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.

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.

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.

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