BACKGROUND & AIMS: Large distentions reliably evoke sensation from the noninflamed, nonischemic bowel, but the specialized afferent axonal structures responsible have not been morphologically identified. We investigated whether their transduction sites are located on major blood vessels close to and within the gut wall. METHODS: In vitro extracellular recordings were made from mesenteric nerve trunks in guinea pig ileum, combined with rapid axonal dye filling and immunohistochemical analysis of nerve trunks. RESULTS: Recordings revealed sensory fibers with focal mechanosensitive sites in the mesenteries that could be activated by von Frey hairs and by stretch. Dye filling revealed varicose branching sensory axons on mesenteric blood vessels but no other anatomically specialized structures in mesenteric membranes or the serosa. Large-amplitude stretch and von Frey hairs also activated sensory endings within the gut wall itself but only if the submucosa was present; mechanotransduction sites in the serosa or outer muscle layers were sparse. Mechanosensitive sites in submucosa were exclusively associated with submucosal blood vessels. Submucosal endings had significantly higher thresholds to stretch than specialized low-threshold mechanoreceptors characterized previously in the rectum (P