The search for alternative pharmacotherapies that target abnormal pain has focused on N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, since they are efficacious in various chronic pain models. However, adverse effects of currently available agents limit their therapeutic usefulness. The naturally derived NMDAR antagonist peptide, histogranin, is thought to interact at a novel site on the NMDAR subunit. Previous studies in our laboratory have suggested the potential for histogranin analogs to attenuate neuropathic pain. The ability of this peptide derivative to reduce inflammatory pain was evaluated in the present study. The effect of intrathecal (i.t.) injection of the stable analog [Ser(1)] histogranin (SH) was evaluated in rats with a unilateral hind paw inflammation. Following injection of complete Freund's adjuvant into the hind paw, responsiveness to noxious thermal and mechanical stimuli were greatly enhanced (hyperalgesia). The i.t. injection of SH partially attenuated mechanical hyperalgesia for up to 2 h post-injection, with no effect on withdrawal thresholds of the non-inflamed paw. In contrast, SH had no effect on thermal hyperalgesia. No attendant motor abnormalities were noted. These results indicate that SH has selective and modest antinociceptive effects on inflammatory pain and suggests that novel histogranin analogs may be safe and useful adjuncts in the management of chronic pain.