Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP

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.nociception | antinociceptive | epoxyeicosatrienoic acid

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

“…This is indeed the case and although the majority of studies imply that sEH inhibition has analgesic properties (Inceoglu et al, 2006(Inceoglu et al, , 2007(Inceoglu et al, , 2011Terashvili et al, 2008;Wagner et al, 2013), other studies have yielded contradictory results and indicate that at least 8,9-EET can sensitize TRPA1-expressing nociceptors to increase pain (Brenneis et al, 2011). In addition, in a model of mechanical pain, 5,6-EET is synthesized after the acute activation of nociceptors and can produce mechanical hypersensitivity via TRPA1 channel activation at central afferent terminals in the spinal cord (Sisignano et al, 2012).…”

Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

“…S1). This high efficacy and longer duration of activity of TUPS supports its utility as a probe to investigate EpFAs (29). To test the hypothesis that sustained inhibition of sEH will attenuate allodynia in a prolonged manner, we monitored the MWT of animals for over 4 d following a single dose of TUPS.…”

Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

“…Using potent inhibitors of sEH to stabilize endogenous EETs (14)(15)(16)(17), sEH has been recently demonstrated in animal models as a novel therapeutic target (4) for treating cardiovascular diseases (18)(19)(20), inflammation (21,22), pain (23)(24)(25), and pulmonary diseases such as pulmonary hypertension (26,27) and tobacco smoke-induced chronic obstructive pulmonary disease (9,10).…”