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Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis.

Abstract

The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12 months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03 mg; 0.1 mL bolus); the CB(1) receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1 mg/kg intraperitoneally). The effect of systemic URB597 administration (5 mg/kg) on joint pain perception in the monoiodoacetate model was determined by hindlimb incapacitance. Peripheral injection of URB597 caused afferent firing rate to be significantly reduced by up to 56% in the rat OA model and by up to 69% in the guinea pig OA model. Systemic co-administration of AM251, but not AM630, abolished the antinociceptive effect of URB597 in both models. URB597 had no effect in saline-injected control rat joints or in nonarthritic guinea pigs. Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain.

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  • Authors+Show Affiliations

    ,

    Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1.

    , , , ,

    Source

    Pain 152:5 2011 May pg 975-81

    MeSH

    Action Potentials
    Afferent Pathways
    Age Factors
    Animals
    Arthralgia
    Benzamides
    Carbamates
    Diclofenac
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Enzyme Inhibitors
    Guinea Pigs
    Indoles
    Iodoacetic Acid
    Male
    Nociceptors
    Osteoarthritis
    Piperidines
    Pyrazoles
    Rats
    Rats, Wistar
    Time Factors
    Weight-Bearing

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    21185649

    Citation

    TY - JOUR T1 - Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. AU - Schuelert,Niklas, AU - Johnson,Michael P, AU - Oskins,Jennifer L, AU - Jassal,Karandeep, AU - Chambers,Mark G, AU - McDougall,Jason J, Y1 - 2010/12/24/ PY - 2010/02/13/received PY - 2010/11/10/revised PY - 2010/11/22/accepted PY - 2010/12/28/entrez PY - 2010/12/28/pubmed PY - 2011/8/24/medline SP - 975 EP - 81 JF - Pain JO - Pain VL - 152 IS - 5 N2 - The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12 months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03 mg; 0.1 mL bolus); the CB(1) receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1 mg/kg intraperitoneally). The effect of systemic URB597 administration (5 mg/kg) on joint pain perception in the monoiodoacetate model was determined by hindlimb incapacitance. Peripheral injection of URB597 caused afferent firing rate to be significantly reduced by up to 56% in the rat OA model and by up to 69% in the guinea pig OA model. Systemic co-administration of AM251, but not AM630, abolished the antinociceptive effect of URB597 in both models. URB597 had no effect in saline-injected control rat joints or in nonarthritic guinea pigs. Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/21185649/abstract/Local_application_of_the_endocannabinoid_hydrolysis_inhibitor_URB597_reduces_nociception_in_spontaneous_and_chemically_induced_models_of_osteoarthritis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3959(10)00710-4 ER -