Recently, we have shown increases in the immunoreactivity for neuropeptide Y and tyrosine hydroxylase in the insular cortex surrounding the focal infarction after middle cerebral artery occlusion. In addition, the immunoreactivity for neuropeptide Y, leucine-enkephalin, dynorphin, and neurotensin increased ipsilaterally in the amygdala. Increases in immunoreactivity were observed in nerve terminals and fibers; changes in the neuropeptides were maximal 3 days after stroke. Local excitotoxic injury of the insular cortex also elicited similar neuropeptide changes unilaterally in the same regions. In this study, immunohistochemistry was used following intracerebroventricular injection of colchicine and stroke to determine whether blockade of axonal transport would prevent these neurochemical changes. These experiments would also locate the putative cellular origins of the neurochemicals involved. Control rats received either colchicine injection or middle cerebral artery occlusion alone. Injection of colchicine enhanced the periinfarct increase in neuropeptide Y but did not alter the increase in tyrosine hydroxylase. The neuropeptide Y increase was observed in local cortical neurons. Colchicine prevented the increases in immunoreactivity for the neuropeptides in the amygdala on the side of stroke, although there were small perikarya that showed immunoreactivity for these neuropeptides within the amygdala on both sides. We conclude that local cortical neurons are responsible for the increase in neuropeptide Y in the periinfarct region, that the cortical increase in tyrosine hydroxylase is not dependent on fast axonal transport, and that axonal transport of signals from the insular cortex to the amygdala is critical in mediating the amygdalar neuropeptide changes seen after stroke.