Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the
endocannabinoid anandamide and other bioactive
lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor,
URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent
pain. When administered by the oral route in mice,
URB937 was highly active (median effective dose, ED(50), to inhibit liver FAAH activity: 0.3mgkg(-1)) and had a bioavailability of 5.3%. The antinociceptive effects of oral
URB937 were investigated in mouse models of acute
inflammation (
carrageenan),
peripheral nerve injury (chronic sciatic nerve
ligation) and
arthritis (complete
Freund's adjuvant). In all models,
URB937 was as effective or more effective than standard
analgesic and anti-inflammatory drugs (
indomethacin,
gabapentin,
dexamethasone) and reversed
pain-related responses (
mechanical hyperalgesia,
thermal hyperalgesia, and
mechanical allodynia) in a dose-dependent manner. ED(50) values ranged from 0.2 to 10mgkg(-1), depending on model and readout. Importantly,
URB937 was significantly more effective than two global FAAH inhibitors,
URB597 and
PF-04457845, in the complete
Freund's adjuvant model. The effects of a combination of
URB937 with the
non-steroidal anti-inflammatory agent,
indomethacin, were examined in the
carrageenan and chronic sciatic nerve
ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate
pain-related behaviors. Furthermore,
URB937 reduced the number and severity of gastric lesions produced by
indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor
URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory
pain. Our findings further suggest that FAAH and
cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other's actions.