Tumour necrosis factor alpha mediates transient receptor potential vanilloid 1-dependent bilateral thermal hyperalgesia with distinct peripheral roles of interleukin-1beta, protein kinase C and cyclooxygenase-2 signalling.
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| Abstract |
TNFalpha plays a pivotal role in rheumatoid arthritis (RA) but little is known of the mechanisms that link the inflammatory and nociceptive effects of TNFalpha. We have established a murine model of TNFalpha-induced TRPV1-dependent bilateral thermal hyperalgesia that then allowed us to identify distinct peripheral mechanisms involved in mediating TNFalpha-induced ipsilateral and contralateral hyperalgesia. Thermal hyperalgesia and inflammation were assessed in both hindpaws following unilateral intraplantar (i.pl.) TNFalpha. The hyperalgesic mechanisms were analysed through pharmacogenetic approaches involving TRPV1(-/-) mice and TRPV1 antagonists. To study the mediators downstream of TNFalpha, cyclooxygenase (COX) and PKC inhibitors were utilised and cytokine and prostaglandin levels assessed. The role of neutrophils was determined through use of the selectin inhibitor, fucoidan. We show that TNFalpha (10pmol) causes thermal hyperalgesia (1-4h) in the ipsilateral inflamed and contralateral uninjured hindpaws, which is TRPV1-dependent. GF109203X, a PKC inhibitor, suppressed the hyperalgesia indicating that PKC is involved in TRPV1 sensitisation. Ipsilateral COX-2-derived prostaglandins were also crucial to the development of the bilateral hyperalgesia. The prevention of neutrophil accumulation with fucoidan attenuated hyperalgesia at 4 but not at 1h, indicating a role in the maintenance but not in the induction of bilateral hyperalgesia. However, TNFalpha-induced IL-1beta generation in both paws and the presence of local IL-1beta in the contralateral paw were essential for the development of bilateral hyperalgesia. These results identify a series of peripheral events through which TNFalpha triggers and maintains bilateral inflammatory pain. This potentially allows a better understanding of mechanisms involved in TNFalpha-dependent pain pathways in symmetrical diseases such as arthritis.
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| Authors | Fiona A Russell, Elizabeth S Fernandes, Jean-Philippe Courade, Julie E Keeble, Susan D Brain |
| Journal | Pain (Pain) Vol. 142 Issue 3 Pg. 264-274 (Apr 2009) ISSN: 1872-6623 [Electronic] United States |
| PMID | 19231080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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