title: Pain management by a new series of dual inhibitors of enkephalin degrading enzymes: long lasting antinociceptive properties and potentiation by CCK2 antagonist or methadone.
abstract: The discovery that the endogenous morphine-like peptides named enkephalins are inactivated by two metallopeptidases, neutral endopeptidase and aminopeptidase N, which can be blocked by dual inhibitors, represents a promising way to develop 'physiological' analgesics devoid of the side effects of morphine. A new series of dual aminophosphinic inhibitors of the two enkephalin-catabolizing enzymes has been recently designed. In this study, one of these inhibitors, RB3007, was tested in various assays commonly used to select analgesics (mouse hot-plate test, rat tail-flick test, writhing and formalin tests in mice, and paw pressure test in rats), and the extracellular levels of the endogenous enkephalins in the ventrolateral periaqueductal grey have been measured by microdialysis after systemic administration of RB3007. In the mouse hot-plate test, the dual inhibitor induced long-lasting (2 h) antinociceptive effects with a maximum of 35% analgesia 60 min after i.v. or i.p. administration. These antinociceptive responses were antagonized by prior injection of naloxone (0.1 mg/kg, s.c.). Similar long lasting effects were observed in the other animal models used. Very interestingly, injection of RB3007 (50 mg/kg, i.p.) significantly increased (82%) the extracellular levels of Met-enkephalin with a peak 60 min after i.p. injection. This increase parallels the antinociceptive responses observed. In addition, strong facilitatory effects of subanalgesic doses of the CCK(2) receptor antagonist, PD-134,308 or the synthetic opioid agonist, methadone on RB3007-induced antinociceptive responses were observed. These findings may constitute promising data for future development of a new class of analgesics that could be of major interest in a number of severe and persistent pain syndromes.
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS FRE2463, UFR des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris Cedex 06, France. leguen@pharmacie.univ-paris5.fr
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Guen
authors.forename: Magdalena
authors.initials: M
authors.lastname: Mas Nieto
authors.forename: Corinne
authors.initials: C
authors.lastname: Canestrelli
authors.forename: Huixiong
authors.initials: H
authors.lastname: Chen
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Annie
authors.initials: A
authors.lastname: Cupo
authors.forename: Rafaël
authors.initials: R
authors.lastname: Maldonado
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Florence
authors.initials: F
authors.lastname: Noble
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019468:Disease Management; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008691:Methadone / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D007211:Indoles; D011355:Prodrugs; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D008691:Methadone