A chronic constriction injury to the sciatic nerve of rat produces a painful peripheral neuropathy whose symptoms resemble those of human disorders. In particular, the rats have abnormal pain sensations including hyperalgesia, allodynia and, perhaps, spontaneous pain (or dysesthesias). Immunocytochemical analyses show that the damaged sciatic nerve's primary afferent neurons cease to synthesize their normal complement of neuropeptides (e.g., substance P). We have found that primary afferent neurons of all size classes begin to synthesize neuropeptide Y (NPY) after nerve injury. NPY is not detectable in the normal case. There are also changes in the binding characteristics of receptors on spinal cord dorsal horn neurons for substances released by primary afferents. Substance P binding is decreased in laminae I-II and V, although there are no changes in binding for calcitonin gene-related peptide. Binding at the channel site of the N-methyl-D-aspartate type of glutamate receptor is increased in laminae I-II by the second day of the neuropathic syndrome but decreased by day 10. Electrophysiological studies show that there is a significant decrease in the magnitude of the dorsal root potential (DRP) ipsilateral to the nerve injury on post-injury day 5 and 10. Decreases in the DRP indicate a decrease in the presynaptic inhibition that normally modulates the effects of primary afferent input to the dorsal horn. Single cell recordings from spinal cord dorsal horn neurons ipsilateral to the neuropathy have revealed several abnormalities at 10 days post-injury, which is near the time of maximal severity for he abnormal pain sensations. Unlike the normal case, about half of the neurons have no detectable cutaneous receptive field RF, significantly fewer respond to innocuous mechanical stimulation. Nearly half of the cells respond to gently tapping the region of the nerve injury; in the normal case tapping the nerve does not evoke any response. These results suggest that pharmacotherapy for neuropathic pain cannot be predicated exclusively on our knowledge of the dorsal horn's normal synaptic transmission because the neuropathy evokes profound changes in the synthesis and binding of several neurotransmitters and neuromodulators. The electrophysiological results suggest that the neuropathy is associated with markedly altered somatosensory processing in the spinal cord gray matter.
