Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat.

To investigate the possible role of excitatory amino acids (EAAs) in the mechanisms of morphine tolerance, rats were treated either with the wide-spectrum EAA antagonist, kynurenic acid (150 mg/kg), or the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist. MK-801 (0.05 mg/kg), during a four-day induction period of morphine tolerance. Morphine was given once daily at a dose of 15 mg kg. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by both EAA antagonists. Control experiments showed that at the same doses neither acute nor chronic administration of these antagonists affected morphine analgesia itself in a manner that can explain these findings. The possible involvement of EAAs in the mechanisms of morphine tolerance is discussed.