We investigated electrical and synaptic behavior of neurons in the colonic submucous plexus during exposure to beta-lactoglobulin in guinea pigs sensitized by ingestion of milk. Microelectrodes were used to record electrical and synaptic behavior in neurons from milk-sensitized and nonsensitized age-matched animals during exposure to beta-lactoglobulin. Neurons in sensitized animals were hyperexcitable. Application of the histamine H2 antagonist cimetidine reversed the hyperexcitability, suggesting endogenously released histamine as one of the responsible factors. Antigenic exposure suppressed stimulus-evoked nicotinic cholinergic fast excitatory postsynaptic potentials (EPSPs). This was blocked by the selective histamine H3 antagonist burimamide. Suppression of the EPSPs resulted from presynaptic inhibition of acetylcholine release. Increased neuronal excitability and suppression of synaptic transmission was only found in milk-sensitized intestine, not in the intestine from age-matched nonsensitized animals. We concluded that signaling from mucosal mast cells to the enteric nervous system is important in colonic defense against antigenic threats. Histamine is a paracrine messenger in the communication network.