Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition.
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.
Morè
Lorenzo
L
Department of In-vivo Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, Frankfurt am Main, Germany.
Gravius
Andreas
A
Pietraszek
Malgorzata
M
Belozertseva
Irina
I
Malyshkin
Andrey
A
Shekunova
Elena
E
Barberi
Caroline
C
Schaefer
Daniela
D
Schmidt
Werner J
WJ
Danysz
Wojciech
W
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*
C516995:A-841720; D000276:Adjuvants, Immunologic; D006575:Heterocyclic Compounds, 3-Ring; D018094:Receptors, Metabotropic Glutamate; D005557:Formaldehyde; D005620:Freund's Adjuvant