Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation
Enhancing endocannabinoid signaling is a potential therapeutic approach to treating anxiety disorders. Here the authors show that a compound leading to 'substrate-selective' inhibition of cyclooxygenase-2 (cox-2) increases endocannabinoid levels without affecting non-endocannabinoid lipids...
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Published in | Nature neuroscience Vol. 16; no. 9; pp. 1291 - 1298 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.09.2013
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Enhancing endocannabinoid signaling is a potential therapeutic approach to treating anxiety disorders. Here the authors show that a compound leading to 'substrate-selective' inhibition of cyclooxygenase-2 (cox-2) increases endocannabinoid levels without affecting non-endocannabinoid lipids or prostaglandin synthesis. This compound decreased anxiety-like behaviors in mice via increased endocannabinoid signaling.
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1097-6256 1546-1726 |
DOI: | 10.1038/nn.3480 |