OBJECTIVES: Irritable bowel syndrome (IBS) is associated with a state of chronic visceral hypersensitivity, but the underlying molecular mechanisms of visceral hyperalgesia remain elusive. This study was designed to examine changes in the excitability and alterations of voltage-gated K currents in subpopulations of colonic dorsal root ganglion (DRG) neurons in a rat model of IBS-like visceral hypersensitivity.METHODS:The model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline from postnatal days 8-21. Experiments were conducted when rats became adults. DRG neurons innervating the colon were identified by 1,1′-dioleoyl-3,3,3′,3-tetramethylindocarbocyanine methanesulfonate (DiI) fluorescence labeling and were immunostained for isolectin B4 (IB4) binding to classify these colonic neurons. Patch-clamp recordings were made from acutely dissociated DiI-labeled DRG neurons, and the expression of K channel in L6-S2 DRG was examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot.RESULTS:(1) Neonatal AA treatment induced long-lasting visceral hypersensitivity without significant inflammation but with mast cell hyperplasia. (2) Colonic DRG neurons contained IB4-positive and negative neurons with different electrophysiological properties. IB4-positive colonic neurons have longer action potentials (APs) and larger A-type K currents (IA) than the IB4-negative neurons, and IB4 phenotypic changes of colonic neurons were not involved in the chronic visceral hypersensitivity. (3) Neonatal AA treatment decreased I A density and changed the electrophysiological properties of IA and IK by shifting the steady-state inactivation toward a negative direction in IB4-positive colonic neurons. The excitability of these cells increased. (4) Kv4.3 was downregulated in neonatal AA-treated rats compared with control rats, which suggests a possible mechanism regarding the changes in electrical activity of DRG neurons in these rats.CONCLUSIONS:A new model for chronic visceral hypersensitivity following a diluted AA stimulus in the neonatal period is described. The hypersensitivity may be associated with mast cell hyperplasia in the colon and increased excitability of IB4-positive colonic neurons as a result of suppression of I A density and a shift in the inactivation curves of IA and IK in a hyperpolarizing direction in these cells. This study identifies for the first time a specific molecular mechanism in subpopulations of colonic DRG neurons that underlies chronic visceral hypersensitivity. © 2009 by the American College of Gastroenterology.