Mrz 2/579, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats

Abstract

The purpose of the present study was to investigate whether uncompetitive NMDA antagonists with fast channel blocking kinetics, which show fewer side effects in man than compounds such as ketamine, affect the development of tolerance to continuous exposure to morphine. Rats were trained on the Randall–Selitto apparatus before being implanted, under halothane anaesthesia, with primed mini-osmotic pumps (240 μl/day). Six rats were implanted with a vehicle filled pump, seven with a morphine filled pump (28.8 mg/kg/day), and eight with a pair of pumps, one containing morphine and the other Mrz 2/579, a new NMDA antagonist (40 mg/kg/day). A fourth group was implanted with a morphine filled pump followed 25 h later by a Mrz 2/579 filled pump. Paw withdrawal tests were undertaken immediately before, and at 2, 4, 6, 8, 10, 12, 24, 48 and 72 h after the first pump was implanted. Before pump implantation, withdrawal thresholds were 120±7 g (mean±SEM, n=30). Vehicle infusion had no effect on withdrawal thresholds, whereas morphine infusion increased them significantly at 2 and 4 h after pump implantation (+2 h: 208±14 g; P<0.001 vs. control). From 6 h the antinociception elicited by morphine declined progressively; at 10 h withdrawal thresholds were significantly lower than the 2 h post-treatment value ( P<0.001). In rats treated with morphine plus Mrz 2/579, thresholds remained significantly higher between 10–72 h post-implantation than with morphine alone ( P<0.05). In contrast, infusion of the same level of Mrz 2/579 once tolerance had developed did not reverse tolerance. These results indicate that fast NMDA channel blockers such as Mrz 2/579 may prove to be useful in enhancing analgesia to continuous morphine administration.