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

• Published in: Nature neuroscience Vol. 16; no. 9; pp. 1291 - 1298
• Main Authors: Hermanson, Daniel J, Hartley, Nolan D, Gamble-George, Joyonna, Brown, Naoko, Shonesy, Brian C, Kingsley, Phillip J, Colbran, Roger J, Reese, Jeffrey, Marnett, Lawrence J, Patel, Sachin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2013; Nature Publishing Group
• Subjects: 631/154; 631/378/1689/1300; Adaptation, Ocular - drug effects; Adaptation, Ocular - genetics; Affective disorders; Amidohydrolases - deficiency; Animal Genetics and Genomics; Animals; Anxiety; Anxiety - drug therapy; Anxiety - genetics; Anxiety - metabolism; Anxiety - physiopathology; Behavioral Sciences; Benzoxazines - pharmacology; Biological Techniques; Biomedicine; Body Temperature - drug effects; Body Temperature - genetics; Calcium Channel Blockers - pharmacology; Cannabinoid Receptor Agonists - pharmacology; Cannabinoid Receptor Antagonists - pharmacology; Care and treatment; COX-2 inhibitors; Cyclooxygenase 2 - deficiency; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - therapeutic use; Disease Models, Animal; Endocannabinoids; Endocannabinoids - chemistry; Endocannabinoids - metabolism; Endocannabinoids - pharmacology; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Freezing Reaction, Cataleptic - drug effects; Freezing Reaction, Cataleptic - physiology; Humans; Indoles - chemistry; Indoles - pharmacology; Male; Maze Learning - drug effects; Maze Learning - physiology; Mice; Mice, Inbred ICR; Mice, Knockout; Morpholines - pharmacology; Naphthalenes - pharmacology; Neurobiology; Neurosciences; Physiological aspects; Prostaglandins; Receptor, Cannabinoid, CB1 - deficiency; Receptor, Cannabinoid, CB1 - genetics; Signal Transduction - drug effects; Signal Transduction - physiology; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3480

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.