Functional up-regulation of P2X3 receptors in the chronically compressed dorsal root ganglion

P2X receptors on dorsal root ganglion (DRG) neurons have been strongly implicated in pathological nociception after peripheral nerve injuries or inflammation. However, nothing is known of a role for purinergic receptors in neuropathic pain produced by a chronic compression of DRG (CCD) - an injury that may accompany an intraforaminal stenosis, a laterally herniated disc or other disorders of the spine leading to radicular pain. In a rat model of DRG compression, hyperexcitable neurons retain functioning axonal connections with their peripheral targets. It is unknown whether such hyperexcitability might enhance chemically mediated nociceptive stimulation of the skin. In this study, CCD facilitated the nocifensive behavior and mechanical hyperalgesia-induced by the P2X3 agonist, α,β-methylene ATP (α,β-meATP). An injection of α,β-meATP into the hind paw of CCD rats resulted in a significantly greater decrease in the mean threshold to von Frey stimuli and a greater duration of paw lifts than in sham-operated control rats. CCD also increased the levels of P2X3 receptor protein and the number of P2X3 immunoreactive, small diameter DRG neurons in the compressed ganglion. P2X3 receptors were co-labeled with the isolectin IB4, consistent with a role in nociception. In addition, a α,β-meATP induced significantly larger fast-inactivating currents in CCD- than in sham-operated acutely dissociated DRG neurons. These currents were accompanied by the generation of action potentials - but only in the CCD neurons. U0126, a specific inhibitor of the MEK1/2, greatly down-regulated the enhanced current. Taken together, these observations suggest that enhanced purinergic responses after CCD are mediated by P2X3 receptors.