Abstract:
:Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain. However, in the absence of an underlying painful state, inhibition of sEH is ineffective. Surprisingly, a pain-mediating second messenger, cAMP, interacts with natural EFAs and regulates the analgesic activity of sEH inhibitors. Concurrent inhibition of sEH and phosphodiesterase (PDE) dramatically reduced acute pain in rodents. Our findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain. Furthermore, we demonstrate that inhibition of various PDE isozymes, including PDE4, lead 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 cross-talk between the two major pathways-one mediated by cAMP and the other by EFAs-paves the way to new approaches to understand and control pain.
journal_name
Proc Natl Acad Sci U S Aauthors
Inceoglu B,Wagner K,Schebb NH,Morisseau C,Jinks SL,Ulu A,Hegedus C,Rose T,Brosnan R,Hammock BDdoi
10.1073/pnas.1101073108subject
Has Abstractpub_date
2011-03-22 00:00:00pages
5093-7issue
12eissn
0027-8424issn
1091-6490pii
1101073108journal_volume
108pub_type
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