THE NMDA RECEPTOR ANTAGONISTS, LY274614 AND MK-801, AND THE NITRIC-OXIDE SYNTHASE INHIBITOR, NG-NITRO-L-ARGININE, ATTENUATE ANALGESIC TOLERANCE TO THE MU-OPIOID MORPHINE BUT NOT TO KAPPA-OPIOIDS

Once daily s.c. administration of 5 mg/kg morphine, a mu-opioid agonis t, or U50488H (U50),:a kappa(1)-opioid agonist, for 5 days in male CD- 1 mice results in a 2-3-fold shift to the right of the respective anal gesic (tail flick) dose-response curves, indicating the development of tolerance. Concurrent s.c. administration of the competitive NMDA rec eptor antagonist, LY274614 (LY), at 24 mg/kg/24 h infusion (osmotic pu mp) or 6 mg/kg i.p. once daily attenuates the development of morphine tolerance, when the response to saline plus morphine, is compared on d ay 5 with LY plus morphine. Using this paradigm, once daily administra tion of either the non-competitive NMDA antagonist, MK-801, at 0.3 mg/ kg i.p. or the nitric oxide synthase inhibitor, NG-nitro-L-arginine (N orArg), at 1 mg/kg i.p. twice daily attenuated the development of morp hine tolerance. None of these drugs modify the tail-flick response or alter the ED(50) for morphine. In contrast, co-administration of LY, M K-801 or NorArg, as above, failed to attenuate the development of tole rance to U50 or to the kappa(3)-opioid agonist, naloxone benzoylhydraz one (NalBzoH). These results suggest that mu-opioid tolerance but not kappa(1)- or kappa(3)-opioid tolerance involves the mediation of NMDA receptors and the nitric oxide system.