RESUMEN
Although it is well known that the anti-inflammatory action of NSAIDs is mediated through cyclooxygenase [COX] enzyme inhibition there is debate about the mechanism of their antinociceptive action. The involvement of the arachidonic acid in the synthesis of endocannabinoids raises a question about the role of cannabinoid receptors in the antinociceptive effect of NSAIDs. The aim of this study is to investigate the relation of the cannabinoid receptors to the antinociceptive action of indomethacin. The antinociceptive effect of indomethacin [9 micro M] was tested after CB 1 receptor blockade in normal freely moving mice using the formalin test and microdialysis technique. It was further tested in CB 1 -/- knockout mice using intrathecal indomethacin [30 nmol] to confirm the participation of CB 1 receptors in the antinociceptive action of indomethacin. The experiment was repeated with supplementation of exogenous PGE 2 both through the microdialysis probe [5.681 micro M] and intrathecaly [283.6 fmol] to confirm that spinal PGE2 production is not related to the antinociceptive action of indomethacin. CB 1 receptor blockade significantly reduced the antinociceptive effect of indomethacin in the formalin test. Additionally, indomethacin was effective in CB 1+/+ but not in CB 1 -/- knockout mice which confirms the role of cannabinoid receptors in the antinociceptive action of indomethacin. However, CB 1 receptor blockade showed insignificant effect on indomethacin-induced inhibition of spinal PGE 2 production. In addition, exogenous supplementation of PGE 2 did not reverse the antinociceptive effect of indomethacin in the formalin test. These findings dissociate the antinociceptive action of indomethacin from its inhibitory effect on spinal PGE 2 production. In the cannabinoid receptors [CB 1] may be involved in the antinociceptive action of indomethacin but not in its inhibitory effect on spinal PGE 2 production. It is possible that inhibition of COX enzyme by indomethacin shifts the accumulated arachidonic acid to produce endocannabinoid with subsequent activation of CB 1 receptors which mediates the antinociceptive effect