Abstract
Cyclooxygenase-2 (COX-2) mediates inflammation and contributes to neurodegeneration. Best known for its pathological up-regulation, COX-2 is also constitutively expressed within the brain and mediates synaptic transmission through prostaglandin synthesis. Along with arachidonic acid, COX-2 oxygenates the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol in vitro. Inhibition of COX-2 enhances retrograde signaling in the hippocampus, suggesting COX-2 mediates endocannabinoid tone in healthy brain. The degree to which COX-2 may regulate endocannabinoid metabolism in vivo is currently unclear. Therefore, we explored the effect of COX-2 inhibition on [3H]AEA metabolism in mouse brain. Although AEA is hydrolyzed primarily by fatty acid amide hydrolase (FAAH), ex vivo autoradiography revealed that COX-2 inhibition by nimesulide redirected [3H]AEA substrate from COX-2 to FAAH in the cortex, hippocampus, thalamus, and periaqueductal gray. These data indicate that COX-2 possesses the capacity to metabolize AEA in vivo and can compete with FAAH for AEA in several brain regions. Temporal fluctuations in COX-2 expression were observed in the brain, with an increase in COX-2 protein and mRNA in the hippocampus at midnight compared with noon. COX-2 immunolocalization was robust in the hippocampus and several cortical regions. Although most regions exhibited no temporal changes in COX-2 immunolocalization, increased numbers of immunoreactive cells were detected at midnight in layers II and III of the somatosensory and visual cortices. These temporal variations in COX-2 distribution reduced the enzyme's contribution toward [3H]AEA metabolism in the somatosensory cortex at midnight. Taken together, our findings establish COX-2 as a mediator of regional AEA metabolism in mouse brain.
Footnotes
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This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant 1-K01-DA021806-01] (to S.T.G.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.168831
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ABBREVIATIONS:
- COX-2
- cyclooxygenase-2
- AEA
- anandamide
- FAAH
- fatty acid amide hydrolase
- IR
- immunoreactivity
- LTP
- long-term potentiation
- 2-AG
- 2-arachidonoylglycerol
- MGL
- monoglyceride lipase
- qRT-PCR
- quantitative real-time polymerase chain reaction
- PAG
- periaqueductal gray
- PBST
- phosphate-buffered saline Tween 20
- CAY10397
- 5-[[4-(ethoxycarbonyl)phenyl]azo]-2-hydroxy-benzeneacetic acid.
- Received March 30, 2010.
- Accepted July 29, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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