: action on enkephalin-containing peptides and other bioactive peptides. Endocrinology 116:1418–1425
D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79
DeLaBaume S, Yi CC, Schwartz JC, Chaillet P, Marcus-Collado H, Constentin J (1983) Participation of both enkephalinase and aminopeptidase activities in the metabolism of endogenous enkephalins. Neuroscience 8:143–151
Evans WO (1961) A new technique for the investigation of some analgesic drugs on a reflexive behavior in the rat. Psychopharmacology 2:318–325
Faden AI, Jacobs TP (1983) Dynorphin produces partially reversible paraplegia in the rat. Eur J Pharmacol 91:321–324
Fournie-Zaluski MC, Chaillet P, Bouboutou P, Couland A, Cherot P, Waksman G, Costentin J, Roques BP (1984) Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes. Eur J Pharmacol 102:525–528
Frederickson RCA, Burgis V, Edwards JD (1977) Hyperalgesia induced by naloxone follows diurnal rhythm in responsivity to painful stimuli. Science 199:1359–1362
Friedman HJ, Jen MF, Chang JK, Lee NM, Loh HH (1981) Dynorphin: a possible modulatory peptide on morphine or beta-endorphin analgesia. Eur J Pharmacol 69:351–360
Fulcher IS, Matsas R, Turner AJ, Kenny AJ (1982) Kidney neutral endopeptidase and the hydrolysis of enkephalin by synaptic membranes show similar sensitivity to inhibitors. Biochem J 203:519–522
Herman BH, Goldstein A (1985) Antinociception and paralysis induced by intrathecal dynorphin A. J Pharmacol Exp Ther 232:27–32
Iadorola MJ, Tang J, Costa E, Yang HTY (1986) Analgesic activity and release of met-enkephalin-Arg6-Gly7-Leu8 from rat spinal cord in vivo. Eur J Pharmacol 121:39–48
Kest B, Orlowski M, Molineaux CJ, Bodnar RJ (1991) Antinociceptive properties of inhibitors of endopeptidase 24.15. Int J Neurosci 56:141–149
Lecomte JM, Constentin J, Vlaiculescu A, Chaillet P, Marcais-Collado H, Llorens-Cortes C, Leboyer M, Schwartz JC (1986) Pharmacological properties of acetorphan, a parentally active “enkephalinase” inhibitor. J Pharmacol Exp Ther 237:937–944
Long JB, Petras JM, Mobley WC, Holaday JW (1988) Neurological dysfunction after intrathecal injection of dynorphin A1-13 in the rat. II Nonopioid mechanisms mediate loss of motor, sensory and autonomic function. J Pharmacol Exp Ther 246:1167–1174
Malfroy B, Swerts JP, Guyon A, Roques BP, Schwartz JC (1978) High affinity enkephalin-degrading peptidase in brain is increased after morphine. Nature 276:523–526
Mellstrom B, Iadarola MJ, Costa E (1987) Effects of peptidase inhibitors on met-enkephalin-Arg6-Phe7 and met-enkephalin-Arg6-Gly7-Leu8-induced antinociception. Eur J Pharmacol 133:185–190
Millan MJ (1989) Kappa-opioid receptor-mediated antinociception in the rat. I Comparative actions of mu- and kappa-opioids against noxious thermal, pressure and electric stimuli. J Pharmacol Exp Ther 251:334–341
Millan MJ (1990) Kappa-opioid receptors and analgesia. TIPS 11:70–76
Molineaux CJ, Ayala JM (1990) An inhibitor of endopeptidase 24.15 blocks the degradation of intraventricularly administered dynorphins. J Neurochem 55:611–618
Nakazawa T, Ikeda M, Kaneko T, Yamatsu K, Kitagawa K, Kiso Y (1989) Bestatin potentiates the antinociception but not the motor dysfunction induced by intracerebrally administered dynorphin-B in mice. Neuropeptides 13:277–283
Orlowski M, Michaud C, Chu TG (1983) A soluble metalloendopeptidase from rat brain. Purification of the enzyme and determination of specificity with synthetic and natural peptides. Eur J Biochem 135:81–88
Orlowski M, Michaud C, Molineaux CJ (1988) Substrate-related potent inhibitors of brain metalloendopeptidase. Biochemistry 27:599–602
Orlowski M, Reznik S, Ayala J, Pierotti AR (1989) Endopeptidase 24.15 from rat testes. Isolation of the enzyme and its specificity toward synthetic and natural peptides, including enkephalin-containing peptides. Biochem J 261:951–958
Pozsgay M, Michaud C, Liebman M, Orlowski M (1986) Substrate and inhibitor studies of thermolysine-like neutral metalloendopeptidase from kidney membrane fractions: comparison with bacterial thermolysine. Biochemistry 25:1292–1299
Roques BP, Fournie-Zaluski MC, Soroca E, Lecomte JM, Malfroy B, Llorens C, Schwartz JC (1980) The enkephalinase inhibitor Thiorphan shows antinociceptive activity in mice. Nature 288:286–288
Sawynok J, Pinsky C, LaBella FS (1979) On the specificity of naloxone as an opiate antagonist. Life Sci 25:1621–1632
Sullivan S, Akil H, Barchas JD (1978) In vitro degradation of enkephalin: evidence for cleavage at the Gly-Phe bond. Commun Psychopharmacol 2:525–531
Takemori AE, Larson DL, Portoghese PS (1981) The irreversible narcotic antagonist and reversible agonistic properties of the fumarate methyl ester derivative of naltrexone. Eur J Pharmacol 70:445–451
Takemori AE, Ho BY, Naeseth JS, Portoghese PS (1988) Norbinaltorphamine, a highly selective kappa-opioid antagonist in analgesic and receptor binding assays. J Pharmacol Exp Ther 246:255–258
Turner AJ, Matsas R, Kenny J (1985) Are there neuropeptide-specific peptidases? Biochem Pharmacol 34:1347–1356
Walker JM, Coy DH, Young EA, Baldrighi G, Siegel SF, Bowen WD, Akil H (1987) [d-ala2, (F5)Phe4]-dynorphin1–13-NH2 (DAFPHEDYN): a potent analogue of dynorphin1–13. Peptides 8:811–817
Young EA, Walker JM, Houghten R, Akil H (1986) The degradation of dynorphin A in brain tissue in vivo and in vitro. Peptides 8:701–707
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Kest, B., Orlowski, M. & Bodnar, R.J. Endopeptidase 24.15 inhibition and opioid antinociception. Psychopharmacology 106, 408–416 (1992). https://doi.org/10.1007/BF02245427
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DOI: https://doi.org/10.1007/BF02245427