Prostaglandin E-2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NF kappa B activity

Background and purpose: Recombinant cyclooxygenase-2 (COX- 2) oxygenates 2-arachidonoylglycerol (2-AG) in vitro. We examined whether prostaglandin E-2 glycerol ester ( PGE(2)-G), a COX- 2 metabolite of 2-AG, occurs endogenously and affects nociception and immune responses. Experimental approach: Using mass spectrometric techniques, we examined whether PGE2-G occurs in vivo and if its levels are altered by inhibition of COX-2, monoacylglycerol (MAG) lipase or inflammation induced by carrageenan. We also examined the effects of PGE(2)-G on nociception in rats and NF kappa B activity in RAW264.7 cells. Key results: PGE(2)-G occurs endogenously in rat. Its levels were decreased by inhibition of COX- 2 and MAG lipase but were unaffected by carrageenan. Intraplantar administration of PGE(2)-G induced mechanical allodynia and thermal hyperalgesia. In RAW264.7 cells, PGE(2)-G and PGE(2) produced similar, dose-related changes in NFkB activity. PGE2- G was quickly metabolized into PGE(2). While the effects of PGE(2) on thermal hyperalgesia and NFkB activity were completely blocked by a cocktail of antagonists for prostanoid receptors, the same cocktail of antagonists only partially antagonized the actions of PGE(2)- G. Conclusions and implications: Thermal hyperalgesia and immunomodulationinduced by PGE2-(G) were only partially mediated by PGE(2), which is formed by metabolism of PGE(2)- G. PGE(2)- G may function through a unique receptor previously postulated to mediate its effects. Taken together, these findings demonstrate that 2-AG is oxygenated in vivo by COX-2 producing PGE(2)- G, which plays a role in pain and immunomodulation. COX-2 could act as an enzymatic switch by converting 2-AG from an antinociceptive mediator to a pro-nociceptive prostanoid.