Marnett and colleagues found that the R-profens inhibited endocannabinoid, but not arachidonic acid, oxygenation.
The researchers also determined that R-profens selectively block endocannabinoid metabolism in isolated dorsal root ganglia (neurons and glial cells from the spinal column). They found that treatment of these cultures with an inflammatory stimulus increased expression of COX-2 and stimulated release of arachidonic acid and endocannabinoids, which were oxidized by COX-2. The R-profens inhibited metabolism of the endocannabinoids (and increased their concentrations), but not arachidonic acid.
The findings offer a potential explanation for the reported observation that R-flurbiprofen is analgesic in people and that it inhibits neuropathic pain in a mouse model.
"We're proposing that R-flurbiprofen is effective in this neuropathic pain setting because it is preventing the metabolism of endocannabinoids by COX-2; so it's maintaining endocannabinoid tone and that's the basis for the analgesic activity," Marnett said.
"It's exciting because you will only see this effect at sites of inflammation where COX-2 might play a role in depleting endocannabinoids. Selective inhibitors like the R-profens could represent a new way to target analgesia without having the GI, and maybe cardiovascular, side effects of traditional NSAIDs."
Marnett and his team will pursue this idea by studying in vivo models of neuroinflammation to determine if these drugs and new compounds they are developing work to inhibit endocannabinoid oxidation and maintain endocannabinoid tone.
|Contact: Leigh MacMillan|
Vanderbilt University Medical Center