TY - JOUR
T1 - Prostaglandin E 2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFκB activity
AU - Hu, S. Shu Jung
AU - Bradshaw, H. B.
AU - Chen, J. S.C.
AU - Tan, B.
AU - Walker, J. Michael
PY - 2008/4
Y1 - 2008/4
N2 - Background and purpose: Recombinant cyclooxygenase-2 (COX-2) oxygenates 2-arachidonoylglycerol (2-AG) in vitro. We examined whether prostaglandin E 2 glycerol ester (PGE 2-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 PGE 2-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 PGE 2-G on nociception in rats and NFκB activity in RAW264.7 cells. Key results: PGE 2-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 PGE 2-G induced mechanical allodynia and thermal hyperalgesia. In RAW264.7 cells, PGE 2-G and PGE 2 produced similar, dose-related changes in NFκB activity. PGE 2-G was quickly metabolized into PGE 2. While the effects of PGE 2 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 PGE 2-G. Conclusions and implications: Thermal hyperalgesia and immunomodulation induced by PGE 2-G were only partially mediated by PGE 2, which is formed by metabolism of PGE 2-G. PGE 2-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 PGE 2-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.
AB - Background and purpose: Recombinant cyclooxygenase-2 (COX-2) oxygenates 2-arachidonoylglycerol (2-AG) in vitro. We examined whether prostaglandin E 2 glycerol ester (PGE 2-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 PGE 2-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 PGE 2-G on nociception in rats and NFκB activity in RAW264.7 cells. Key results: PGE 2-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 PGE 2-G induced mechanical allodynia and thermal hyperalgesia. In RAW264.7 cells, PGE 2-G and PGE 2 produced similar, dose-related changes in NFκB activity. PGE 2-G was quickly metabolized into PGE 2. While the effects of PGE 2 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 PGE 2-G. Conclusions and implications: Thermal hyperalgesia and immunomodulation induced by PGE 2-G were only partially mediated by PGE 2, which is formed by metabolism of PGE 2-G. PGE 2-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 PGE 2-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.
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U2 - 10.1038/bjp.2008.33
DO - 10.1038/bjp.2008.33
M3 - Article
C2 - 18297109
AN - SCOPUS:41649118003
SN - 0007-1188
VL - 153
SP - 1538
EP - 1549
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 7
ER -