The present study investigated whether inhibition of fatty acid amide
hydrolase (FAAH), the enzyme responsible for anandamide catabolism, produces
antinociception in the acetic acid-induced abdominal stretching model of
visceral nociception. Genetic deletion or pharmacological inhibition of FAAH
reduced acetic acid-induced abdominal stretching. Transgenic mice that express
FAAH exclusively in the nervous system displayed the antinociceptive
phenotype, indicating the involvement of peripheral fatty acid amides. The
cannabinoid receptor 1 (CB1) receptor antagonist, rimonabant, but
not the cannabinoid receptor 2 (CB2) receptor antagonist, SR144528,
blocked the antinociceptive phenotype of FAAH(-/-) mice and the analgesic
effects of URB597 (3β²-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) or
OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenyl heptane), respective irreversible
and reversible FAAH inhibitors, administered to C57BL/6 mice. The opioid
receptor antagonist, naltrexone, did not block the analgesic effects of either
FAAH inhibitor. URB597, ED50 [95% confidence interval (CI) = 2.1
(1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac
sodium [ED50 (95% CI) = 9.8 (8.2-11.7) mg/kg], dose-dependently
inhibited acetic acid-induced abdominal stretching. Combinations of URB597 and
diclofenac yielded synergistic analgesic interactions according to
isobolographic analysis. It is important that FAAH(-/-) mice and
URB597-treated mice displayed significant reductions in the severity of
gastric irritation caused by diclofenac. URB597 lost its gastroprotective
effects in CB1(-/-) mice, whereas it maintained its efficacy in
CB2(-/-) mice, indicating a CB1 mechanism of action.
Taken together, the results of the present study suggest that FAAH represents
a promising target for the treatment of visceral pain, and a combination of
FAAH inhibitors and NSAIDs may have great utility to treat visceral pain, with
reduced gastric toxicity