Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to theoperant decrement produced by naloxone in morphine-treated rats

Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect in itial changes in opioid systems that underlie physical dependence. Glutamat e receptors are implicated in the development and expression of opioid depe ndence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype o f glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal, The present study evaluated the ability of a competit ive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin- 4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitizati on to naloxone in rats trained to lever-press on a multiple-trial, fixed-ra tio 10 schedule of food reinforcement, D-CPPene (0.3-3 mg/kg) was administe red either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg), D -CPPene failed to prevent morphine-induced potentiation of the naloxone-pro duced decrement in operant performance. Thus, these results suggest that ag onist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade. (C) 2001 Lippincott Williams & W ilkins.