BACKGROUND In the present study, the effect of dextromethorphan on antinociception and tolerance induced by water swim-stress in the formalin test was investigated. METHODS Swim-stress at 8 masculineC induces antinociception in both phases of the formalin test. Intraperitoneal administration of dextromethorphan (60 mg/kg) also induces antinociception in the second phase of the formalin test. The lower doses of dextromethorphan (1.25, 2.5, and 5 mg/kg) which did not induce antinociception alone, but did so in combination with swim- stress (40 second), showed antinociceptive effect in both phases of the test. Exposure to water swimming stress with a period of 20 sec, once daily for three days, altered swim- stress- induced antinociception in the formalin test, when tested on the fourth day. RESULTS In these animals, exposure to either water swimming stress alone or water swimming stress in combination with dextromethorphan showed potentiation of antinociception induced by swim- stress up to 20 second and decreased the response induced by 40 and 60 second swim- stress, indicating a tolerance induction. Dextromethorphan (20 mg/kg) did not alter the changes induced by three days exposure to swim- stress. CONCLUSIONS The results may indicate a possible involvement of n-methyl-d-aspartate receptor mechanism in the antinociception but not tolerance induced by swim- stress at 8 masculineC.