Prostaglandin E 2 glycerol ester, an endogenous COX‐2 metabolite of 2‐arachidonoylglycerol, induces hyperalgesia and modulates NFκB activity

Hu, S Shu‐Jung; Bradshaw, H B; Chen, J S‐C; Tan, B; Walker, J Michael

doi:10.1038/bjp.2008.33

Cited by 151Pain Mechanisms and TreatmentsInflammatory mediators and NSAID effectsCannabis and Cannabinoid Research

Prostaglandin E 2 glycerol ester, an endogenous COX‐2 metabolite of 2‐arachidonoylglycerol, induces hyperalgesia and modulates NFκB activity

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Hu, S Shu‐Jung, Bradshaw, H B, Chen, J S‐C, Tan, B, Walker, J Michael·2008·British Journal of Pharmacology

DOI 10.1038/bjp.2008.33PMC PMC2437899

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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 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.

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COX-2 converts the endocannabinoid 2-arachidonoylglycerol (2-AG) into prostaglandin E2 glycerol ester (PGE2-G), which is pro-nociceptive.
“COX-2 converts the endocannabinoid 2-arachidonoylglycerol (2-AG) into prostaglandin E2 glycerol ester (PGE2-G), which is pro-nociceptive because, when administered into the footpad, it induces mechanical allodynia and thermal hyperalgesia [23].”
From Endocannabinoid involvement in endometriosis. (2010) · cites this paper as [23]

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“For example, COX-2 converts the endocannabinoid 2arachidonoylglycerol (2-AG) into prostaglandin E2 glycerol ester (PGE2-G), which is pro-nociceptive because, when administered into the footpad, it induces mechanical allodynia and thermal hyperalgesia [23].”
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Authors: Hu, S. S., Bradshaw, H. B., Chen, J. S., Tan, B., & Walker, J. M.
Affiliations: Indiana University Bloomington (US)
Corresponding author: Bradshaw, H B
ORCID: Hu, S Shu‐Jung
Bradshaw, H B
Tan, B
Venue: British Journal of Pharmacology
Publisher: Wiley
Published: 2008-04
Volume: 153
Issue: 7
Pages: 1538-1549
ISSN: 0007-1188 (ISSN-L)
1476-5381
DOI: 10.1038/bjp.2008.33
PMC: PMC2437899
OpenAlex: W1491261527
Cited by: 151
References: 39
Citations by year: 2025: 1 · 2023: 6 · 2022: 10 · 2021: 8 · 2020: 8 · 2019: 8 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 8 · 2014: 18 · 2013: 9 · 2012: 10
FWCI: 8.57
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 303 d)
Locations: British Journal of Pharmacology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Eli Lilly and Company
National Institutes of Health (1f32da016825-01)
National Institute on Drug Abuse (F32-DA-016825, DA-011322, DA 018224, R01DA011322, R01DA020402, R01DA018224, DA-020402)
Topics: Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Keywords: 2-arachidonoylglycerol, cyclooxygenase-2, monoacylglycerol lipase, hyperalgesia, mechanical allodynia, thermal hyperalgesia, NF-κB, prostanoid receptors, endocannabinoid metabolism, immunomodulation, carrageenan-induced inflammation
MeSH terms: Animals, Arachidonic Acids, Cell Line, Glycerides, Hot Temperature, Hyperalgesia, Macrophages, Male, Pain, Pain Measurement, Receptors, Prostaglandin, Mass Spectrometry, Dinoprostone, NF-kappa B, Rats, Sprague-Dawley, Mice, Rats, Cyclooxygenase 2, Endocannabinoids

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Prostaglandin E 2 glycerol ester, an endogenous COX‐2 metabolite of 2‐arachidonoylglycerol, induces hyperalgesia and modulates NFκB activity

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