Behavioral and histological effects of endoneurial administration of nerve growth factor: Possible implications in neuropathic pain

Animal models of neuropathic pain involving incomplete nerve injury result in causalgia-like symptoms, including thermal hyperalgesia and mechanical allodynia. Although current evidence links the overexpression of nerve growth factor (NGF) to peripheral neuropathic pain, the direct effect of NGF inside a nerve has not been evaluated yet. The purpose of this study was to investigate whether a single, low-dose (1-30 ng), endoneurial administration of NGF reproduces behavioral consequences of a partial nerve injury and to analyze the changes on myelinated fibers induced by NGF. Significant thermal hyperalgesia appeared on days 3 and 5 post-injection of NGF. NGF did not evoke mechanical allodynia at any of the assayed doses. On day 1, NGF induced focal degeneration and demyelination of fibers at the site of injection. Starting on day 5 clusters of small axons enclosed within one Schwann cell and associated with fibroblasts were observed, revealing axonal sprouting. Both thermal hyperalgesia and demyelination-sprouting processes induced by NGF were dose-dependent (1-30 ng) and the time course of both effects was similar. The injection of vehicle did not produce any behavioral or histological effect. These results suggest that overexpression of NGF may induce endoneurial sprouting and triggers the development of thermal hyperalgesia, but not mechanical allodynia, in peripheral neuropathic pain states. © 2004 Elsevier B.V. All rights reserved.