Investigation into the role of P2X_3/P2X_(2/3) receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study

摘要

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 Aδ 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 Aδ 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.