We assessed whether intrathecal administration of the uncompetitive and competitive NMDA receptor antagonists ketamine and (+/-)CPP, respectively, could produce differential modulation on chemical and mechanical nociception in normal and monoarthritic rats. In addition, the antinociceptive interaction of ketamine and (+/-)CPP on monoarthritic pain was also studied using isobolographic analysis. Monoarthritis was produced by intra-articular injection of complete Freund's adjuvant into the tibio-tarsal joint. Four weeks later, the antinociceptive effect of intrathecal administration of the drugs alone or combined was evaluated by using the intraplantar capsaicin and the paw pressure tests. Ketamine (0.1, 1, 10, 30, 100, 300 and 1000 mu g i.t.) and (+/-)CPP (0.125, 2.5, 7.5, 12.5, 25 and 50 mu g i.t.) produced significantly greater dose-dependent antinociception in the capsaicin than in the paw pressure test. Irrespective of the nociceptive test employed, both antagonists showed greater antinociceptive activity in monoarthritic than in healthy rats. Combinations produced synergy of a supra-additive nature in the capsaicin test, but only additive antinociception in paw pressure testing. The efficacy of the drugs, alone or combined, is likely to depend on the differential sensitivity of tonic versus phasic pain and/or chemical versus mechanical pain to NMDA antagonists. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.