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The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice.

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 CB(1) 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 CB(2) 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.

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  • Authors+Show Affiliations

    ,

    Department of Experimental Pharmacology, University of Naples, Italy.

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    Source

    MeSH

    Administration, Oral
    Amidohydrolases
    Analgesics
    Animals
    Benzamides
    Capillary Permeability
    Carbamates
    Enzyme Inhibitors
    Hyperalgesia
    Male
    Mice
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Spinal Cord

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17412883

    Citation

    Russo, Roberto, et al. "The Fatty Acid Amide Hydrolase Inhibitor URB597 (cyclohexylcarbamic Acid 3'-carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain After Oral Administration in Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 322, no. 1, 2007, pp. 236-42.
    Russo R, Loverme J, La Rana G, et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J Pharmacol Exp Ther. 2007;322(1):236-42.
    Russo, R., Loverme, J., La Rana, G., Compton, T. R., Parrott, J., Duranti, A., ... Piomelli, D. (2007). The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. The Journal of Pharmacology and Experimental Therapeutics, 322(1), pp. 236-42.
    Russo R, et al. The Fatty Acid Amide Hydrolase Inhibitor URB597 (cyclohexylcarbamic Acid 3'-carbamoylbiphenyl-3-yl Ester) Reduces Neuropathic Pain After Oral Administration in Mice. J Pharmacol Exp Ther. 2007;322(1):236-42. PubMed PMID: 17412883.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. AU - Russo,Roberto, AU - Loverme,Jesse, AU - La Rana,Giovanna, AU - Compton,Timothy R, AU - Parrott,Jeff, AU - Duranti,Andrea, AU - Tontini,Andrea, AU - Mor,Marco, AU - Tarzia,Giorgio, AU - Calignano,Antonio, AU - Piomelli,Daniele, Y1 - 2007/04/05/ PY - 2007/4/7/pubmed PY - 2007/8/31/medline PY - 2007/4/7/entrez SP - 236 EP - 42 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 322 IS - 1 N2 - 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 CB(1) 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 CB(2) 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17412883/The_fatty_acid_amide_hydrolase_inhibitor_URB597__cyclohexylcarbamic_acid_3'_carbamoylbiphenyl_3_yl_ester__reduces_neuropathic_pain_after_oral_administration_in_mice_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17412883 DB - PRIME DP - Unbound Medicine ER -