Patients with acute herpes zoster, and to a lesser extent post-herpetic neuralgia (PHN), have been reported to respond to local anesthetic blockade of the sympathetic nervous system. In animal models of nerve injury, local injection of adrenergic agonists after nerve injury, but not before, excites nociceptors. In some patients with chronic neuropathic pain, local application of norepinephrine evokes pain. In 15 subjects with PHN, the role of adrenergic receptors in PHN pain was assessed in a two-session double blind study comparing the response to cutaneous infiltration of epinephrine or phenylephrine (30 micrograms in 3 ml) with the response to normal saline in both the painfully affected skin and mirror-image normal skin. Two adjacent sites were studied on each side of the body, one site for injection and the other for measuring sensory effects of the injection. In the morning part of each session, mirror-image normal skin was injected. In the afternoon portion of each session, skin in the most painful area affected by PHN was injected. Injection of saline or the adrenergic agonist in normal skin produced mild and transient pain without development of allodynia and without affecting overall PHN pain intensity. In PHN skin, injection of saline and the adrenergic agonist produced an equivalent degree of transient pain that was slightly greater than injection into mirror-image normal skin. After injection of the adrenergic agonist into PHN skin, both overall PHN pain and allodynia severity were significantly greater than after saline injection, peaking at 10-15 min post-injection. Even when PHN has been present for years, adrenergic receptor stimulation in PHN skin increases pain, most likely through direct activation of C-nociceptors in the painful skin. Increased allodynia is most likely mediated centrally and driven by the increase in C-nociceptor input.