Fig. 1. Light micrographs of rat sciatic nerve after topical application of 1.25 mg amitriptyline in a 0.2-ml volume of saline vehicle immediately adjacent to the nerve. The perineurium was not damaged when the drug was applied, and the vehicle does not cause nerve damage. One day after application of the drug, significant pathologic changes were noted, including extensive edema in the subperineurial and perivascular (*) regions. Axons were darkly stained (arrow ), indicating the beginning process of Wallerian degeneration. Wallerian degeneration is a progressive pathologic process, so by day 3, there were many swollen axons with pale-staining axoplasm and progressive edema. Schwann cells (arrow ) were also activated at this time point, and fibroblasts could be seen in the endoneurial space. By day 7, there was evidence of continuing Wallerian degeneration, which peaked at the injury site during this time with disintegration and phagocytosis of myelin sheaths and axon debris. Some axons were devoid of myelin, and these are also phagocytosed by hematogenous macrophages entering the endoneurial space. The stain used in these sections is methylene blue, azure II. Lipophilic structures stain dark blue or black, and collagen stains red. Note the perineurium (a collagen structure) in the lower right of the day 7 micrograph that is thickened by a reaction to the amitriptyline placed in the adjacent epineurial space. Primary magnification: objective ×20, phototube ×16.