Inhibition of morphine withdrawal by the association of RB 101, an inhibitor of enkephalin catabolism, and the CCKB antagonist PD-134,308.
1. The effects induced in rats on naloxone-precipitated morphine withdrawal syndrome by the new mixed inhibitor of enkephalin catabolism able to cross the blood-brain barrier RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-ox-opropyl-L-phenylalanine benzyl ester) given alone or associated with the selective CCKB antagonist, PD-134,308, were investigated. 2. The systemic administration of RB 101 (5, 10 and 20 mg kg-1, i.v.) elicited a significant decrease in 8 of the 14 withdrawal signs evaluated. PD-134,308 (3 mg kg-1, i.p.) did not modify the expression of morphine abstinence when given alone, but induced a strong facilitation of RB 101 responses (12 of 14 withdrawal signs were decreased). This potentiation was particularly intense in peripherally mediated withdrawal signs. 3. In order to clarify the biochemical mechanisms implicated in these responses, the effects induced by the association of RB 101 and PD-134,308 on the occupation of brain opioid receptors by endogenous enkephalins were also investigated in mice. PD-134,308, as well as RB 101, inhibited [3H]-diprenorphine binding to opioid receptors. These results suggest that an increase in endogenous enkephalin levels induced by PD-134,308 could participate in the facilitation of RB 101 behavioural responses. 4. RB 101 has a promising potential role in the management of the opiate withdrawal syndrome. CCKB antagonists, such as PD-134,308 may be useful in potentiating this anti-withdrawal effect.
Maldonado
R
R
Département de Pharmacochimie Moléculaire et Structurale, U266 INSERM-URA D1500 CNRS, Université René Descartes-Faculté de Pharmacie, Paris, France.
Valverde
O
O
Ducos
B
B
Blommaert
A G
AG
Fournie-Zaluski
M C
MC
Roques
B P
BP
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D004174:Diprenorphine / Q000493:pharmacokinetics; D004220:Disulfides / Q000494:pharmacology / Q000627:therapeutic use*; D004338:Drug Combinations; D004357:Drug Synergism; D004745:Enkephalins / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009020:Morphine / Q000009:adverse effects*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D015431:Weight Loss / Q000187:drug effects
D000700:Analgesics; D004220:Disulfides; D004338:Drug Combinations; D004745:Enkephalins; D007211:Indoles; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C074024:RB 101; D004174:Diprenorphine; D009270:Naloxone; D010649:Phenylalanine; D008536:Meglumine; D009020:Morphine