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


METHODS
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.


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
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.
Hu
S Shu-Jung
SS
Department of Psychological and Brain Sciences, the Gill Center for Biomolecular Science, Indiana University, Bloomington, IN, USA.
Bradshaw
H B
HB
Chen
J S-C
JS
Tan
B
B
Walker
J Michael
JM
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000209:etiology; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D016328:NF-kappa B; D011982:Receptors, Prostaglandin; C518978:prostaglandin E2 glyceryl ester; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2; D015232:Dinoprostone