Calcitonin gene-related peptide-alpha (CGRP alpha) is a putative neurotransmitter in the brain and in peripheral tissues. Quantitative receptor autoradiography was used to localize and quantify the distribution of specific binding sites for radiolabeled human CGRP alpha in the canine gastrointestinal tract. The canine gastrointestinal tract was chosen as a model since it is similar in both size and structure to the human gastrointestinal tract. In the stomach CGRP alpha binding sites were localized to smooth muscle cells in the muscularis mucosa and muscularis externa, the smooth muscle and endothelium of medium and small arteries, neurons in the myenteric plexus, mucosal epithelial cells and the germinal centers of lymph nodules. In the intestines, the prominent cells types expressing CGRP alpha receptors were myenteric neurons and the germinal centers of lymph nodules. Since previous studies have demonstrated that CGRP-containing sensory neurons innervate the muscularis externa in the stomach and since CGRP alpha receptors are expressed by smooth muscle cells in the muscularis externa, these results suggest that sensory neurons may directly regulate gastric motility by releasing CGRP. In correlation with previous physiological data, the present study suggests that CGRP is involved in the regulation of a variety of gastrointestinal functions including gastric motility, mucosal ion transport, hemodynamics, digestive enzyme secretion, neuronal excitability, and the inflammatory and immune response.