This study aimed to investigate whether the endogenous release of noradrenaline would influence hyperalgesia to heat in skin sensitized by the topical application of 0.6% capsaicin. To release endogenous stores of noradrenaline, tyramine was introduced transcutaneously by iontophoresis into the volar aspect of the forearm of 19 healthy subjects. The heat pain threshold fell from 43.7 +/- 3.8 degrees C to 41.3 +/- 4.0 degrees C after the iontophoresis of tyramine in capsaicin-treated skin (P < 0.001), but did not change significantly after tyramine iontophoresis in untreated skin. The heat pain threshold decreased by 0.5 +/- 2.2 degrees C after the iontophoresis of saline, indicating that nonspecific factors did not fully account for the hyperalgesic effect of tyramine. Iontophoresis of the alpha-adrenergic antagonist, phenoxybenzamine, after the capsaicin treatment blocked the hyperalgesic effect of tyramine, suggesting that thermal hyperalgesia was mediated by alpha-adrenoceptors. However, iontophoresis of phenoxybenzamine before the capsaicin treatment was ineffective. These findings suggest that release of endogenous stores of noradrenaline increases sensitivity to heat in skin sensitized by capsaicin. In addition, neurogenic inflammation appears to increase access to the receptors that facilitate thermal hyperalgesia.