CONTINUOUS COADMINISTRATION OF DEXTROMETHORPHAN OR MK-801 WITH MORPHINE - ATTENUATION OF MORPHINE-DEPENDENCE AND NALOXONE-REVERSIBLE ATTENUATION OF MORPHINE-TOLERANCE

N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusi on of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furt hermore, this prolonged antinociception was completely reversible by n aloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, resp ectively) revealed different profiles of effects, however, on locomoto r activity and naloxone-precipitated abstinence/withdrawal symptoms. W ith regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and stri king increase in locomotor activity as compared with rats having recei ved morphine alone. With regard to naloxone-precipitated withdrawal sy mptoms, continuous (48 h) subcutaneous coinfusion of either MK-801 (0. 01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-pre cipitated hyperalgesia as compared with rats infused with morphine alo ne. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdr awal symptoms (teeth chattering, jumping and wet dog shakes). The effe cts of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous ob servations by showing that the prolonged antinociception observed foll owing coadministration of morphine and an NMDA antagonist is completel y naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The diff erent profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symp toms by MK-801 may be an artifact of toxicity, and (2) DM may prove cl inically useful for the prevention of morphine tolerance, given its la ck of observable side effects when administered concurrently with morp hine to rodents.