Researchers at the University of California, Davis have discovered that analgesia mediated by inhibitors of the enzyme soluble epoxide hydrolase (sEH) is dependent on a pain-mediating second messenger known as cyclic adenosinemonophosphate (cAMP).
The study was published March 7 in an early edition of the Proceedings of the National Academy of Sciences. The paper is titled “Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP.”
The messenger, cAMP, relays responses and mediates the action of many biological processes, including inflammation as well as cardiac and smooth muscle contraction. The UC-Davis team conducted its research in rodents using an established class of drugs called phosphodiesterase (PDE) inhibitors and a new class of compounds called sEH inhibitors.
The researchers confirmed earlier studies at UC-Davis that showed that stabilization of natural epoxy-fatty acids (EFAs) through inhibition of sEH reduces pain. “However, in the absence of an underlying painful state, inhibition of sEH is ineffective,” explains lead researcher Bora Inceoglu of the Bruce Hammock lab, UC-Davis department of entomology. “To our surprise, we found that cAMP interacts with natural EFAs and regulates the analgesic, or pain activity, of sEH inhibitors,” says Inceoglu.
Concurrent inhibition of sEH and PDE dramatically reduced acute pain in rodents, the investigators report. Their findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain.
Furthermore, they show that inhibition of various PDE isozymes including PDE4 leads to significant increases in EFA levels through a mechanism independent of sEH, suggesting that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs.
“The interaction of many complex biological pathways is essential for the development of persistent pain, whether inflammatory or neuropathic,” notes Inceoglu.
Phosphodiesterase inhibitors likely exert part of their action by increasing the levels of natural compounds in the body called EETs (epoxyeicosatrienoic acids). The scientists had previously reported that a new class of experimental drugs called soluble epoxide hydrolase inhibitors stabilize and also increase EETs.
Practical and basic? “A practical application of this work demonstrated by Bora Inceoglu is that the combination of this old and new class of drugs is highly effective in controlling pain,” says Hammock, senior author of the paper. “Of course, the basic aspects of the work include new insights in how EETs, cyclic nucleotides, and the enzymes that degrade them interact to regulate a variety of biological functions.”