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

Daniel J. Hermanson, Nolan D. Hartley, Joyonna Gamble-George, Naoko Brown, Brian C. Shonesy, Phillip J. Kingsley, Roger J. Colbran, Jeffrey Reese, Lawrence J. Marnett*, Sachin Patel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1291-1298
Number of pages8
JournalNature neuroscience
Volume16
Issue number9
DOIs
StatePublished - Sep 2013
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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