Effects of COX-2 inhibition on spinal nociception: the role of endocannabinoids.
Open accessAbstract
BACKGROUND AND PURPOSE: Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB(1)) receptors was determined. EXPERIMENTAL APPROACH: Effects of spinal and peripheral administration of nimesulide (1-100 microg per 50 microL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB(1) receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry. KEY RESULTS: Spinal, but not peripheral, injection of nimesulide (1-100 microg per 50 microL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB(1) receptor antagonist AM251 (1 microg per 50 microL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide. CONCLUSIONS AND IMPLICATIONS: Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB(1) receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia.
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Specific COX-2 inhibitors could act centrally to reduce hyperalgesia by preventing 2-AG breakdown into pro-nociceptive molecules.
“Thus, specific COX-2 inhibitors, which alleviate endometriosis-associated pain [12], could, as has recently been shown, act centrally to reduce hyperalgesia by preventing 2-AG breakdown into pro-nociceptive molecules [7,47,50].”
From Endocannabinoid involvement in endometriosis. (2010) · cites this paper as [47]
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Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation
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Endocannabinoid involvement in endometriosis.
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“Thus, specific COX-2 inhibitors, which alleviate endometriosis-associated pain [12], could, as recently shown, act centrally to reduce hyperalgesia by preventing 2-AG breakdown into pro-nociceptive molecules [7,47,50].”
Background
- Authors
- Staniaszek, L., Norris, L., Kendall, D., Barrett, D., & Chapman, V
- Affiliations
- University of Nottingham (GB)
- Corresponding author
- Staniaszek, LE
- ORCID
- Chapman, V
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2010-05-19
- Volume
- 160
- Issue
- 3
- Pages
- 669-676
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC2931566
- OpenAlex
- W1482895394
- Cited by
- 36
- References
- 50
- Citations by year
- 2026: 1 · 2025: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 5
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Nottingham
- Medical Research Council
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- COX-2 inhibition, nimesulide, endocannabinoids, spinal nociception, CB1 receptor, anandamide, oleoylethanolamide, 2-arachidonoylglycerol, dorsal horn neurons, mechanical nociception, nonsteroidal anti-inflammatory drugs, analgesia
- MeSH terms
- Animals, Dose-Response Relationship, Drug, Drug Administration Routes, Evoked Potentials, Male, Pain, Piperidines, Pyrazoles, Spinal Cord, Sulfonamides, Cyclooxygenase Inhibitors, Rats, Sprague-Dawley, Posterior Horn Cells, Receptor, Cannabinoid, CB1, Rats, Cyclooxygenase 2, Cannabinoid Receptor Modulators, Endocannabinoids
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