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Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception

Academic Article
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Overview

authors

  • Naidu, P. S.
  • Booker, L.
  • Cravatt, Benjamin
  • Lichtman, A. H.

publication date

  • April 2009

journal

  • Journal of Pharmacology and Experimental Therapeutics  Journal

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 (CB(1)) receptor antagonist, rimonabant, but not the cannabinoid receptor 2 (CB(2)) 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, ED(50) [95% confidence interval (CI) = 2.1 (1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac sodium [ED(50) (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 CB(1)(-/-) mice, whereas it maintained its efficacy in CB(2)(-/-) mice, indicating a CB(1) 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.

subject areas

  • Acetic Acid
  • Amidohydrolases
  • Animals
  • Benzamides
  • Carbamates
  • Cyclooxygenase Inhibitors
  • Diclofenac
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Inhibitors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Naltrexone
  • Narcotic Antagonists
  • Nociceptors
  • Pain
  • Protective Agents
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Stomach Ulcer
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Identity

PubMed Central ID

  • PMC2670588

International Standard Serial Number (ISSN)

  • 0022-3565

Digital Object Identifier (DOI)

  • 10.1124/jpet.108.143487

PubMed ID

  • 19118134
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Additional Document Info

start page

  • 48

end page

  • 56

volume

  • 329

issue

  • 1

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