The dual peptidase inhibitor RB101 induces a long-lasting increase in the extracellular level of Met-enkephalin-like material in the nucleus accumbens of freely moving rats.
This study was carried out to analyze the extracellular levels of Met-enkephalin-like material in the nucleus accumbens, a brain structure involved in the effects of opioids on motor activity and reward processes, using microdialysis in awake and freely moving rats, combined with a sensitive radioimmunoassay. The levels of Met-enkephalin-like material were measured after administration of a dual inhibitor of enkephalin-degrading enzymes, RB101, to evaluate its in vivo protecting effects. The basal levels of Met-enkephalin-like immunoreactivity in the nucleus accumbens were approximately 1.2 pg/30 min or 2.2 fmol/30 min (37 pM). Perfusion of KCI (100 mM) produced a 17-fold increase in the level of Met-enkephalin-like material in this structure. During the 8-h perfusion, which started at 9 a.m., a spontaneous increase of the basal level of Met-enkephalin-like material in the nucleus accumbens occurred between 4 and 4:30 p.m., suggesting the existence of variation in opioid peptide secretion, at least in this structure. Intraperitoneal injection of RB101 induced a dose-dependent and long-lasting (210-min) increase in the extracellular levels of Met-enkephalin-like material. A prolonged effect was also observed in the behavioral studies in which the inhibitor increased global motor activity of rats 210 min after injection. These data represent the first direct evidence that dual inhibitors of enkephalin-degrading enzymes increase in vivo the extracellular levels of Met-enkephalin-like material in awake and freely moving rats.
Daugé
V
V
Départment de Pharmacochimie Moléculaire et Structurale, U. 266 INSERM, URA D1500 CNRS, Faculté de Pharmacie, Université René Descartes, Paris, France.
Mauborgne
A
A
Cesselin
F
F
Fournié-Zaluski
M C
MC
Roques
B P
BP
D000818:Animals; D000918:Antibody Specificity; D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000494:pharmacology*; D004744:Enkephalin, Methionine / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000201:enzymology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar
D004220:Disulfides; D004791:Enzyme Inhibitors; C074024:RB 101; D010649:Phenylalanine; D004744:Enkephalin, Methionine; D011189:Potassium Chloride