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Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation.


Hermanson DJDaniel J , Hartley ND Nolan D , Gamble-George J Joyonna , Brown N Naoko , Shonesy BC Brian C , Kingsley PJ Phillip J , Colbran RJ Roger J , Reese J Jeffrey , Marnett LJ Lawrence J , Patel S Sachin . Nature neuroscience. 2013 9 ; 16(9). 1291-8


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.