<abstract xmlns="http://www.w3.org/1999/xhtml"> The existing ideas about the ketorolac mechanism of analgetic potency are associated with its effect on COX isoenzymes and its significant potency needs to be explained more completely. Its impact on vanilloid receptors 1 (TRPV1) can also be an effective mechanism of analgetic action. We have evaluated the analgetic potential of ketorolac on the basis of its influence on TRPV1. It is known that Tyr511 and Ser512 amino acids are active central components of TRPV1. Thereby the synthesis of the dipeptide Tyr-Ser has been conducted as a model of the TRPV1 active centre. In our model test, using spectrofluorometry, the formation of intermolecular complexes was shown: “ketorolac - Tyr-Ser” and “capsaicin - Tyr-Ser” at stability constants Kr=0.53 • 10-4 L/mol; Kkor= 0.998 and Kr =0.3 • 10-4 L/mol; Kkor=0.998, respectively. Verification of the data was proved in experiments in vitro (the preparation of portal vein) and in vivo (Tail-flick model), with the TRPV1 agonist and antagonist. On portal vein, it was established (from initial level) by Krebs solution that the range of relaxation of smooth muscles of the portal vein (SM) was as follows at the concentration of capsaicin 0.1 μmol/L +30.3%±5.3%, capsazepine 0.5 μmol/L -3.2±2.7% and ketorolac 1.0 μmol/L -60.0±7.0%. In the experiment, at the above mentioned doses of ketorolac on the background of the action of the capsaicin (capsazepine), the range of relaxation of smooth muscles (SM) of the portal vein was -59.3±5.0% and -63.0±6.0% respectively testifying to the fact that the effect of capsaicinoids was neutralised by ketorolac. On the Tail-flick model, an atypical potentiation of the ketorolac antinociception at simultaneous use with the capsaicin was shown. The obtained data allow suggesting that TRPV1 can activate the ketorolac antinociceptive effects.</abstract>

The existing ideas about the ketorolac mechanism of analgetic potency are associated with its effect on COX isoenzymes and its significant potency needs to be explained more completely. Its impact on vanilloid receptors 1 (TRPV1) can also be an effective mechanism of analgetic action. We have evaluated the analgetic potential of ketorolac on the basis of its influence on TRPV1. It is known that Tyr511 and Ser512 amino acids are active central components of TRPV1. Thereby the synthesis of the dipeptide Tyr-Ser has been conducted as a model of the TRPV1 active centre. In our model test, using spectrofluorometry, the formation of intermolecular complexes was shown: “ketorolac - Tyr-Ser” and “capsaicin - Tyr-Ser” at stability constants Kr=0.53 • 10-4 L/mol; Kkor= 0.998 and Kr =0.3 • 10-4 L/mol; Kkor=0.998, respectively. Verification of the data was proved in experiments in vitro (the preparation of portal vein) and in vivo (Tail-flick model), with the TRPV1 agonist and antagonist. On portal vein, it was established (from initial level) by Krebs solution that the range of relaxation of smooth muscles of the portal vein (SM) was as follows at the concentration of capsaicin 0.1 μmol/L +30.3%±5.3%, capsazepine 0.5 μmol/L -3.2±2.7% and ketorolac 1.0 μmol/L -60.0±7.0%. In the experiment, at the above mentioned doses of ketorolac on the background of the action of the capsaicin (capsazepine), the range of relaxation of smooth muscles (SM) of the portal vein was -59.3±5.0% and -63.0±6.0% respectively testifying to the fact that the effect of capsaicinoids was neutralised by ketorolac. On the Tail-flick model, an atypical potentiation of the ketorolac antinociception at simultaneous use with the capsaicin was shown. The obtained data allow suggesting that TRPV1 can activate the ketorolac antinociceptive effects.

Involvement of the vanilloid receptor 1 in the mechanism of analgetic effect of ketorolac

Department of analgesic and anti-inflammatory drugs, SE “Institute of pharmacology and toxicology for NAMS of Ukraine”, Kiev, Ukraine

Department of the synthesis of biologically active substances, SE “Institute of pharmacology and toxicology for NAMS of Ukraine”, Kiev, Ukraine

Department of Experimental Therapeutics, SE “Institute of pharmacology and toxicology for NAMS of Ukraine”, Kiev, Ukraine

European Pharmaceutical Journal

The existing ideas about the ketorolac mechanism of analgetic potency are associated with its effect on COX isoenzymes and its significant potency needs to be...

Involvement of the vanilloid receptor 1 in the mechanism of analgetic effect of ketorolac

Online veröffentlicht: 31. Dez. 2013

Seitenbereich: 49 - 55

DOI: https://doi.org/10.2478/afpuc-2013-0016

This content is open access.