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Mode of antinociceptive action of flupirtine in the rat
Author(s) -
Szelenyi I.,
Nickel B.,
Borbe H.O.,
Brune K.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb12023.x
Subject(s) - nociception , pharmacology , action (physics) , mode of action , medicine , neuroscience , anesthesia , chemistry , psychology , receptor , physics , biochemistry , quantum mechanics
1 Flupirtine is a novel, centrally acting, non‐opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. The antinociceptive responses to the test compounds were examined in the tail‐flick test. 2 The selective destruction of noradrenergic pathways by 6‐hydroxydopamine considerably reduced the flupirtine‐induced inhibition of nociceptive responses but not the clonidine‐induced antinociception which was significantly enhanced. Depletion of spinal 5‐hydroxytryptaminergic pathways by pretreatment with 5,7‐dihydroxytryptamine failed to affect the action of flupirtine and clonidine. 3 The depletion of neurotransmitters by reserpine totally abolished the antinociceptive action of flupirtine. By contrast, clonidine‐induced inhibition of nociceptive responses remained unchanged. 4 Inhibition of the synthesis of noradrenaline by α‐methyl‐L‐p‐tyrosine attenuated the antinociception induced by flupirtine. In contrast, inhibition of the synthesis of 5‐hydroxytryptamine by (±)−6‐fluorotryptophan did not influence the antinociceptive activity of flupirtine. 5 Inhibition of noradrenaline uptake by imipramine led to a significant augmentation of flupirtine‐induced antinociception. 6 Selective antagonists at α‐adrenoceptors significantly decreased the antinociceptive action of flupirtine. Antinociception induced by clonidine was significantly diminished by idazoxan but not by prazosin. 7 The 5‐hydroxytryptamine (5‐HT) antagonist, ketanserin diminished the antinociceptive activity of flupirtine, probably due to its additional α 1 ‐adrenoceptor antagonist activity. The antinociceptive effect of clonidine was not influenced by ketanserin. 8 Cholinoceptor antagonists such as mecamylamine and pirenzepine did not alter the antinociceptive action of flupirtine. Flupirtine‐induced antinociception also remained unchanged after pretreatment with haloperidol. 9 Flupirtine has no pharmacologically relevant affinity for α 1 ‐, α 2 ‐adrenoceptors, 5‐HT 1 ‐ and 5‐HT 2 ‐receptors as shown in direct binding studies. 10 The present results indicate that the antinociceptive action induced by flupirtine depends on the descending noradrenergic pain‐modulating system.