Genetic differences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats

Abstract

The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan on morphine-induced antinociception was studied with the hot plate test in Sprague-Dawley (SD), Wistar-Kyoto (WK), Spontaneously Hypertensive (SHR) and Dark-Agouti (DA) rats. Subcutaneous morphine at 5 mg/kg induced significant antinociception in all four rats strains. Subcutaneous dextromethorphan at 15 and 45 mg/kg, but not 5 mg/kg, significantly and dose-dependently potentiated morphine-induced antinociception in SDs, WKs and SHRs, but not in DAs. In SHRs and DAs the antinociceptive effect of morphine was followed by prolonged hyperalgesia, which was reduced (SHRs) or abolished (DAs) by dextromethorphan. These results suggest that there are significant differences among rat strains in their response to morphine and in the ability of dextromethorphan to potentiate morphine-induced antinociception. These differences are possibly of genetic origin. Moreover, these data show that morphine, at least in some strains of rats, induced a delayed and NMDA receptor-dependent hyperalgesic response, supporting the notion that administration of opiates may activate NMDA receptors, leading to reduced antinociceptive effect and the development of hyperalgesia.