Nerve lesions and the generation of pain.

This review addresses the issue of how axotomy of peripheral nerve fibers leads to pain and hyperalgesia. The point of axotomy (the nerve injury site), the dorsal root ganglia, and the dorsal horn of the spinal cord are candidate sites for generation of the pain signal that is likely to be critical for maintaining the neuropathic pain state. This review considers neuropathic pain from a "systems" perspective, tracing concepts of neuropathic pain from the work of Henry Head to the present. Surprisingly, the nerve injury site and the dorsal root ganglion belonging to a transected spinal nerve do not give rise to spontaneous activity in putative C-fiber nociceptors. The intact nociceptor belonging to adjacent uninjured spinal nerves, however, does acquire abnormal spontaneous activity and a chemical sensitivity to catechols. It is suggested that partially denervated tissues in the nerve, skin, and other locations may release substances that, in turn, sensitize the intact nociceptors. These abnormalities in the intact nociceptor, which arise in the context of Wallerian degeneration, probably play a role in creating or maintaining the abnormal pain state. These considerations probably also apply to the understanding of pain arising in other neuropathies. The findings relative to the "intact" nociceptor provide a rationale by which to understand how therapies distal to the nerve injury site may diminish pain.