Abstract | OBJECTIVE: The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA). METHOD: OA was induced in male Wistar rats by intra-articular injection of sodium monoiodo- acetate with a recovery period of 14 days. Immunohistochemistry was used to evaluate the expression of CB(2) and transient receptor potential vanilloid channel-1 (TRPV1) receptors in the dorsal root ganglion (DRG) and synovial membrane of sham- and sodium mono-iodoacetate (MIA)-treated animals. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint both before and following close intra-arterial injection of different doses of GW405833. The effect of intra-articular GW405833 on joint pain perception was determined by hindlimb incapacitance. An in vitro neuronal release assay was used to see if GW405833 caused release of an inflammatory neuropeptide ( calcitonin gene-related peptide - CGRP). RESULTS: CB(2) and TRPV1 receptors were co-localized in DRG neurons and synoviocytes in both sham- and MIA-treated animals. Local application of the GW405833 significantly reduced joint afferent firing rate by up to 31% in control knees. In OA knee joints, however, GW405833 had a pronounced sensitising effect on joint mechanoreceptors. Co-administration of GW405833 with the CB(2) receptor antagonist AM630 or pre-administration of the TRPV1 ion channel antagonist SB366791 attenuated the sensitising effect of GW405833. In the pain studies, intra-articular injection of GW405833 into OA knees augmented hindlimb incapacitance, but had no effect on pain behaviour in saline-injected control joints. GW405833 evoked increased CGRP release via a TRPV1 channel-dependent mechanism. CONCLUSION: These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.
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Authors | N Schuelert, C Zhang, A J Mogg, L M Broad, D L Hepburn, E S Nisenbaum, M P Johnson, J J McDougall |
Journal | Osteoarthritis and cartilage
(Osteoarthritis Cartilage)
Vol. 18
Issue 11
Pg. 1536-43
(Nov 2010)
ISSN: 1522-9653 [Electronic] England |
PMID | 20863899
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. |
Chemical References |
- 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole
- Cannabinoids
- Indoles
- Morpholines
- Receptor, Cannabinoid, CB2
- TRPV Cation Channels
- TRPV1 receptor
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Topics |
- Animals
- Cannabinoids
(analysis)
- Disease Models, Animal
- Electrophysiology
- Ganglia, Spinal
(metabolism)
- Immunohistochemistry
- Indoles
(pharmacology)
- Injections, Intra-Articular
- Knee Joint
(drug effects, physiology)
- Male
- Morpholines
(pharmacology)
- Nerve Fibers
(drug effects, physiology)
- Osteoarthritis, Knee
(complications, metabolism)
- Pain
(drug therapy, etiology)
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB2
(agonists)
- Synovial Membrane
(metabolism)
- TRPV Cation Channels
(analysis)
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