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Generically Dependent Continuant
Proceedings of the Western Pharmacology Society
RDF description of Characterization of the peripheral mechanism of action involved in the potentiation of the antinociceptive effect of ketorolac by caffeine - http://orbis.uaslp.mx/vivo/individual/scopus718
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We studied the possible peripheral mechanisms of the antinociceptive (AN) effect of ketorolac (KET) in combination with caffeine (CAP) in the pain-induced functional impairment model in the rat. CAP, by itself, did not produce any AN effect, but significantly increased the effect of KET. Since CAP did not modify KET blood concentrations, a pharmacokinetic mechanism can be excluded. We also established that CAP potentiation was not due to an antagonism of a possible pronociceptive action of adenosine, as when adenosine was given to rats treated with KET-CAF, the AN effect was further increased instead of decreasing. We have previously described that activation of the L-arginine-NO-cGMP pathway is involved in the AN effect of KET in addition to COX inhibition. Hence, we studied the participation of this pathway in CAF-induced potentiation. The NO synthesis inhibitor L-NAME was able to block CAF potentiation. Local administration of 8-Br-cGMP significantly increase the effect of the KET-CAF combination, but was ineffective by itself and also failed to increase the AN effect induced by KET alone. These results can be interpreted as follows. KET induces activation of the L-arginine-NOcGMP pathway, which contributes to its AN activity. The generated cGMP, however, is rapidly catabolized by phosphodiesterase (PD) activity. Since CAF is a nonspecific inhibitor of PD, co-administration of KET-CAF result in an accumulation of cGMP which increase the AN effect. Our results, however, do not rule out the participation of central mechanisms in addition to peripheral pathways in the potentiation of NSAID analgesia by CAF.
Characterization of the peripheral mechanism of action involved in the potentiation of the antinociceptive effect of ketorolac by caffeine