ATP in human skin elicits a dose-related pain response which is potentiated under conditions of hyperalgesia

Despite the considerable interest in the possibility that ATP may function as a peripheral pain mediator, there has been little quantitative study of the pain-producing effects of ATP in humans. Here we have used iontophoresi s to deliver ATP to the forearm skin of volunteers who rated the magnitude of the evoked pain on a visual analogue scale. ATP consistently produced a modest burning pain, which began within 20 s of starting iontophoresis and was maintained for several minutes. Persistent iontophoresis of ATP led to desensitization within 12 min but recovery from this was almost complete 1 h later. Different doses of ATP were delivered using different iontophoreti c driving currents. Iontophoresis of ATP produced a higher pain rating than saline, indicating that the pain was specifically caused by ATP The averag e pain rating for ATP, but not saline, increased with increasing current. U sing an 0.8 mA current, subjects reported pain averaging 27.7 +/- 2.8 (maxi mum possible = 100). Iontophoresis of ATP caused an increase in blood flow, as assessed using a laser Doppler flow meter. The increase in blood how wa s significantly greater using ATP than saline in both the iontophoresed ski n (P < 0.01) and in the surrounding skin, 3 mm outside the iontophoresed ar ea (P < 0.05). The pain produced by ATP was dependent on capsaicin-sensitiv e sensory neurons, since in skin treated repeatedly with topical capsaicin pain was reduced to less than 25% of that elicited on normal skin (2.1 +/- 0.4 compared with 9.3 +/- 1.5 on normal skin). Conversely, the pain-produci ng effects of ATP were greatly potentiated in several models of hyperalgesi a. Thus, with acute capsaicin treatment when subjects exhibited touch-evoke d hyperalgesia but no ongoing pain, there was a threefold increase in the a verage pain rating during ATP iontophoresis (22.7 +/- 3.1) compared with pr e-capsaicin treatment (7.8 +/- 2.6). Moreover, ATP iontophoresed into skin 24 h after solar simulated radiation (2 x minimal erythymic dose) resulted in double the pain rating of normal skin, increasing from 15.3 +/- 4.1 to 3 2.7 +/- 4.1. The pain response to saline was not significantly altered afte r UV irradiation at any time-point studied. We conclude that ATP produces p ain by activating capsaicin-sensitive nociceptive afferents when applied to skin. The possibility that ATP activates nociceptors indirectly via its de gradation products cannot be ruled out. The effects of ATP are dose-depende nt and responses desensitize only slowly. In inflammatory conditions, ATP m ay be a potent activator of nociceptors and an endogenous mediator of pain.