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Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis.
Pain 2011; 152(5):975-81PAIN

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.

Authors+Show Affiliations

Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21185649

Citation

Schuelert, Niklas, et al. "Local Application of the Endocannabinoid Hydrolysis Inhibitor URB597 Reduces Nociception in Spontaneous and Chemically Induced Models of Osteoarthritis." Pain, vol. 152, no. 5, 2011, pp. 975-81.
Schuelert N, Johnson MP, Oskins JL, et al. Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. Pain. 2011;152(5):975-81.
Schuelert, N., Johnson, M. P., Oskins, J. L., Jassal, K., Chambers, M. G., & McDougall, J. J. (2011). Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. Pain, 152(5), pp. 975-81. doi:10.1016/j.pain.2010.11.025.
Schuelert N, et al. Local Application of the Endocannabinoid Hydrolysis Inhibitor URB597 Reduces Nociception in Spontaneous and Chemically Induced Models of Osteoarthritis. Pain. 2011;152(5):975-81. PubMed PMID: 21185649.
* Article titles in AMA citation format should be in sentence-case
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 DB - PRIME DP - Unbound Medicine ER -