An adrenergic mechanism is thought to contribute to pain in conditions that sometimes develop during chronic inflammation and after nerve or tissue injury. There is some doubt, however, about whether adrenergic activity influences nociception in acute inflammation. To investigate this issue, the noncompetitive alpha-(alpha) adrenergic antagonist phenoxybenzamine was introduced by iontophoresis into the skin of 16 healthy volunteers either before or after the topical application of capsaicin. When applied before capsaicin, phenoxybenzamine increased thermal hyperalgesia at normal ambient temperatures and during body warming. These findings suggest that phenoxybenzamine blocked an analgesic mechanism when applied before the onset of inflammation. However, this effect disappeared during body cooling. When applied after capsaicin, phenoxybenzamine inhibited thermal hyperalgesia at normal ambient temperatures, and during body warming and cooling. Thus, phenoxybenzamine blocked a hyperalgesic mechanism when applied after the onset of inflammation. It was concluded that the presence of inflammation influences the nociceptive effect of alpha-adrenergic blockage, possibly by increasing access to excitatory adrenergic receptors on nociceptive afferents. An excitatory adrenergic influence on nociception may overcome an inhibitory adrenergic influence during inflammation.