title: Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition.
abstract: In the current study we compared the potency of the selective metabotropic glutamate receptor (mGluR1) antagonist A-841720 (7-Azepan-1-yl-4-dimethylamino-7H-9-thia-1,5,7-triaza-fluoren-8-one) in rodent models of pain with its effects in models of learning and memory, to obtain information regarding the therapeutic window of this compound. A-841720 significantly reduced formalin-induced behaviours and complete Freund's adjuvant (CFA)-induced tactile allodynia, starting at doses of 1 and 10 mg/kg, respectively. At the dose of 3 mg/kg, however, A-841720 significantly reduced the percentage of spontaneous alternations in a radial-maze task. In contextual-fear conditioning, A-841720, given at the dose of 10 mg/kg before acquisition, significantly reduced freezing behaviour tested 24 h later. In the same task, repeated treatment for 5 days did not reduce the impairing effect of the challenge dose, indicating a lack of tolerance development. In a passive-avoidance task, A-841720 at 10 mg/kg administered before acquisition, significantly reduced the latency to enter the dark box on the retention test. Given that complete Freund's adjuvant is a better measure of analgesia, these results indicate that the selective mGluR1 antagonist A-841720 has analgesic potential in a dose range at which it also produces memory impairments. This diminishes its therapeutic potential for the treatment of chronic pain.
authors.affiliation: Department of In-vivo Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, Frankfurt am Main, Germany.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Morè
authors.forename: Andreas
authors.initials: A
authors.lastname: Gravius
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pietraszek
authors.forename: Irina
authors.initials: I
authors.lastname: Belozertseva
authors.forename: Andrey
authors.initials: A
authors.lastname: Malyshkin
authors.forename: Elena
authors.initials: E
authors.lastname: Shekunova
authors.forename: Caroline
authors.initials: C
authors.lastname: Barberi
authors.forename: Daniela
authors.initials: D
authors.lastname: Schaefer
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Schmidt
authors.forename: Wojciech
authors.initials: W
authors.lastname: Danysz
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D004347:Drug Interactions; D005239:Fear / Q000187:drug effects; D005557:Formaldehyde / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D007858:Learning / Q000187:drug effects*; D008297:Male; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: C516995:A-841720; D000276:Adjuvants, Immunologic; D006575:Heterocyclic Compounds, 3-Ring; D018094:Receptors, Metabotropic Glutamate; D005557:Formaldehyde; D005620:Freund's Adjuvant