Nerve growth factor (NGF), in addition to acting as a growth factor for nerves that include capsaicin-sensitive fibres, is a potent mediator of inflammatory hyperalgesia. Work in this laboratory has demonstrated that the thermal hyperalgesia mediated by NGF is neutrophil-dependent (Bennett et al. 1998). These studies have now been extended to investigate the mechanisms via which neutrophils accumulate in response to NGF in the skin (Foster et al. 2003). Rats were injected either intraplantarly or intradermally with test agents under short term anaesthesia (2% isofluorane). At the end of the experiments myeloperoxide was obtained from the skin of humanely killed rats and assayed as an index of neutrophil accumulation. The mechanism by which NGF (40 pmol/site) induces neutrophil accumulation in the rat is protein synthesis-dependent in that actinomycin D (1μmol/site) inhibited neutrophil accumulation measured over 5h. This indicates that the neutrophil accumulation is secondary to upregulation of endothelial cell adhesion molecules. Intracellular adhesion molecule-1 (ICAM-1) plays an important role in neutrophil emigration. Thermal hyperalgesia was measured by the Hargreaves method where the reaction time to an automated heat source was determined. A monoclonal antibody to endothelial-derived ICAM-1 inhibited thermal hyperalgesia, in addition to neutrophil accumulation. In separate experiments, a similar response of neutrophil accumulation and thermal hyperalgesia was observed in response to intraplantar NGF in both wildtype and tachykinin NK1 receptor knockout mice, indicative that the NK1 receptor is neither involved in the neutrophil accumulation nor the hyperalgesic response. The results provide evidence that an important step in NGF-induced hyperalgesia is the activation of endothelial cells to express adhesion molecules that then act to promote neutrophil accumulation and in turn thermal hyperalgesia. The relevance of this to inflammatory hyperalgesia in disease is not yet known.