Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive

Abstract

We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators - fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively - which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

“…Interestingly, the octanoyl-MP-hydrolase activity, representative of fatty acid amide hydrolase activity, was significantly lowered (p < 0.05) at 2 and 4 days after OME discontinuation and in the presence of TPPU. The anti-hyperalgsic effect of TPPU during the 2 and 4 day washout period of OME might be at least in part due to altering FAAH activity (Sasso et al, 2012, Sasso et al, 2015). …”

“…The final doses of OME and TPPU were 100 mg/kg and 3 mg/kg respectively administered in a volume of 2 mL/kg of PEG400. An intermediate dose of OME was selected based on available literature on P450 1A and P450 2B induction in rats (Masubuchi et al, 1997), and the dose of TPPU was selected based on literature on the anti-hyperalgesic effect of TPPU and similar sEH inhibitors in rats (Sasso et al, 2015; Inceoglu et al, 2011; Inceoglu et al, 2012). …”

Parabens inhibit fatty acid amide hydrolase: A potential role in paraben-enhanced 3T3-L1 adipocyte differentiation

“…While the potency of parabens is relatively weak compared to drugs optimized to target FAAH, the efficacy of FAAH inhibition may be enhanced by other factors. Recent reports have demonstrated FAAH inhibition synergizes with other targets including soluble epoxide hydrolase (sEH) (Sasso et al, 2015) and cyclooxygenase (COX) (Naidu et al, 2009). While these studies investigate synergy in the context of nociception, both sEH and COX are generally relevant to adipo-genesis and the regulation of inflammation (Karaliota et al, 2009; De Taeye et al, 2010).…”

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

“…With a molecular weight of 359 Da, four hydrogen bond accepting groups and two hydrogen bond donors as well as an n -octanol/water coefficient of 2.4 ± 0.5 17 , it fulfills all criteria of Lipinski’s rule of five 35 of a drugable compound. Moreover, the potency to inhibit sEH is high (human IC 50 0.9 nM; rat 5 nM and mice IC 50 6 nM 36 ) and TPPU has been successfully used in several animal disease models such as LPS induced sepsis 19 and cardiac fibrosis 22 in mice.…”