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

Abstract

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