Abstract
Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1–50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB1 receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB2 antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
Footnotes
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This work was supported by grants from National Institute on Drug Abuse (DA-12447 and DA-3412), the University of California Discovery Program (to D.P.), Kadmus Pharmaceuticals, Inc., and Ministero dell'Istruzione, Università e Ricerca (to A.C., A.T., and G.T.).
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U.S. patent 7176201 on this work was filed by the University of California and is licensed to Kadmus Pharmaceuticals, Inc.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.119941.
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ABBREVIATIONS: PEA, palmitoylethanolamide; FAE, fatty acid ethanolamide; FAAH, fatty-acid amide hydrolase; CB1, cannabinoid receptor type I; URB597 (KDS-4103), cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester; CCI, chronic constriction injury; 2-AG, 2-arachidonoylglycerol; SR144528, N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide; SR141716, rimonabant, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide; LC, liquid chromatography; MS, mass spectrometry; OEA, oleoylethanolamide; AUC, area under the curve; CB2, cannabinoid receptor type II.
- Received January 17, 2007.
- Accepted April 4, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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