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 ataxis, as previously described, while at 3.0 mg/kg animals appeared to lose muscle tone, becoming limp. These results demonstrate 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.
Trujillo
K A
KA
Mental Health Research Institute, University of Michigan, Ann Arbor, MI 48109-0720.
Akil
H
H
D000818:Animals; D002375:Catalepsy / Q000139:chemically induced*; D016291:Dizocilpine Maleate / Q000633:toxicity*; D004357:Drug Synergism; D007928:Lethal Dose 50; D008297:Male; D009020:Morphine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D009020:Morphine