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

Hermanson DJ, Hartley ND, Gamble-George J, Brown N, Shonesy BC, Kingsley PJ, Colbran RJ, Reese J, Marnett LJ, Patel S
Nat Neurosci. 2013 16 (9): 1291-8

PMID: 23912944 · PMCID: PMC3788575 · DOI:10.1038/nn.3480

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.

MeSH Terms (26)

Adaptation, Ocular Amidohydrolases Animals Anxiety Benzoxazines Body Temperature Calcium Channel Blockers Cannabinoid Receptor Agonists Cannabinoid Receptor Antagonists Cyclooxygenase 2 Cyclooxygenase Inhibitors Disease Models, Animal Endocannabinoids Exploratory Behavior Freezing Reaction, Cataleptic Humans Indoles Male Maze Learning Mice Mice, Inbred ICR Mice, Knockout Morpholines Naphthalenes Receptor, Cannabinoid, CB1 Signal Transduction

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