Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the mu-opioid receptor agonists morphine (5 mg kg(-1), s.c.), meperidine (25 mg kg(-1), s.c.) and codeine (25 mg kg(-1), s.c.), and the kappa-opioid agonists nalbuphine (8 mg kg(-1), s.c.) and U-50,488H (20 mg kg(-1), s.c.) were studied using the tail-flick test in male Sprague-Dawley rats. Coadministration of DM (20 mg kg(-1), i.p.) with these opioids was also performed and investigated. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC.It was found that DM potentiated the antinociceptive effects of some mu-opioid agonists but not codeine or kappa-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine). The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids.