The major initiator of the body's physiological stress response is the release of corticotropin releasing hormone (CRH). CRH, produced within the hypothalamus (as well as by immune cells, including human lymphocytes and mast cells), is the principal regulator of the basal and stress-induced pituitary-adrenal axis which, in turn, activates glucocorticoid (e.g. cortisol) and adrenal androgen secretion. Though results have been variable, the majority of studies support an enhanced HPA axis responsiveness in at least a subset of adults with IBS. (26-30) CRH receptors (CRH-R) are widely expressed within the gastrointestinal tract and immune cells, where CRH-R activation has multiple effects which may be relevant in the etiology of FGIDs. These effects include alteration of autonomic balance, visceral sensitivity, motility disturbances, and inflammation. The most important mechanism by which CRH may generate pain is through interaction with inflammatory cells, directly and via epithelial cells and enteric nerves. CRH mediates visceral hypersensitivity by activating mucosal mast cells with subsequent mediator sensitization of afferent sensory enteric nerves. (31,32) Gastric mast cells have been shown to be increased in adults with dyspepsia and may contain both pre-formed and newly synthesized cytokines (including IL-4, IL-5, IL-6, and TNF-α, among others). (33-34) The investigators have demonstrated delayed gastric emptying and increased gastric dysrhythmia in children/adolescents with FD with elevated antral mast cell density. (35) The investigators have also demonstrated this dysrhythmia to be associated with increased post-prandial pain. (36) Adult humans have demonstrated selective luminal release of tryptase and histamine from jejunal mast cells under cold stress; the magnitude of release was shown to be similar to that induced by antigen exposure in food allergic patients. (37) This is a rapid response with peak histamine and tryptase concentrations occurring between 15 and 30 minutes. Mast cells may also recruit eosinophils as a secondary effector cell. Eosinophils are increased in the duodenal mucosa of 71% of children with FD and they have also been found to be increased in adults with FD. (38,39) These eosinophils are highly activated and the investigators have demonstrated clinical improvement with treatment directed at mucosal eosinophils. (40,41) The investigators have previously found a high correlation between anxiety scores and mucosal eosinophil density, providing preliminary support for the role of CRH in downstream eosinophil recruitment and activation. (42) Stress also has been shown to shift the relative proportion and trafficking of T helper lymphocytes towards a Th2 or "allergic" phenotype. This shift is driven by catecholamines and central CRH as well as CRH from peripheral nerves and inflammatory cells. The Th2 phenotype is associated with release of IL 4,IL 10, and IL 13, which stimulate growth and activation of mast cells and eosinophils. (43) CRH also has been associated with increased expression of TNF-α, MCP1, and IL 8, which have, in turn, been associated with hyperalgesia. (44-46) As described above, CRH can initiate an inflammatory cascade which may lead to pain directly or indirectly by causing dysmotility and visceral hypersensitivity.