Depressant effect on a C-fibre reflex in the rat, of RB101, a dual inhibitor of enkephalin-degrading enzymes.
The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the C-fibre reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg kg(-1), i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The ED(50) was calculated as 16.9 mg kg(-1). Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors, confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide range of stimulus intensities, albeit excluding the highest.
Benoist
Jean-Michel
JM
Laboratoire de Physiopharmacologie du Système nerveux, INSERM U161, 2 rue d'Alésia, 75014 Paris Cedex, France.
Keime
Florence
F
Montagne
Jacqueline
J
Noble
Florence
F
Fournié-Zaluski
Marie-Claude
MC
Roques
Bernard P
BP
Willer
Jean-Claude
JC
Le Bars
Daniel
D
D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects* / Q000502:physiology
D004220:Disulfides; C074024:RB 101; D010649:Phenylalanine; D000626:Aminopeptidases; C025579:enkephalin degrading enzyme; D018826:CD13 Antigens; D015260:Neprilysin