The pathogenesis of experimental toxic and metabolic neuropathies will be investigated using electron probe x-ray microanalysis, radioautography, electrophysiology, measurements of endoneurial pressure, teased nerve fiber studies, electron microscopic histochemistry and morphometry. The objectives are to understand the mechanisms producing diabetic neuropathy in an alloxan model that reproduces each of the various lesions comprising human diabetic neuropathy. The questions to be resolved concern the type of neuropathy; distal axonopathy vs. demyelinating, the role of suspected permeability changes, and the origin and composition of abnormal deposits in axons, Schwann cells and vessel walls. Other neuropathies will be studied for comparative purposes including lead, mercury and thallium neuropathies as well as steroid, n-hexane and hexachlorophene neuropathies. Key questions concern endoneurial pressure alterations, changes in vascular permeability, precise localization of toxic metals and inter-relationship between axonal and Schwann cell injuries. We hope to apply the understanding gained and the techniques developed to relevant human neuropathies of which diabetic neuropathy is the most common.