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Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain.

Abstract

Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve ligation or sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30 microg in 50 microl) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of sham-operated rats. Intraplantar URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.

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  • Authors+Show Affiliations

    ,

    School of Biomedical Sciences, Medical School, Queens Medical Centre, University of Nottingham, Nottinghamshire NG7 2UH, United Kingdom. maulik.jhaveri@nottingham.ac.uk

    , , ,

    Source

    MeSH

    Amidohydrolases
    Analgesics
    Animals
    Benzamides
    Carbamates
    Disease Models, Animal
    Enzyme Inhibitors
    Injections, Spinal
    Male
    Pain
    Pain Measurement
    Rats
    Rats, Sprague-Dawley
    Receptor, Cannabinoid, CB1

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17182782

    Citation

    Jhaveri, Maulik D., et al. "Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 26, no. 51, 2006, pp. 13318-27.
    Jhaveri MD, Richardson D, Kendall DA, et al. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J Neurosci. 2006;26(51):13318-27.
    Jhaveri, M. D., Richardson, D., Kendall, D. A., Barrett, D. A., & Chapman, V. (2006). Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 26(51), pp. 13318-27.
    Jhaveri MD, et al. Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain. J Neurosci. 2006 Dec 20;26(51):13318-27. PubMed PMID: 17182782.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. AU - Jhaveri,Maulik D, AU - Richardson,Denise, AU - Kendall,David A, AU - Barrett,David A, AU - Chapman,Victoria, PY - 2006/12/22/pubmed PY - 2007/1/9/medline PY - 2006/12/22/entrez SP - 13318 EP - 27 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 26 IS - 51 N2 - Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve ligation or sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30 microg in 50 microl) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of sham-operated rats. Intraplantar URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/17182782/Analgesic_effects_of_fatty_acid_amide_hydrolase_inhibition_in_a_rat_model_of_neuropathic_pain_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&amp;pmid=17182782 DB - PRIME DP - Unbound Medicine ER -