We examined the relationship between hyperalgesia and degranulation of mast cells in rats following treatment with nerve growth factor (NGF) and inflammatory mediators. Intracutaneous injection to the rat's paw of NGF (50-5000 ng, 50 microl) evoked dose-dependent thermal hyperalgesia as measured by paw withdrawal latency to noxious heat. Even more intense hyperalgesia was induced by an inflammatory mediators soup' containing BK, 5HT, PGE2 and histamine (10 microM). Counts of mast cells in the dermis were performed on coded slides under x 1000 magnification after fixation in Carnoy's solution and staining with toluidine blue. After injection of three different concentrations of NGF (50, 500, 5000 ng in 50 microl), the proportion of mast cells that were degranulated was significantly higher (P < 0.001) than after saline injection. No significant differences were found among the three concentrations of NGF. The effect of inflammatory soup on the proportion of degranulated mast cells was similar to that of NGF. These results indicate that NGF activates cutaneous mast cells and stimulates the release of inflammatory tissue mediators in the acute phase of NGF-induced hyperalgesia in the rat's paw. However, the finding that degranulation was not dose-dependent indicates that other mechanisms, independent of mast cells, are probably operating in response to NGF.