Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor α

Abstract

1. Peripheral inflammation is characterized by heightened pain sensitivity. This hyperalgesia is the consequence of the release of inflammatory mediators, cytokines and growth factors. A key participant is the induction of the neurotrophin nerve growth factor (NGF) by interleukin-1β (IL-1β).

2. Tumour necrosis factor α (TNFα) has been shown both to produce hyperalgesia and to upregulate IL-1β. We have now examined whether the induction of TNFα in inflammatory lesions contributes to inflammatory sensory hypersensitivity by inducing IL-1β and NGF.

3. The intraplantar injection of complete Freund's adjuvant (CFA) in adult rats produced a localized inflammation of the hindpaw with a rapid (3 h) reduction in withdrawal time in the hot plate test and in the mechanical threshold for eliciting the flexion withdrawal reflex.

4. The CFA-induced inflammation resulted in significant elevation in the levels of TNFα, IL-1β and NGF in the inflamed paw. In the case of TNFα, an elevation was detected at 3 h, rose substantially at 6 h, peaked at 24 h and remained elevated at 5 days, with similar but smaller changes in the contralateral non-inflamed hindpaw. No increase in serum TNFα was detected at 24 h post CFA injection.

5. Intraplantar recombinant murine TNFα injections produce a short-lived (3–6 h) dose-dependent (50–500 ng) increase in thermal and mechanical sensitivity which was significantly attenuated by prior administration of anti-NGF antiserum.

6. Intraplantar TNFα (100–500 ng) also elevated at 6 but not 48 h the levels of IL-1β and NGF in the hindpaw.

7. A single injection of anti-TNFα antiserum, 1 h before the CFA, at a dose sufficient to reduce the effects of a 100 ng intraplantar injection of TNFα, significantly delayed the onset of the resultant inflammatory hyperalgesia and reduced IL-1β but not NGF levels measured at 24 h.

8. The elevation of TNFα in inflammation, by virtue of its capacity to induce IL-1β and NGF, may contribute to the initiation of inflammatory hyperalgesia.

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