Proinflammatory mediators in the mucosa such as histamine, tryptase, among others, are increased in IBS. These mediators, together with histamine and tryptase from MC, activate G protein–coupled receptors (GPCRs) on MC, resulting in degranulation of numerous vesicular mediators (histamine, tryptase, PGE2, etc.) and induction of transcriptional activation of COX2, which increases the synthesis of prostaglandins, including PGE2. MC located close to sensory nerve fibers in the submucosa release PGE2, which acts on sensory fiber EP2 receptors and potentiates the action of pronociceptive mediators released by mechanical or chemical stimulation, leading to the development of VH.