title: Role of endogenous cholecystokinin in the facilitation of mu-mediated antinociception by delta-opioid agonists.
abstract: Published results suggest that delta-opioid agonists can modulate the mu-mediated analgesia. In this work, the antinociceptive effects produced by the mu agonist [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin or the mixed inhibitor of enkephalin-degrading enzymes RB 101 (N- [(R,S)-2-benzyl-3[(S)(2-amino-4-methyl- thio)butyldithio]-1-oxopropyl]-L-phenylalanine benzyl ester) were studied after administration of the systemically active and selective delta agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu- Thr(O-tert-butyl). In the hot-plate test in mice, Tyr-D-Ser(O-tert-butyl)-Gly- Phe-Leu-Thr(O-tert-butyl) (i.v.) potentiated the antinociceptive responses elicited by [D-Ala2,NMe-Phe4,Gly-ol5]enkephalin (i.v.) or RB 101 (i.v.). These facilitatory effects were reversed not only by prior administration of the delta-selective antagonist naltrindole (0.5 mg/kg s.c.), but also unexpectedly by the selective cholecystokinin CCK-A antagonist MK-329 (20 micrograms/kg i.p.). In addition, the CCK analog [Boc- Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-Phe-NH2] (a mixed CCK-A/CCK-B agonist) increased the jump latency and this effect was blocked by MK-329 (20 micrograms/kg i.p.) and by naloxone, but not by the selective CCK-B antagonist L-365,260 (5 mg/kg i.p.). In contrast, the selective CCK-B agonist BC 264 (62 micrograms/kg i.v.) produced a hyperalgesic effect that was antagonized by L-365,260 (5 mg/kg i.p.). Taken together, these findings suggest that the potentiating effects of delta agonists on mu-mediated analgesia are due to an increase in the release of endogenous CCK interacting with CCK-A and CCK-B receptors and resulting in positive and negative regulation of the endogenous opioid system.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Département de Pharmacochimie Moléculaire et Structurale, U266 Institut National de la Santé et de la Recherche Médicale, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Noble
authors.forename: C
authors.initials: C
authors.lastname: Smadja
authors.forename: B P
authors.initials: BP
authors.lastname: Roques
mesh_terms: D000595:Amino Acid Sequence; D000698:Analgesia; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002766:Cholecystokinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D020109:Devazepide; D004220:Disulfides / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C084553:BC 264; D001570:Benzodiazepinones; D004220:Disulfides; D004745:Enkephalins; D009842:Oligopeptides; D010446:Peptide Fragments; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C062971:tyrosyl-seryl(O-t-butyl)-glycyl-phenylalanyl-leucyl-threonine(O-t-butyl); C074024:RB 101; D009270:Naloxone; D010649:Phenylalanine; D009271:Naltrexone; D002766:Cholecystokinin; C047716:cholecystokinin (27-33), tert-butyloxycarbonyl-Nle(28,31)-; C055382:naltrindole; D020109:Devazepide; D012844:Sincalide