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Intrathecally applied flurbiprofen produces an endocannabinoid‐dependent antinociception in the rat formalin test
Author(s) -
Ates Mehmet,
Hamza May,
Seidel Kay,
Kotalla Carolin E.,
Ledent Catherine,
Gühring Hans
Publication year - 2003
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2003.02470.x
Subject(s) - chemistry , flurbiprofen , anandamide , pharmacology , nociception , cannabinoid receptor , arachidonic acid , cyclooxygenase , cannabinoid , endocannabinoid system , hyperalgesia , fatty acid amide hydrolase , am251 , phospholipase a2 , prostaglandin , antagonist , receptor , biochemistry , medicine , enzyme
It is generally accepted that the phospholipase‐A 2 ‐cyclooxygenase‐prostanoids‐cascade mediates spinal sensitization and hyperalgesia. However, some observations are not in line with this hypothesis. The aim of the present work was to investigate whether different components of this cascade exhibit nociceptive or antinociceptive effects in the rat formalin test. Intrathecal (i.th.) injection of prostaglandin E 2 (PGE 2 ) induced a dose‐dependent antinociceptive effect on the formalin‐induced nociception. Furthermore, thimerosal, which inhibits the reacylation of arachidonic acid thereby enhancing arachidonic acid levels, had an antinociceptive effect rather than the expected pronociceptive effect when given i.th. While the phospholipase A 2 inhibitor methyl arachidonyl fluorophosphonate (MAFP; i.th.) had a significant antinociceptive effect, its analogue palmitoyl trifluoromethyl ketone (PTFMK; i.th.) had no significant effect on the formalin‐induced nociception. However, MAFP, but not PTFMK, showed a cannabinoid CB 1 agonistic effect as shown by the inhibition of electrically evoked contractions of the vas deferens isolated from CB 1 wild‐type mice but not of that from CB 1 knockout mice. The antinociceptive effect of MAFP was completely reversed by the CB 1 receptor antagonist AM‐251 (i.th.), thus attributing such effect to its CB 1 agonistic effect. Moreover, the antinociceptive effect of the cyclooxygenase inhibitor, flurbiprofen (i.th.) was reversed by the co‐administration of AM‐251, but not by PGE 2 . Finally. the combination of phenylmethylsulfonyl fluoride (PMSF; intraperitoneal), which inhibits the degradation of anandamide through the inhibition of fatty acid amidohydrolase, with thimerosal (i.th.) produced a profound CB 1 ‐dependent antinociception. The present results show that endocannabinoids play a major role in mediating flurbiprofen‐induced antinociception at the spinal level.