Sg. Hamilton et al., ATP in human skin elicits a dose-related pain response which is potentiated under conditions of hyperalgesia, BRAIN, 123, 2000, pp. 1238-1246
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.