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- Title
Prostaglandin E2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFkappaB activity.
- Authors
Hu, S. Shu-Jung; Bradshaw, H. B.; Chen, J. S.-C.; Tan, B.; Walker, J. Michael
- 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
- Subjects
METABOLITES; HYPERALGESIA; CYCLOOXYGENASE 2; IMMUNOREGULATION; LIPASES; ANIMAL experimentation; ARACHIDONIC acid; CELL lines; CELL receptors; DRUGS; GLYCERIDES; HEAT; MACROPHAGES; MASS spectrometry; MICE; NEUROTRANSMITTERS; OXIDOREDUCTASES; PAIN; RATS; RESEARCH funding; DNA-binding proteins; PAIN measurement; DINOPROSTONE
- Publication
British Journal of Pharmacology, 2008, Vol 153, Issue 7, p1538
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/bjp.2008.33