Macroglial cells express ionotropic glutamate receptors. In the adult optic nerve, reverse transcription-PCR showed that the native receptors are formed by subunits belonging to the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate classes. Because activation of AMPA and kainate receptors can be toxic to oligodendrocytes in vitro, I examined the nature of the damage caused by kainate, an agonist of both receptor classes, applied directly onto the optic nerve. Acute infusion or chronic slow delivery of the agonist caused massive nerve damage that was more extensive in the latter. Interestingly, chronic delivery also produced inflammation and demyelination in well circumscribed areas of the nerve, together with other pathological features that closely resemble those observed in multiple sclerosis patients. Acute and chronic kainate lesions were both prevented by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. However, GYKI53655, a specific AMPA receptor antagonist, did not significantly reduce the size of the lesion, suggesting that the kainate toxicity was mainly mediated through activation of kainate-preferring glutamate receptors. These observations suggest that alterations in glutamate signaling may be detrimental to oligodendrocytes and may be involved in the pathogenesis of multiple sclerosis and other demyelinating diseases.