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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptation, Ocular / drug effects
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Adaptation, Ocular / genetics
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Amidohydrolases / deficiency
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Animals
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Anxiety / drug therapy
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Anxiety / genetics
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Anxiety / metabolism*
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Anxiety / physiopathology
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Benzoxazines / pharmacology
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Body Temperature / drug effects
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Body Temperature / genetics
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Calcium Channel Blockers / pharmacology
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Cannabinoid Receptor Agonists / pharmacology
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Cannabinoid Receptor Antagonists / pharmacology
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Cyclooxygenase 2 / deficiency
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Cyclooxygenase 2 / metabolism*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Cyclooxygenase Inhibitors / therapeutic use
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Disease Models, Animal
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Endocannabinoids / chemistry
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Endocannabinoids / metabolism*
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Endocannabinoids / pharmacology
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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Freezing Reaction, Cataleptic / drug effects
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Freezing Reaction, Cataleptic / physiology
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Humans
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Indoles / chemistry
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Indoles / pharmacology
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Mice
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Mice, Inbred ICR
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Mice, Knockout
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Morpholines / pharmacology
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Naphthalenes / pharmacology
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Receptor, Cannabinoid, CB1 / deficiency
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Receptor, Cannabinoid, CB1 / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology*
Substances
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Benzoxazines
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CNR1 protein, mouse
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Calcium Channel Blockers
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Cannabinoid Receptor Agonists
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Cannabinoid Receptor Antagonists
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Cyclooxygenase Inhibitors
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Endocannabinoids
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Indoles
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LM-4131
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Morpholines
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Naphthalenes
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Receptor, Cannabinoid, CB1
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Amidohydrolases
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fatty-acid amide hydrolase