Prostaglandin E2 glycerol ester, an endogenous COX‐2 metabolite of 2‐arachidonoylglycerol, induces hyperalgesia and modulates NFκB activity

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Abstract
Background and purpose: Recombinant cyclooxygenase‐2 (COX‐2) oxygenates 2‐arachidonoylglycerol (2‐AG) in vitro. We examined whether prostaglandin E2 glycerol ester (PGE2‐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 PGE2‐G on nociception in rats and NFκB activity in RAW264.7 cells.Key results: PGE2‐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 PGE2‐G induced mechanical allodynia and thermal hyperalgesia. In RAW264.7 cells, PGE2‐G and PGE2 produced similar, dose‐related changes in NFκB activity. PGE2‐G was quickly metabolized into PGE2. While the effects of PGE2 on thermal hyperalgesia and NFκB activity were completely blocked by a cocktail of antagonists for prostanoid receptors, the same cocktail of antagonists only partially antagonized the actions of PGE2‐G.Conclusions and implications: Thermal hyperalgesia and immunomodulation induced by PGE2‐G were only partially mediated by PGE2, which is formed by metabolism of PGE2‐G. PGE2‐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 PGE2‐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.British Journal of Pharmacology (2008) 153, 1538–1549; doi:10.1038/bjp.2008.33; published online 25 February 2008

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