Effect of oxygenated derivatives of endocannabinoids on mechanical hyperalgesia induced by peripheral inflammation

In recent years, endocannabinoids (eCB), namely 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA), were proposed as promising bioactive lipids to modulate nociception. However, eCB metabolism is complex. Besides their hydrolysis into arachidonic acid (precursor of the prostaglandins (PG)), eCBs can undergo oxygenation by COX-2 to form PG glycerol esters (PG-Gs) and prostamides (PG-EAs) from 2-AG and AEA, respectively. While the pharmacology and actions of PGs are well described, the involvement of PG-Gs and PG-EAs in inflammatory conditions and nociception is still not clear. The first aim of this work was to explore the effects of PGD2-G on inflammatory pain and to explore part of its mechanism of action. To this end, we set up a model of carrageenan-induced hyperalgesia and edema in mice to test the local administration of PGD2-G. In a second part, we explored the substrate-selective inhibition of COX-2 by R-flurbiprofen, to modulate selectively PG-G and PG-EA synthesis, in different models of inflammation and nociception. We also explored, in parallel, the effects of PGs, PG-Gs and PG-EAs in a model of inflammatory pain induced by lipopolysaccharides in mice. Through all these studies, we showed that eCB oxygenation is a relevant pathway in nociception. While modulation of PG-G and PG-EA synthesis remains a challenge, this approach could unravel new therapeutic strategies to counteract inflammatory pain.