Intra-articular ampa/kainate glutamate receptor antagonists alleviate inflammation and pain in rat antigen induced arthritis
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1
Cardiff University, Pathophysiology and Repair Division, United Kingdom
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2
Cardiff University, Rheumatology Research Laboratory, United Kingdom
Concentrations of the neurotransmitter glutamate are greatly increased in synovial fluids of RA and OA patients, where they correlate with cytokine concentrations. Previously, we demonstrated that human synoviocytes express functional glutamate receptors (GluRs) and that activation of NMDA GluRs decreases proMMP2 expression, whilst activation of kainate GluRs increases IL-6 release (1). High glutamate concentrations in the joint cause arthritic pain which is alleviated by intra-articular injection of GluR antagonists. However, the effects of such inhibitors on arthritis progression via activation of GluRs expressed on other joint tissues have not been considered. We are investigating the hypothesis that specific GluR subunits in the arthritic synovium mediate proinflammatory, degradative and proliferative responses, and may be therapeutically targeted to reduce disease progression and pain.{BR}Using the mono-articular antigen induced arthritis (AIA) rat model, we used intra-articular injection of NBQX to inhibit AMPA/kainate receptors at the time of arthritis induction, prior to peak IL-6 levels. Over a 21 day period, we measured knee swelling and gait patterns from AIA, AIA + NBQX and normal rats (n=6 for each group). A combination of motion analysis, using Qualisys Pro-Reflex MCU-1000 cameras, and footprint characteristics revealed limping and abnormal movements as an indirect measure of pain. On day 21, joint tissues were taken for reverse transcription PCR assays, immunohistochemistry and histology to examine GluR expression and joint destruction. {BR}Significantly less knee swelling (P<0.0006) was found in NBQX treated rats compared to AIA rats. Using a footprint severity scoring system on a scale of 0 (entire footprint) to 4 (no footprint at all), NBQX treated rats displayed significantly less pain related behaviour during the initial flare of arthritis compared to AIA rats (P=0.0002). Ionotropic and metabotropic GluR mRNA was differentially expressed in cartilage, synovium, meniscus, fat pad, patella, femoral head and shaft of rat knees. {BR}We have shown that intra-articular NBQX treatment alleviates inflammation and pain in arthritis in vivo and that GluRs are differentially expressed in knee joint tissues. This supports our hypothesis that kainate GluRs may be specifically targeted to ease pain, inflammation and pathology in arthritis. {BR}(1) Flood et al. (2007) Arthritis Rheum, 56: 2523-2534.
Keywords:
Bones,
Bone Research
Conference:
2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society, Cambridge, United Kingdom, 27 Jun - 29 Jun, 2011.
Presentation Type:
Oral
Topic:
Abstracts
Citation:
Bonnet
C,
Williams
A and
Mason
D
(2011). Intra-articular ampa/kainate glutamate receptor antagonists alleviate inflammation and pain in rat antigen induced arthritis.
Front. Endocrinol.
Conference Abstract:
2011 joint meeting of the Bone Research Society & the British Orthopaedic Research Society.
doi: 10.3389/conf.fendo.2011.02.00006
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Received:
30 Sep 2011;
Published Online:
30 Sep 2011.
*
Correspondence:
Dr. C Bonnet, Cardiff University, Pathophysiology and Repair Division, Cardiff, CF10 3AX, United Kingdom, bonnetcs@cf.ac.uk