Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation

Daniel J. Hermanson, Joyonna C. Gamble-George, Lawrence J. Marnett*, Sachin Patel

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

72 Scopus citations


Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of the canonical eCB inactivation pathways - fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-arachidonoylglycerol. We review here the experimental evidence that cyclooxygenase-2 (COX-2)-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of 'substrate-selective' COX-2 inhibitors (SSCIs) that prevent eCB inactivation by COX-2 without affecting prostaglandin (PG) generation from arachidonic acid (AA). Lastly, we review recent data on the potential therapeutic applications of SSCIs with a focus on neuropsychiatric disorders.

Original languageEnglish (US)
Pages (from-to)358-367
Number of pages10
JournalTrends in Pharmacological Sciences
Issue number7
StatePublished - Jul 2014
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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