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 Journal Article


Authors: Elliott, K.; Minami, N.; Kolesnikov, Y. A.; Pasternak, G. W.; Inturrisi, C. E.
Article Title: 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
Abstract: Once daily s.c. administration of 5 mg/kg morphine, a mu-opioid agonist, or U50488H (U50), a kappa1-opioid agonist, for 5 days in male CD-1 mice results in a 2-3-fold shift to the right of the respective analgesic (tail flick) dose-response curves, indicating the development of tolerance. Concurrent s.c. administration of the competitive NMDA receptor antagonist, LY274614 (LY), at 24 mg/kg/24 h infusion (osmotic pump) or 6 mg/kg i.p. once daily attenuates the development of morphine tolerance, when the response to saline plus morphine is compared on day 5 with LY plus morphine. Using this paradigm, once daily administration 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 (NorArg), at 1 mg/kg i.p. twice daily attenuated the development of morphine tolerance. None of these drugs modify the tail-flick response or alter the ED50 for morphine. In contrast, co-administration of LY, MK-801 or NorArg, as above, failed to attenuate the development of tolerance to U50 or to the kappa3-opioid agonist, naloxone benzoylhydrazone (NalBzoH). These results suggest that mu-opioid tolerance but not kappa1- or kappa3-opioid tolerance involves the mediation of NMDA receptors and the nitric oxide system. © 1994.
Keywords: controlled study; nonhuman; mouse; pain; animal experiment; morphine; drug tolerance; mu opiate receptor; 3,4 dichloro n methyl n [2 (1 pyrrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate; naloxone benzoylhydrazone; kappa opiate receptor; intraperitoneal drug administration; opioid tolerance; dizocilpine; subcutaneous drug administration; n methyl dextro aspartic acid receptor blocking agent; male; priority journal; article; mk-801; n(g) nitroarginine; nitric oxide synthase inhibitor; u50488h; decahydro 6 phosphonomethyl 3 isoquinolinecarboxylic acid; nmda receptor antagonist; kappa1-agonist; kappa3-agonist; ly274614; mu-agonist; ng-nitro-l-arginine
Journal Title: Pain
Volume: 56
Issue: 1
ISSN: 0304-3959
Publisher: Elsevier Science BV  
Date Published: 1994-01-01
Start Page: 69
End Page: 75
Language: English
DOI: 10.1016/0304-3959(94)90151-1
PROVIDER: scopus
PUBMED: 7512709
DOI/URL:
Notes: Export Date: 14 January 2019 -- Article -- CODEN: PAIND C2 -- Source: Scopus
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  1. Gavril W Pasternak
    414 Pasternak