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Carbachol interactions with nonsteroidal anti-inflammatory drugs

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Abstract:



The inhibition of cyclooxygenase enzymes by nonsteroidal anti-inflammatory drugs (NSAIDs) does not completely explain the antinociceptive efficacy of these agents. It is known that cholinergic agonists are antinociceptive, and this study evaluates the interactions between carbachol and some NSAIDs. Antinociceptive activity was evaluated in mice by the acetic acid writhing test. Dose–response curves were constructed for NSAIDs and carbachol, administered either intraperitoneally (i.p.) or intrathecally (i.t.). The interactions of carbachol with NSAIDs were evaluated by isobolographic analysis after the simultaneous administration of fixed proportions of carbachol with each NSAID. All of the drugs were more potent after spinal than after systemic administration. The combinations of NSAIDs and carbachol administered i.p. were supra-additive; however, the i.t. combinations were only additive. Isobolographic analysis of the coadministration of NSAIDs and carbachol and the fact that atropine antagonized the synergistic effect suggest that carbachol may strongly modulate the antinociceptive activity of NSAIDs; thus, central cholinergic modulation would be an additional mechanism for the antinociceptive action of NSAIDs, unrelated to prostaglandin biosynthesis inhibition.Key words: antinociception, nonsteroidal anti-inflammatory drugs, cholinergic, carbachol, writhing test.

L'inhibition des cyclooxygénases par les anti-inflammatoires non stéroïdiens (AINS) n'explique pas totalement l'efficacité antinociceptive de ces agents. On sait que les agonistes cholinergiques sont antinociceptifs et la présente étude évalue les interactions entre le carbachol et certains AINS. L'activité antinociceptive a été évaluée chez des souris en utilisant le test de contorsions à l'acide acétique. Des courbes dose-réponse ont été établies pour les AINS et le carbachol, administrés par voie intrapéritonéale (i.p.) ou intrathécale (i.t.). Les interactions carbachol–AINS ont été évaluées par l'analyse des isoboles après l'administration simultanée de concentrations fixes de carbachol avec chacun des AINS. Tous les médicaments ont été plus puissants après l'administration spinale qu'après l'administration systémique. Les combinaisons AINS–carbachol administrées par voie i.p. ont été supra-additives; toutefois, les combinaison i.t. ont été uniquement additives. L'analyse des isoboles de la co-administration AINScarbachol et l'antagonisme de l'effet synergique par l'atropine donnent à penser que le carbachol pourrait moduler fortement l'activité antinociceptive des AINS; ainsi, la modulation cholinergique centrale serait un mécanisme additionnel de l'action antinociceptive des AINS, sans rapport avec l'inhibition de la biosynthèse des prostaglandines.Mots clés : antinociception, anti-inflammatoires non stéroïdiens, cholinergique, carbachol, test de contorsions.[Traduit par la Rédaction]
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