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Excitatory amino acids (EAAs) are involved in the development of opioid tolerance. The present study reveals that an increasing of CSF EAAs concentration might be responsible for the losing of morphine's antinociceptive effect in morphine tolerant rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters and one microdialysis probe, then continuously infused i.t. for 5 days with saline (1 μl/h; control group), morphine (15 μg/h), the NMDA antagonist, MK-801 (5 μg/h), or morphine (15 μg/h) plus MK-801 (5 μg/h). Each day, tail-flick responses were measured; in addition, CSF dialysates were collected and CSF amino acids measured by high performance liquid chromatography using a fluorescence detector. Morphine started to lose its analgesic effect on day 2 and this effect was overcome by MK-801. The AD₅₀ (AD: analgesic dose) was 1.33 μg in control animals, 83.83 μg in morphine-tolerant rats (a …