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

Russell, Fiona A.; Fernandes, Elizabeth S.; Courade, Jean-Philippe; Keeble, Julie E.; Brain, Susan D.

doi:10.1016/j.pain.2009.01.021

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Volume 142, Issue 3 , Pages 264-274, April 2009

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

Fiona A. Russell
- Cardiovascular Division, Franklin-Wilkins Building, King’s College London, Waterloo Campus, 150 Stamford St., London SE1 9NH, UK
Elizabeth S. Fernandes
- Cardiovascular Division, Franklin-Wilkins Building, King’s College London, Waterloo Campus, 150 Stamford St., London SE1 9NH, UK
Jean-Philippe Courade
- IPC 351, Pain Therapeutic Area, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Julie E. Keeble
- Cardiovascular Division, Franklin-Wilkins Building, King’s College London, Waterloo Campus, 150 Stamford St., London SE1 9NH, UK
Susan D. Brain
- Cardiovascular Division, Franklin-Wilkins Building, King’s College London, Waterloo Campus, 150 Stamford St., London SE1 9NH, UK
- Corresponding author. Tel.: +44 207 848 4453; fax: +44 207 848 3743.

Received 8 August 2008; received in revised form 15 January 2009; accepted 21 January 2009. published online 24 February 2009.

Abstract

TNFα plays a pivotal role in rheumatoid arthritis (RA) but little is known of the mechanisms that link the inflammatory and nociceptive effects of TNFα. We have established a murine model of TNFα-induced TRPV1-dependent bilateral thermal hyperalgesia that then allowed us to identify distinct peripheral mechanisms involved in mediating TNFα-induced ipsilateral and contralateral hyperalgesia. Thermal hyperalgesia and inflammation were assessed in both hindpaws following unilateral intraplantar (i.pl.) TNFα. The hyperalgesic mechanisms were analysed through pharmacogenetic approaches involving TRPV1^−/− mice and TRPV1 antagonists. To study the mediators downstream of TNFα, 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 TNFα (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, TNFα-induced IL-1β generation in both paws and the presence of local IL-1β in the contralateral paw were essential for the development of bilateral hyperalgesia. These results identify a series of peripheral events through which TNFα triggers and maintains bilateral inflammatory pain. This potentially allows a better understanding of mechanisms involved in TNFα-dependent pain pathways in symmetrical diseases such as arthritis.