title: Nonsteroidal antiinflammatory drug modulation of behavioral responses to intrathecal N-methyl-D-aspartate, but not to substance P and amino-methyl-isoxazole-propionic acid in the rat.
abstract: Antinociception by nonsteroidal antiinflammatory drugs, notably diclofenac and S(+)-ibuprofen, has traditionally been attributed to peripheral tissue cyclooxygenase inhibition. This study investigates the potential role of the nitric oxide system for the central antinociceptive effects of diclofenac, S(+)-, and R(-)-ibuprofen. Diclofenac and S(+)- but not R(-)-ibuprofen inhibited the behavioral response dose dependently, "biting, scratching, and licking (BSL)," induced by the spinal application of N-methyl-D-aspartate, but not that of amino-methylisoxazole-propionic acid or substance P. Diclofenac and S(+)-ibuprofen induced a parallel shift in the number of BSL responses and in the duration of the response in the behavioral model at their approximate median effective doses (diclofenac 1 mumol and S(+)-ibuprofen 5 mumol). Pretreatment with L-arginine, the natural substrate for the nitric oxide synthetase, antagonized diclofenac, and S(+)-ibuprofen-induced suppression of the biting, scratching, and licking response evoked by intrathecal N-methyl-D-aspartate. D-arginine did not antagonize the diclofenac- and S(+)-ibuprofen-induced antinociception. The study results indicate that analgesia after diclofenac and S(+)-ibuprofen involves a central mechanism which may add to the peripheral antinociceptive effect of these agents. The central action of diclofenac and S(+)-ibuprofen is partly mediated by an interaction with the N-methyl-D-aspartate receptor and nitric oxide-generating mechanisms.
authors.affiliation: Division of Clinical Pharmacology, University of Gothenburg, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Björkman
authors.forename: K M
authors.initials: KM
authors.lastname: Hallman
authors.forename: J
authors.initials: J
authors.lastname: Hedner
authors.forename: T
authors.initials: T
authors.lastname: Hedner
authors.forename: M
authors.initials: M
authors.lastname: Henning
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004008:Diclofenac / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D013373:Substance P; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007052:Ibuprofen