Stimulation of delta-opioid receptors reduces the in vivo binding of the cholecystokinin (CCK)-B-selective agonist [3H]pBC 264: evidence for a physiological regulation of CCKergic systems by endogenous enkephalins.
Cholecystokinin (CCK) and enkephalins appear to be colocalized in several brain structures, and a physiological interaction between these peptides has been suggested by a large number of pharmacological studies. In this work we have shown, by in vivo binding experiments, that the endogenous enkephalins, protected from degrading enzymes by mixed inhibitors such as kelatorphan and N-[(R,S)-2-benzyl-3-[(S)-2-amino-4-methylthiobutyldithio]-1-oxo pro pyl]- L-phenylalanine benzyl ester (RB 101), a systemically active prodrug, modulate CCK release in mouse brain, leading to an overall increase in the extracellular levels of CCK. This was quantified by measuring the effects of both inhibitors on the in vivo binding of [3H]propionyl-Tyr(SO3H)-gNle-mGly-Trp-(N-Me)Nle-Asp-Phe-NH2 ([3H]pBC 264), a selective and highly potent CCK-B agonist. Thus, intracerebroventricular injection of kelatorphan produced a dose-dependent inhibition of the in vivo binding of [3H]pBC 264 with a maximal effect (40%) at 50 nmol. A similar response was observed after intravenous injection of RB 101 (40 mg/kg). The specific binding of [3H]pBC 264 was also inhibited (25%) by intravenous injection of the selective delta-opioid agonist H-Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu)-OH (BUBUC; 2 mg/kg) but not by the mu-agonist H-Tyr-D-Ala-Gly-(N-Me)Phe-Gly-ol (5 mg/kg), suggesting a preferential involvement of delta-opioid receptors in the modulation of CCK release. This was confirmed by using the selective delta-opioid antagonist naltrindole, which prevented the inhibitory effects of BUBUC and of enkephalin-degrading enzyme inhibitors on [3H]pBC 264 binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Ruiz-Gayo
M
M
Département de Chimie Organique, INSERM U. 266, CNRS UA 1500, Paris, France.
Durieux
C
C
Fournié-Zaluski
M C
MC
Roques
B P
BP
D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002766:Cholecystokinin / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000502:physiology*; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000502:physiology; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D000700:Analgesics; D000701:Analgesics, Opioid; D004151:Dipeptides; D004220:Disulfides; D004745:Enkephalins; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D011355:Prodrugs; D011949:Receptors, Cholecystokinin; D011957:Receptors, Opioid; C062342:pBC 264; C074024:RB 101; C042591:kelatorphan; D010649:Phenylalanine; D002766:Cholecystokinin