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

Br J Pharmacol. 2008 Apr;153(7):1538-49. doi: 10.1038/bjp.2008.33. Epub 2008 Feb 25.


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 NFkappaB 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 NFkappaB activity. PGE2-G was quickly metabolized into PGE2. While the effects of PGE2 on thermal hyperalgesia and NFkappaB 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism*
  • Cell Line
  • Cyclooxygenase 2 / metabolism*
  • Dinoprostone / analogs & derivatives*
  • Dinoprostone / biosynthesis
  • Dinoprostone / metabolism*
  • Dinoprostone / pharmacology
  • Endocannabinoids
  • Glycerides / metabolism*
  • Hot Temperature
  • Hyperalgesia / etiology*
  • Macrophages / metabolism
  • Male
  • Mass Spectrometry
  • Mice
  • NF-kappa B / metabolism
  • Pain / etiology
  • Pain Measurement
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin / metabolism


  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • NF-kappa B
  • Receptors, Prostaglandin
  • prostaglandin E2 glyceryl ester
  • glyceryl 2-arachidonate
  • Cyclooxygenase 2
  • Dinoprostone