Clinical investigations support the notion that stress contributes to visceral hypersensitivity of the gut, and experimental models have been developed that recapture some of the features observed in IBS patients with regard to stress-related hyperalgesia, sex differences, and comorbidity with anxiety/depression. Tremendous progress in our understanding of the biochemical coding of stress, in particular, as it relates to the characterization and brain distribution of CRF ligands, and CRF receptor subtypes and the development of selective CRF antagonists, have allowed us to gain insight into the underlying mechanisms of stress-related gut responses including visceral pain. Converging experimental data using pharmacologic approaches in various models support the notion that the activation of brain CRF1-signaling pathways contributes to the development of visceral hyperalgesia induced by various extero-ceptive or interoceptive stressors, as well as in models of genetically anxiety prone strains. However, there is a glaring lack of knowledge of how dysregulation of the CRF-signaling pathways impact brain circuitry regulating visceral pain at the level of facilitatory and/or inhibitory mechanisms (Fig. 2). In light of the promising functional preclinical reports that CRF1 receptors alleviate acute and chronic stress-induced visceral hyperalgesia to CRD, CRF1 antagonists may provide an additional option for future therapeutic interventions by dampening the behavioral, sacral parasympathetic and gut enteric/mast cell response to stress (161).

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