title: Effects of pre-treatment with amantadine on morphine induced antinociception during second phase formalin responses in rats.
abstract: The clinically available NMDA-receptor antagonist drug, amantadine, has been shown to result in morphine sparing effects in humans after surgery. However, no data are available to describe the exact form of interaction. The present study aims to profile the possible effects of amantadine (0, 12.5, 25 or 50 mgkg(-1) i.p.) pre-treatment on morphine (0, 0.63, 1.25, 2.5 or 5 mgkg(-1) s.c.) induced antinociception in rats. The (automated) formalin test (5% formalin, 50 microl) was used to assess if amantadine enhances the antinociceptive activity of morphine. Possible motor impairment was assessed with a rotarod test. Morphine was measured in serum of amantadine or vehicle treated rats to search for possible pharmacokinetic interactions between amantadine and morphine. Isobolographic analysis provided evidence for a synergistic interaction between amantadine and morphine in the second phase of the formalin test. No evidence was found to indicate that amantadine induced motor impairment at the doses potentiating morphine during the second phase of the formalin test. There was no evidence for a pharmacokinetic interaction between amantadine and morphine. Since, the second phase of the formalin test is dependent on activation of the NMDA receptor system it is concluded that an antagonistic activity of amantadine at the NMDA receptor most likely contributes to the synergistic interaction observed between amantadine and morphine in rats.
authors.affiliation: Department of Anesthesiology/Pain Centre, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Department of Biological Psychology, Nijmegen Institute for Cognition and Information, Radboud University Nijmegen, Nijmegen, The Netherlands Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium.
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Snijdelaar
authors.forename: Clementina M
authors.initials: CM
authors.lastname: van Rijn
authors.forename: Petra
authors.initials: P
authors.lastname: Vinken
authors.forename: Theo F
authors.initials: TF
authors.lastname: Meert
mesh_terms: D000547:Amantadine / Q000008:administration & dosage*; D000700:Analgesics / Q000008:administration & dosage; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects*; D010146:Pain / Q000175:diagnosis* / Q000188:drug therapy* / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D045442:Rotarod Performance Test; D016896:Treatment Outcome
chemical_list: D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; D000547:Amantadine