Background: Irritable bowel syndrome (IBS) is a common disorder of the gut with symptoms such as diarrhoea, constipation, abdominal pain and bloating, that are frequently exacerbated by stress. Circulating levels of the pro-inflammatory cytokine, interleukin-6 (IL-6), which can activate colonic enteric neurons, are elevated in IBS patients. These studies aim to explore the relationship between IL-6 and the stress peptide, corticotropin-releasing factor (CRF) in colonic submucosal neurons.Methods: Calcium imaging, Ussing chamber electrophysiology and immunohistochemistry were conducted on rat distal colons to investigate potential crosstalk between IL-6 and CRF.Key results: Colonic secretions from the maternal separation rat model of IBS stimulated increases in intracellular calcium in naive submucosal neurons via CRF1 receptors (n = 15, p < 0.05). Moreover, IL-6 (n = 50, p < 0.01) but not IL-1 beta (n = 46, p > 0.05) or TNF alpha (n = 46, p > 0.05) potentiated the CRF-evoked calcium response. CRF (1 mu M, 1 h, n = 5) stimulation also induced colonic secretion of IL-6 and inhibited the pro-secretory effects of IL-6 on colonic ion transfer (n = 12).Conclusions and inferences: These studies demonstrate the modulatory effects of CRF on colonic IL-6 secretion, neuronal activation and secretory function. These findings may provide an insight into the molecular mechanisms underlying symptom flares in IBS during periods of high stress. (C) 2013 Elsevier Inc. All rights reserved.