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Repeated systemic administration of the mixed inhibitor of enkephalin-degrading enzymes, RB101, does not induce either antinociceptive tolerance or cross-tolerance with morphine.

Abstract：

:The potent analgesic responses elicited by systemic administration of RB101, N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopro pyl]- 1-oxopropyl]-L-phenylalanine benzyl ester, a prodrug able to inhibit enkephalin-degrading enzymes completely after in vivo bioactivation, has made it possible to investigate the development of antinociceptive tolerance after chronic potentiation of endogenous enkephalins. The ED50 values of RB101 obtained 10 min after i.v. injection were not significantly different in mice treated for 4 days with i.p. administered vehicle (ED50 = 9.50 (6.37-14.15) mg/kg), or with 80 mg/kg of RB101 twice daily (ED50 = 9.50 (5.86-15.39) mg/kg). In contrast, a parallel rightwards shift of the dose-response curves, corresponding to a significant 1.92 (1.49-2.52)-fold decrease in analgesic potency, was observed after i.v. administration of morphine in mice chronically treated with morphine (3 mg/kg, twice daily for 4 days) (ED50 = 3.10 (2.52-3.81) mg/kg) vs. saline (ED50 = 1.60 (1.22-2.09) mg/kg). No tolerance to RB101 was observed even after a longer period (8 days) of chronic treatment with the prodrug. Moreover, no cross-tolerance between morphine and RB101 appeared to occur since the ED50 values obtained after i.v. administration of RB101 were not significantly different in mice chronically pretreated with vehicle (ED50 = 9.50 (6.37-14.15) mg/kg) or with morphine (ED50 = 10.00 (6.62-15.10) mg/kg). The analgesic effect of RB101 observed in morphine-tolerant mice was antagonized by prior injection of naloxone, but not naltrindole (delta-selective antagonist), supporting a preferential involvement of mu-opioid receptors in the antinociceptive effect of RB101, at least in mice in the hot-plate test.(ABSTRACT TRUNCATED AT 250 WORDS)

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Noble F,Turcaud S,Fournié-Zaluski MC,Roques BP

doi

10.1016/0014-2999(92)90821-k

keywords:

subject

Has Abstract

pub_date

1992-11-13 00:00:00

pages

83-9

issue

eissn

0014-2999

issn

1879-0712

pii

0014-2999(92)90821-K

journal_volume

223

pub_type

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Repeated systemic administration of the mixed inhibitor of enkephalin-degrading enzymes, RB101, does not induce either antinociceptive tolerance or cross-tolerance with morphine.