Focal injury to peripheral nerve that leaves it intact can produce a painful hyperesthetic state referred to as neuropathic pain or causalgia. The mechanisms by which an acutely painful event can progress toward chronic pain are not known but there are certainly structural, physiologic, and biochemical changes in nerve that influence dorsal root ganglia and spinal cord neurons. The recent development of a non-neuroma rodent model of hyperesthesia is a major advance in pain research that can be used to elucidate the mechanisms of the hyperesthetic state. The model consists of the placement of loose ligatures around rat sciatic nerve and behavioral testing of hyperesthesia to heat or pressure applied to the affected foot pad. The hyperesthesia develops within 2 days, peaks at 5-7 days and resolves within one month. Preliminary studies reveal reductions in nerve blood flow associated with endoneurial edema and nerve fiber injury to small myelinated fibers. C fibers appear not to be severely affected, a finding consistent with our observation that capsaicin treatment does not affect the hyperesthesia to heat stimuli. Our preliminary work has also revealed that several different focal nerve injuries produce hyperesthesia to heat and mechanical stimuli including a pure ischemia model in which the epineurial circulation is removed from the surface of the nerve. The similarities in pathophysiology and in histological findings suggest a common pathogenic mechanism in which increased endoneurial fluid pressure and decreased nerve blood flow may be critical factors in the development of the hyperesthesia state. These experiments have also shown that blockade of retrograde axonal transport eliminates the hyperesthetic response to nerve compression and that the hyperesthetic state can be modified by pharmacological inhibition or excitation of different receptors on spinal cord neurons. Our working hypothesis is that focal nerve lesions resulting in increased endoneurial fluid pressure with local nerve ischemia cause morphological changes in nerve, increased peripheral afferent sensitivity, and trophic changes in spinal pathways that produce the hyperesthetic state. In this study we will explore these hypothesized mechanisms in five clinically relevant models of neuropathic pain, using physiological, behavioral, pharmacological, and histological methods. The results of these basic scientific studies should provide the rationale for pharmacological intervention in humans with neuropathic pain.
| Gaultier, Alban; Arandjelovic, Sanja; Li, Xiaoqing et al. (2008) A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents. J Clin Invest 118:161-72 |
| Shubayev, Veronica I; Branemark, Rickard; Steinauer, Joanne et al. (2004) Titanium implants induce expression of matrix metalloproteinases in bone during osseointegration. J Rehabil Res Dev 41:757-66 |
| Johnson, Kristen; Svensson, Camilla I; Etten, Deborah Van et al. (2004) Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs. Arthritis Rheum 50:1216-25 |
| Hua, X Y; Chen, P; Fox, A et al. (1996) Involvement of cytokines in lipopolysaccharide-induced facilitation of CGRP release from capsaicin-sensitive nerves in the trachea: studies with interleukin-1beta and tumor necrosis factor-alpha. J Neurosci 16:4742-8 |
