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

Abstract

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 delta 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 delta 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.

• Authors: Caroline J Sharp, Alison J Reeve, Sue D Collins, Jo C Martindale, Scott G Summerfield, Becky S Sargent, Simon T Bate, Iain P Chessell
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 148 Issue 6 Pg. 845-52 (Jul 2006) ISSN: 0007-1188 [Print] England
• PMID: 16770326 (Publication Type: Journal Article)

Chemical References

• A-317491
• P2rx2 protein, rat
• P2rx3 protein, rat
• Phenols
• Polycyclic Compounds
• Receptors, Purinergic P2
• Receptors, Purinergic P2X2
• Receptors, Purinergic P2X3

Topics

• Animals
• Constriction, Pathologic
• Evoked Potentials (drug effects)
• Male
• Nerve Fibers, Unmyelinated (drug effects, physiology)
• Neuralgia (drug therapy, etiology, physiopathology)
• Phenols (pharmacokinetics, pharmacology)
• Polycyclic Compounds (pharmacokinetics, pharmacology)
• Rats
• Receptors, Purinergic P2 (physiology)
• Receptors, Purinergic P2X2
• Receptors, Purinergic P2X3
• Spinal Cord (drug effects, physiology)