Abstract
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 (3′-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.
Footnotes
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This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants P01-DA017259, R01-DA15197, R01-DA03672, T32-DA007027].
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We dedicate this article to our beloved mentor and world renowned pharmacologist, the late Professor Billy R. Martin, whose keen insight, wisdom, and advice were invaluable.
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doi:10.1124/jpet.108.143487.
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ABBREVIATIONS: CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; FAAH, fatty acid amide hydrolase; THC, Δ9-tetrahydrocannabinol; URB597, 3′-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate; OL-135, 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenyl heptane; CNS, central nervous system; NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase; FAAH-NS, nervous system FAAH-restricted; ANOVA, analysis of variance; 2-AG, 2-arachidonoyl glycerol; SR144528, N-[(1S)-endo-1,3,3,-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methyl-benzyl)-pyrazole-3-carboxamide; WIN55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone.
- Received July 12, 2008.
- Accepted December 31, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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