Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

Previously we reported that the cuff model of peripheral neuropathy, in which a 2 man polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague-Dawley rats 2-6 weeks after Cuff implantation we found that elevated discharge rate of single lumbar (L3-4) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the Cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons similar to 40% (n=18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by similar to 60% (n=19; P<0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. Furthermore. in cuff-implanted rats WDR neurons (n=5) responded to mechanical cutaneous stimulation with all exaggerated afterdischarge which was reversed entirely by proximal nerve conduction block. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synaptically-mediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from Multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy. (C) 2008 Elsevier Inc. All rights reserved.