Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation
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Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.
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When COX-2 is inhibited, AEA and, to a lesser extent, 2-AG accumulate in the brain.
“When COX-2 is inhibited, AEA and, to a lesser extent, 2-AG accumulate in the brain (Hermanson et al., 2013).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Hermanson et al., 2013
Inhibition of COX-2 causes accumulation of eCBs, increases the tissue content of AEA and to a lesser degree 2-AG, and enhances eCB-mediated retrograde synaptic suppression.
“inhibition of COX-2 causes accumulation of eCBs as revealed, firstly, by increases in the tissue content of AEA and, to a lesser degree, 2-AG and, secondly, by enhanced eCB-mediated retrograde synaptic suppression - in the form of depolarization-induced suppression of inhibition (DSI) and tonic eCB-suppression of glutamate release (Hermanson et al., 2013; Kim and Alger, 2004; Slanina and Schwe”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hermanson et al., 2013
COX-2 regulates eCB signaling at the synaptic, neurochemical and behavioral level in a manner that only partially overlaps with FAAH and MAGL inhibition, and may have a role in anxiety-like behavior and stress-responsivity.
“emerging data that one of these pathways, COX-2, regulates eCB signaling at the synaptic, neurochemical and behavioral level in a manner that only partially overlaps with FAAH and MAGL inhibition (Hermanson et al., 2014; Hermanson et al., 2013), but nonetheless may have a role in the mediation of anxiety-like behavior and stress-responsivity (Gamble-George et al., 2016; Hermanson et al., 2013).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hermanson et al., 2013
The anxiolytic-like effects of LM-4131 in the light-dark exploration test are fully prevented by co-administration of a CB1R antagonist, consistent with eCB-dependency of the COX-2 inhibitor's effects.
“the anxiolytic-like effects of LM-4131 were fully prevented (in the light-dark exploration test) by co-administration of a CB1R antagonist - consistent with eCB-dependency of the COX-2 inhibitor’s effects (Hermanson et al., 2013).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hermanson et al., 2013
Systemic administration of LM-4131 decreases mouse anxiety-like behavior in open field, light-dark exploration, and elevated plus-maze assays.
“systemic administration of the prototypic SSCI, LM-4131, was found to decrease mouse anxiety-like behavior in a range of assays (open field, light-dark exploration, elevated plus-maze) (Hermanson et al., 2013).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Hermanson et al., 2013
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- Authors
- Hermanson, D. J., Hartley, N. D., Gamble-George, J., Brown, N., Shonesy, B. C., Kingsley, P. J., Colbran, R. J., Reese, J., Marnett, L. J., & Patel, S.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Marnett, Lawrence J
- Patel, Sachin
- Venue
- Nature Neuroscience
- Published
- 2013-08-04
- Volume
- 16
- Issue
- 9
- Pages
- 1291-1298
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3788575
- OpenAlex
- W2133748767
- Cited by
- 126
- References
- 57
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 12 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 10 · 2017: 13 · 2016: 11 · 2015: 23 · 2014: 19 · 2013: 4
- FWCI
- 13.98
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL096967, HL-109199, HL-96967, R01HL109199)
- National Institute of Mental Health (R01MH100096, MH100096, R01MH063232, K08MH090412, MH090412, T32MH065215)
- National Institute on Drug Abuse (DA031572, F31DA031572)
- National Cancer Institute (R01CA089450, CA89450)
- National Institute of General Medical Sciences (GM 15431, P50GM015431, P01GM015431, R25GM062459)
- National Institute of Neurological Disorders and Stroke (R01NS078291, R01NS064278, NS078291, NS064278)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- cyclooxygenase-2, endocannabinoid signaling, anxiety-like behavior, anxiety disorders, arachidonic acid, prostaglandins, mood disorders
- MeSH terms
- Fatty Acid Amide Hydrolases, Adaptation, Ocular, Amidohydrolases, Animals, Anxiety, Body Temperature, Calcium Channel Blockers, Disease Models, Animal, Exploratory Behavior, Humans, Indoles, Male, Mice, Inbred ICR, Morpholines, Naphthalenes, Signal Transduction, Cyclooxygenase Inhibitors, Mice, Knockout, Maze Learning, Receptor, Cannabinoid, CB1, Freezing Reaction, Cataleptic, Benzoxazines, Mice, Cyclooxygenase 2, Cannabinoid Receptor Agonists, Cannabinoid Receptor Antagonists, Endocannabinoids
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