COMPETITIVE AND NONCOMPETITIVE NMDA ANTAGONISTS BLOCK THE DEVELOPMENTOF ANTINOCICEPTIVE TOLERANCE TO MORPHINE, BUT NOT TO SELECTIVE MU-OPIOID OR DELTA-OPIOID AGONISTS IN MICE

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to bl ock the development of antinociceptive tolerance to morphine. Assessme nt of the effects of NMDA antagonists on development of antinociceptiv e tolerance to selective opioid mu (mu) and delta (delta) agonists, ho wever, has not been reported. In these experiments, selective mu and d elta receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or af ter pretreatment with systemic NMDA antagonists. Antinociception was e valuated using a warm-water tail-flick test. Repeated i.c,v. injection s of mu agonists including morphine, fentanyl, [D-Ala(2), NMePhe(4), G ly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Al a(2), Glu(4)]deltorphin, a delta agonist, or s.c, injections of morphi ne or fentanyl, produced antinociceptive tolerance as shown by a signi ficant rightward displacement of the agonist dose-response curves comp ared to controls. Single injections or repeated administration of MK80 1 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavi oral toxicity, antinociception or alter the acute antinociceptive effe cts of the tested opioid agonists. Consistent with previous reports, p retreatment with MK801 or LY235959 (30 min prior to agonist administra tion throughout the tolerance regimen) prevented the development of an tinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antag onist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala(2), Glu(4)]deltorphin. Additional ly, MK801 pretreatment did not affect the development of antinocicepti ve tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretr eatment also did not affect the development of tolerance to the antino ciception resulting from a cold-water swim-stress episode, previously shown to be a delta-opioid mediated effect. These data lead to the sug gestion that the mechanisms of tolerance to receptor selective mu and delta opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reac hed with studies employing morphine cannot always be extended to 'opia tes' in general.