THE NMDA RECEPTOR ANTAGONIST MK-801 INCREASES MORPHINE CATALEPSY AND LETHALITY

Interactions between excitatory amino acids and opioids were examined by studying the ability of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to affect morphine catalepsy and lethality. MK-801 (0.3 mg/kg) reduced the ED50 for morphine-induced catalepsy from approximately 30 mg/kg to less than 10 mg/kg, and reduced the LD50 for morphine from approximately 100 mg/kg to approximately 10 mg/kg. Lower doses of MK-801 did not affect morphine catalepsy or lethality. MK-801, in the absence of morphine, produced no catalepsy or lethality at doses up to 3.0 mg/kg; at 0.3 mg/kg MK-801 caused weaving, body rolling and ataxia, as previously described, while at 3.0 mg/kg animals appeared to lose muscle tone, becoming limp. These results demomstrate that blockade of NMDA receptors can dramatically potentiate morphine catalepsy and lethality, and suggest a potential dangerous interaction with opioids in the clinical use of NMDA receptor antagonists.