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Spinal cathepsin S and fractalkine contribute to chronic pain in collagen induced arthritis.

Authors: Clark, AK  Grist, J  Al-Kashi, A  Perretti, M  Malcangio, M 
Citation: Clark AK, etal., Arthritis Rheum. 2011 Dec 27. doi: 10.1002/art.34351.
Pubmed: (View Article at PubMed) PMID:22213084
DOI: Full-text: DOI:10.1002/art.34351

OBJECTIVE: The induction of Rheumatoid Arthritis (RA) by active and passive immunization of mice results in the development of pain at the same time as swelling and inflammation, with both peripheral and central sensitization contributing to joint pain. Here we examined the development of pain in the rat Collagen Induced Arthritis (CIA) model and evaluated the contribution of neuro-immune interactions to established arthritis pain. METHODS: Mechanical hypersensitivity was assessed in female Lewis rats before and up to 18 days after induction of CIA by immunization with type II collagen. The effect of selective inhibitors of microglia were then evaluated by prolonged intrathecal delivery of a Cathepsin S (CatS) inhibitor and a Fractalkine (FKN) neutralizing antibody, from days 11 to 18 following immunization. RESULTS: CIA rats developed significant mechanical hypersensitivity which started on day 9, before the onset of clinical scores. Mechanical hypersensitivity peaked with the severity of the disease, when significant microglial and astrocytic response, alongside T-cell infiltration were observed in the spinal cord. Intrathecal delivery of microglial inhibitors, a CatS inhibitor or FKN neutralizing antibody, attenuated mechanical hypersensitivity and spinal microglial response in CIA rats. CONCLUSION: The inhibition of microglial targets by centrally-penetrant CatS inhibitors and FKN/CX3CR1 receptor antagonists represents a potential therapeutic avenue for the treatment of pain in RA.


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RGD Object Information
RGD ID: 5686870
Created: 2012-01-30
Species: All species
Last Modified: 2012-01-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.