Tumour necrosis factor α mediates transient receptor potential vanilloid 1-dependent bilateral thermal hyperalgesia with distinct peripheral roles of interleukin-1β, protein kinase C and cyclooxygenase-2 signalling

TNF alpha plays a pivotal role in rheumatoid arthritis (RA) but little is known of the mechanisms that link the inflammatory and nociceptive effects of TNF alpha . We have established a murine model of TNF alpha-induced TRPV1-dependent bilateral thermal hyperalgesia that then allowed us to identify distinct perpheral mechanisms involved in mediating TNF alpha-induced ipsilateral and contralateral hyperalgesia. Thermal hyperalgesia and inflammation were assessed inboth hindpaws following unilteral intraplantar (i.pl.) TNF alpha. The hyperalgesic mechanisms were analysed through pharmacognetic approaches involving TRPV1 mice and TRPV1 antagonists. To study the mediators downstream of TNF alpha coclooxygenase (COX) and PKC inhibitors were utilized and cytokine and prostaglandin levels assessed. The role of neutrophils was determined through use of the selectin inhibitor, fucoidan. We show that TNF alpha (10 pmol) causes thermal hyperalgesia (1-4 h) 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 focoidan attenuated hyperalgesia at 4 but not at 1 h, indicating a role in the maintenance but not in the induction of bilateral hyperalgesia. However, TNF alpha-induced IL-1 beta generation in both paws and the presence of local IL-1 beta in the contralateral paw were essential for the development of bilateral hyperalgesia. These results identify a series of peripheral events through which TNF alpha triggers and maintains bilateral inflammatory pain. this potentially allows a better understanding of mechanisms involved in TNF alpha dependent pain pathways in symmetrical diseases such as arthritis. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.