Supersensitivity to noradrenaline contributes to certain vascular disorders (e.g., hypertension) and chronic neuropathic pain conditions (e.g., complex regional pain syndrome). We aimed to develop a procedure for inducing adrenergic supersensitivity that could be used to investigate the role of catecholamines in these clinical conditions. In the first study, three doses of guanethidine were administered by iontophoresis to separate small patches of skin in the forearm of healthy human volunteers. Four to five hours later. the vasoconstrictor response to the adrenergic releasing agent tyramine was inhibited in a dose-dependent manner by iontophoretic pretreatment with guanethidine, indicating that guanethidine had depleted endogenous adrenergic stores. In a second study, guanethidine and saline were administered by iontophoresis four times over approximately 2 weeks at separate sites in the forearm. One to two days after the final pretreatment, vasoconstriction to the iontophoresis of a weak dose of noradrenaline was enhanced at sites pretreated with guanethidine. To investigate the effect of guanethidine pretreatment on thermal hyperalgesia. the experimental sites were sensitized to heat by the topical application of 0.6% capsaicin. Both before and after the application of capsaicin, the heat-pain threshold and heat-pain ratings to suprathreshold stimulation were similar at sites pretreated for 2 weeks with guanethidine or saline. However, after the iontophoresis of noradrenaline, thermal hyperalgesia was greater at the guanethidine-pretreated site than the saline pretreated site. These observations indicate that prolonged depletion of adrenergic stores by guanethidine induces adrenergic supersensitivity in cutaneous vessels, and that adrenergic supersensitivity enhances thermal hyperalgesia in the presence of noradrenaline.