OBJECTIVE To analyze the mode of interaction of combined administration of intrathecal morphine with subcutaneous morphine or buprenorphine. METHODS Different groups of rats were scheduled to undergo administration of intrathecal (ith) morphine, subcutaneous (s.c.) morphine, s.c. buprenorphine, and the combinations of ith morphine with s.c. morphine or buprenorphine in a series of dose ratios. Nociceptive responses of hind paws of each animal were measured by means of "plantar stimulation" test. The test latency was converted to the percent of maximal possible effect (% MPE). RESULTS Morphine ith, morphine s.c., buprenorphine s.c., as well as combinations in all dose ratios increased the % MPE in a dose-dependent manner. Isobolograms showed that the ED50 points determined for the combinations were plotted significantly left to the theoretical additive line. CONCLUSIONS The combination of morphine ith with either morphine s.c. or buprenorphine s.c. resulted in a synergistic effect. This interaction might be due to the activation of the synergistic antinociceptive mechanisms between supraspinal and spinal levels.