Investigation into the role of P2X 3 /P2X 2/3 receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study

1 Two P2X 3 /P2X 2/3 receptor antagonists with different potencies were profiled electrophysiologically in a rat model of nerve injury. 2 A‐317491 has poor CNS penetrance (blood : brain, 1 : <0.05), and was therefore administered intravenously in chronic constriction injury (CCI)‐ and sham‐operated rats to study the involvement of P2X 3 subunit‐containing receptors in the periphery in neuropathic pain. A‐317491 and Compound A were administered topically to the spinal cord to investigate the central contribution. 3 There were no significant inhibitory effects of A‐317491 intravenous (i.v.) seen in sham‐operated animals compared to vehicle controls. In CCI‐operated animals, there were significant inhibitory effects of 3 mg kg −1 A‐317491 i.v. on C fibre‐evoked responses, and with 10 mg kg −1 A‐317491 i.v. on A δ and C fibre‐evoked responses. No significant effects of A‐317491 were observed after topical application to the spinal cord. In contrast, when Compound A was administered spinally in CCI animals, there was a decrease in A δ and C fibre‐evoked responses, and wind up. 4 These changes indicate that A‐317491 has a selective effect on neuronal responses in CCI animals compared to sham, demonstrating an increased involvement of P2X 3 /P2X 2/3 receptors in sensory signalling following nerve injury. In addition, the more potent antagonist Compound A was effective spinally, unmasking a potential central role of P2X 3 /P2X 2/3 receptors at this site post nerve injury. These data support a role for P2X 3 /P2X 2/3 antagonists in the modulation of neuropathic pain.British Journal of Pharmacology (2006) 148 , 845–852. doi: 10.1038/sj.bjp.0706790