Ay. Bespalov et al., N-methyl-D-aspartate receptor antagonists and the development of toleranceto the discriminative stimulus effects of morphine in rats, J PHARM EXP, 290(1), 1999, pp. 20-27
Citations number
43
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor an
tagonists prevent the development of analgesic tolerance to opiates. Some e
ffects of opiates, such as their discriminative stimulus effects, are known
to be more resistant to tolerance induction. In this study, adult male Lon
g-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from w
ater (vehicle) using a standard, two-lever fixed ratio 10 schedule of food
reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days
b.i.d.) was administered, which induced tolerance-like rightward shifts in
the dose-effect curves for both morphine's discriminative stimulus and res
ponse rate-suppressing effects. Withdrawal-induced, response rate reduction
s indicative of behavioral dependence appeared as well. Separate groups wer
e then treated repeatedly with a combination of morphine or its vehicle and
one of the following competitive or noncompetitive NMDA antagonists: dizoc
ilpine(0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic
acid (D-CPPene; 3 and 5.6 mg/kg i.p.), eliprodil (17.3 mg/kg i.p.), or R()-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The developm
ent of tolerance to morphine's stimulus effects was attenuated by eliprodil
and the higher dose of D-CPPene, but not by dizocilpine, the lower dose of
D-CPPene, nor R(+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists preven
ted the induction of tolerance to morphine's response rate effects. Dizocil
pine and o-CPPene (5.6 mg/kg) appeared to prevent the induction of behavior
al dependence as well. NMDA antagonists can prevent tolerance to the discri
minative stimulus effects of morphine, and perhaps to its behavioral depend
ence effects, but their site of action on the NMDA receptor complex confers
a different ability to do so.