S1800 Characterization of a Reproducible Gastric Pain Model Using Oral Capsaicin Titration: A Placebo-Controlled, Double-Blind Study

Abstract

Background and aims. Extrinsic sensory neurons to the gut mediate both sensation and gastrointestinal reflexes important for gut function in health and disease. Different classes of afferents which convey various types of information about the gut wall and contents can be reliably identified by characterizing the morphology of their physiologically-identified peripheral axons. “Muscular mucosal” afferents have been identified on the basis of their responses to both colorectal distension and to light mucosal stroking. Methods. Extracellular recording from colonic nerves in isolated preparations of guinea pig distal colon were combined with biotinamide filling In Vitro. Results. When all layers of the colon were present in the preparation, a class of afferents could be strongly activated by light von Frey hairs (0.1 10 mN, maximum instantaneous firing: 83+/-18 Hz, n=6). The same units could also be activated by circumferential distension with constant loads (10 100mN) evoking firing of 52+/-30 Hz (n=10). Both types of activity were preserved in preparations where the muscularis externa had been removed prior to recording, suggesting that transduction sites were located in the submucosa or mucosa. Surprisingly, afferents of this class also fired in concert with spontaneous contractions of preparations, measured under isotonic conditions. The action potentials of these units were significantly larger and of shorter duration than action potentials from mechanonociceptors axons recorded from the same nerve trunks (341+/-146 vs 139+/-34μV P<0.01, 0.4+/-0.1 vs 1.1+/-0.8 ms, P<0.05, n=9). None of 9 “muscular mucosal” axons recorded responded to focal application of capsaicin (0.3 μM) and their mechanosensitivity persisted in calcium-free solution (with raised [Mg++]). This suggests that they are intrinsically mechanosensitive rather than relying on release of mediators from other cells. Biotinamide dye filling revealed fine branching axons running in the subepithelial plexus in regions corresponding closely to mechanosensitive receptive fields of these units (n=4). Conclusions. We conclude that “muscular mucosal” afferents comprise a discrete and distinctive class of spinal afferent innervation, well suited to detect physiological levels of mucosal shear in the distal colon of the guinea-pig.