TY - JOUR
T1 - Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive
AU - Sasso, Oscar
AU - Wagner, Karen
AU - Morisseau, Christophe
AU - Inceoglu, Bora
AU - Hammock, Bruce D.
AU - Piomelli, Daniele
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.phrs.2015.04.001
DO - 10.1016/j.phrs.2015.04.001
M3 - Article
C2 - 25882247
AN - SCOPUS:84928393991
VL - 97
SP - 7
EP - 15
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
ER -