Neuropathic pain occurs in a variety of peripheral nerve diseases, including diabetic and HI V-associated neuropathies, as well as nerve injuries. The mechanisms underlying neuropathic pain remain incompletely understood. Animal models of neuropathic pain based on partial nerve injuries have provided important insights. Using a modification of the spinal nerve ligation (SNL) model of Chung in which the rat L5 mixed spinal root was ligated and transected, we have confirmed the development of mechanical and thermal hyperalgesia in the hindpaw. Three observations from our labs using this modified SNL lesion underlie the proposed studies: 1) The hyperalgesia is not reversed by an L5 dorsal rhizotomy. 2) Spontaneous activity develops in intact C fibers of the adjacent, uninjured L4 dorsal root. 3) There is prominent remodeling of the Remak bundles containing surviving C fibers in the sciatic nerve and its distal branches. These observations are most economically explained by the hypothesis that Wallerian degeneration in the distal nerve plays an important role in neuropathic pain. An attractive possibility is that the Remak bundles of the distal sciatic system frequently contain C fibers from more than one spinal root, so that when the L5 root is transected many Remak bundles are only partially denervated. The Schwann cells of these Remak bundles are postulated to respond as though they were wholly denervated, with production of excessive amounts of growth factors (e.g., NGF) and cytokines (e.g., TNF-alpha). The increased NGF is taken up by the surviving (L4) C fibers of that Remak bundle and transported back to the nerve cell bodies, where it induces expression of proteins (e.g., sodium channels) associated with increased excitability. This sequence could contribute to hyperalgesia as well as central sensitization. These processes could be especially relevant to slowly progressive degenerative neuropathies involving small nerve fibers, many of which have spontaneous pain and hyperalgesia. The proposed studies are centered around a three-way analysis of hyperalgesia, morphological changes in the distal nerve including Remak bundle remodeling, and spontaneous activity in C fibers of the adjacent, uninjured IA root. A set of lesions to the L5 spinal root system was chosen to dissect out the underlying mechanisms: 1) L5 dorsal root ganglionectomy to produce a selective lesion of primary afferents, 2) capsaicin application to the L5 mixed spinal root to produce a selective lesion of nociceptive afferents, 3) L5 ventral rhizotomy to produce a selective lesion of myelinated motor efferents, and 4) bilateral lumbar sympathectomy to produce a selective lesion of sympathetic efferents. We will also investigate if molecular changes in or relevant to the remodeled Remak bundles account for the spontaneous activity in the L4 C fibers. This research should provide additional insights into the mechanisms underlying neuropathic pain.
