BACKGROUND: A single agent administered is not effective enough to block nociception. Combination of agents acting through different mechanisms may be one of the best ways for better analgesic methods. The purpose of this study was to investigate the spinally mediated analgesic interaction between 5-HT3 receptor agonist (m-CPBG) and NMDA receptor antagonist (MK801) in the rat formalin test. METHODS: A polyethylene catheter was inserted in the atlanto-occipital membrane to the thoracolumbar level of the spinal cord. On postoperative 7 day, the normal saline (n = 6), m-CPBG (10, 30, 100microgram: n = 18) and MK801 (0.1, 1, 10microgram: n = 18) were injected intrathecally before subcutaneous injection of 5% formalin. The combinations of each 1/2ED50 + 1/2ED50, 1/4ED50 + 1/4ED50, 1/8ED50 + 1/8ED50 were tested and the ED50 of the combination was determined. The experimental ED50 values were compared with the theoretical additive values. RESULTS: m-CPBG dose-dependently decreased the number of flinches in both phase 1 and 2. MK801 dose-dependently reduced the number of flinches in phase 2, but not in phase 1. The combination of m-CPBG and MK801 produced dose-dependent decreases of flinches on both phase 1 and 2. ED50 values (2.75microng for m-CPBG and 0.076microgram for MK801) of phase 2 in the combination were significantly less than the calculated additive values (20.0microgram for m-CPBG and 0.55microgram for MK801)(P<0.01). CONCLUSIONS: Intrathecally administered m-CPBG and MK801 had synergistic analgesic effects on formalin-induced hyperalgesia as well as antinociceptive effects in phase 1 on the rat formalin test.