A new study has uncovered surprising new insights into the actions of non-steroidal anti-inflammatory drugs (NSAIDs), suggesting the possibility of developing a new class of inflammation and pain fighting medicines.
NSAIDs block the activity of the cyclooxygenase enzymes COX-1 and COX-2.
“Until about three years ago, we thought we knew everything there was to know about these enzymes and these inhibitors, but we were unaware of some of the details of how they work,” said Lawrence Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology and professor of Biochemistry, Chemistry and Pharmacology.
In the current report, the researchers surveyed a series of different types of NSAIDs for inhibition of COX-2.
They included the “mirror-image” versions of ibuprofen, naproxen and flurbiprofen (these drugs come in two different chemical configurations – a “right hand” (R) version and a “left hand” (S) version – over-the-counter ibuprofen is a mixture of both forms).
It had previously been assumed that only the S-forms of these NSAIDs (S-profens) were able to inhibit COX-2.
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,” he added.
The findings were reported Sept. 25 in Nature Chemical Biology.