The effects of the P2X2/3 antagonist A-317491 (Jarvis et al., 2002) were assessed on the response of dorsal horn neurones in chronic constriction injury (CCI) operated and control rats. Single unit recordings were made using multi-electrode arrays from second order dorsal horn neurones in the spinal cord of 26 saffan-anaesthetized male Random Hooded rats (150-270g), at depths of 1036.9 ± 40.5μm from the surface of the spinal cord. In CCI-operated animals, electrophysiology was carried out 15-29 days post-surgery. Baseline responses were evoked by electrical stimulation (20 pulses, 0.5Hz; 2ms, 6mA) and mechanical stimulation (9 von Frey Filaments, force 1-165g, 10 second application per filament) of the hind paw. A-317491, or vehicle (1% DMSO, 66% PEG200, 33% saline), was administered i.v. (1, 3 and 10mg/kg). Electrical and mechanical stimulation were applied every 15 min for 45 min following each dose. Counts of action potentials per stimulus were analysed by Student′s unpaired t-test. Data is presented as mean ± sem. A P value of <0.05 was taken as significant. A-317491 had no effect on the Aβ-fibre-evoked responses in both control and CCI operated rats (naive n=30, 6 rats; CCI n=30, 6 rats). The Aδ-fibre-evoked responses were significantly inhibited compared to vehicle control at 3 (P<0.05) and 10mg/kg (P<0.01) in both naive (n=30) and CCI (n=28) rats. In naive animals, the C-fibre-evoked response was inhibited by 24.2 ± 8.6% at 10mg/kg (n=28; P<0.05 vs. time-matched vehicle controls); in CCI-operated rats, the C-fibre evoked response to electrical stimulation following A-317491 was significantly inhibited at both 3 (51.3 ± 7.9%) and 10mg/kg (74.0 ± 4.6%; P<0.001 vs. vehicle control; n=18), and wind-up was significantly reduced by 39.2 ± 19.3% at 3mg/kg (P<0.05 vs. vehicle control, n=12). Spontaneous activity was significantly inhibited by 25.9 ± 10.3% and 35.6 ± 9.4% at 3 and 10mg/kg respectively in CCI rats (P<0.05 vs. vehicle control, n=30). There was no inhibitory effect on responses to mechanical stimulation in either control or neuropathic animals. These data indicate an increased involvement of the P2X2/3 receptor following chronic constriction injury of the sciatic nerve, thus suggesting a role for P2X2/3 receptors in the modulation of neuropathic pain.