Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors

Abstract

Combination therapies have long been used to treat inflammation while reducing side effects. The present study was designed to evaluate the therapeutic potential of combination treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and previously undescribed soluble epoxide hydrolase inhibitors (sEHIs) in lipopolysaccharide (LPS)-challenged mice. NSAIDs inhibit cyclooxygenase (COX) enzymes and thereby decrease production of metabolites that lead to pain and inflammation. The sEHIs, such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), stabilize anti-inflammatory epoxy-eicosatrienoic acids, which indirectly reduce the expression of COX-2 protein. Here we demonstrate that the combination therapy of NSAIDs and sEHIs produces significantly beneficial effects that are additive for alleviating pain and enhanced effects in reducing COX-2 protein expression and shifting oxylipin metabolomic profiles. When administered alone, AUDA-BE decreased protein expression of COX-2 to 73 ؎ 6% of control mice treated with LPS only without altering COX-1 expression and decreased PGE 2 levels to 52 ؎ 8% compared with LPS-treated mice not receiving any therapeutic intervention. When AUDA-BE was used in combination with low doses of indomethacin, celecoxib, or rofecoxib, PGE 2 concentrations dropped to 51 ؎ 7, 84 ؎ 9, and 91 ؎ 8%, respectively, versus LPS control, without disrupting prostacyclin and thromboxane levels. These data suggest that these drug combinations (NSAIDs and sEHIs) produce a valuable beneficial analgesic and anti-inflammatory effect while prospectively decreasing side effects such as cardiovascular toxicity.arachidonic acid ͉ cyclooxygenase ͉ epoxygenase ͉ pain ͉ linoleic acid

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

“…1D). The suppression of spinal COX2 message is in parallel to an earlier report using another sEHI in which we showed a reduction in cox-2 protein level in livers of inflamed mice (20). The potent activity of intraspinal sEHI, the spinal repression of COX2 induction by sEHIs, along with detection of both sEHIs in the brain strongly supports a centrally mediated antihyperalgesic mechanism of action for sEHIs.…”

“…As shown earlier, sEHI restored the plasma EET/DHET ratio (Fig. S5) (20). The hypothesis that AA release is required for sEHI-mediated antihyperalgesia remains to be tested.…”

Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase

“…In these studies, nbAUDA was effective in attenuating cisplatin-induced renal injury; the protective effect of AUDA was marginal and highly variable (data not shown). Although both AUDA and its butyl ester have been found to be effective in vivo in other systems (Smith et al 2005;Schmelzer et al 2005;Liu et al 2005;Inceoglu et al 2006;Schmelzer et al 2006;Xu et al 2006), it is not surprising that the free acid is less effective under conditions where it needs to be continually available to protect the kidney.…”

“…sEH inhibitors have been shown to normalize blood pressure in spontaneously hypertensive rats (Yu et al 2000) and in rats challenged with angiotensin (Imig et al 2002). Furthermore, the sEH inhibitors have been found to be strongly antiinflammatory in several in vivo bioassays (Smith et al 2005;Schmelzer et al 2005;Liu et al 2005;Inceoglu et al 2006;Schmelzer et al 2006;Xu et al 2006). Arachidonic acid epoxides [epoxyeicosatrienoic acids (EETs)] are endogenous regulators that influence inflammation (Node et al 1999) and blood pressure (Roman 2002) in the kidney; both inflammation and renal blood flow are critical mediators of cisplatin-mediated acute kidney injury (Jo et al 2005;Winston and Safirstein 1985).…”

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

“…Stabilization of the EpFAs using sEH inhibitors (sEHI) results in beneficial effects in a number of disease models, demonstrating antihyperalgesic, antiinflammatory, and other effects (15,21,24). EpFAs transcriptionally down-regulate cyclooxygenase-2 in addition to redirecting the flow of AA among the three branches of the cascade (16,19,25,26). Given that glucose itself can influence nociceptive thresholds, we asked if the antinociceptive effects of inhibiting sEH are independent from affecting the glycemic status of rats (27).…”