Previous research has shown that the hippocampus processes pain related-information, probably through hippocampal neurons that respond exclusively to painful stimulation. In the current experiments we tested whether blocking NMDA receptors in the hippocampal CA1 region and dentate gyrus could reduce nociceptive behaviors in rats. The competitive and noncompetitive NMDA receptor antagonists 2-amino-5-phosphonopentanoic acid (AP5; 3.75 microg/0.75 microl) and MK801 (1.5, 3, 6 microg/0.5 microl) were injected into the dentate gyrus and CA1 area of behaving rats 5 min before subcutaneous injection of formalin irritant. Pain behaviors in both acute and tonic phases of the formalin test were significantly reduced by AP5 (3.75 microg/0.75 microl) and MK801 (3 microg/0.5 microl, but not 1.5 and 6 microg/0.5 microl) injection to the dentate gyrus. In the CA1, injection of AP5 had no effect while injection of the effective dose of MK801 (3 microg/0.5 microl) had a significant antinociceptive effect. This effect was apparent only during the late phase of the formalin test. These results support the hypothesis that NMDA-sensitive mechanisms are involved in acute and persistent pain-related processing in the dentate gyrus and with tonic pain processing in the hippocampal CA1 region.