Introduction: Duchenne Muscular Dystrophy (DMD) is characterised by severe progressive wasting of skeletal muscle and a shortened life expectancy of between 20-30 years. Deficiency of the protein dystrophin, results in progressive necrosis, muscle fibre degeneration and a chronic inflammatory response. The pro-inflammatory myokine, interleukin-6 (IL-6), is elevated in patients with DMD. Dystrophin is absent from smooth muscle cells; and a little-reported symptom of DMD is altered gastrointestinal (GI) function. Patients suffer from bloating, constipation and in more severe cases, acute gastric dilation and intestinal pseudo-obstruction. The aims of this study are to investigate IL-6 and the stress hormone, corticotropin-releasing factor (CRF) in mdx mice to determine if elevation of IL-6 and possible interactions with CRF are associated with changes in (GI) physiology. Methods: Morphology was investigated in transverse sections (10µm) of colon stained with Haematoxylin & Eosin. Diameter and thickness of the mucosal and muscular layers were scored. Whole colon sections taken from wildtype (WT) and mdx (C57BL/10ScSn-Dmdmdx/J) mice (10 weeks old) were suspended in organ baths to compare contractile activity under basal conditions and following stimulation with IL-6 (200nM) and/or CRF (200nM). Results: Histological investigations determined that mdx mice exhibit a thickened muscular layer (141±7.918µm, n=4) as compared to WT mice (95.26±7.494µm, n=4, p<0.001). The mucosal layer and colonic diameter was unchanged from WT mice. To assess if the thickening of the muscle translated into changes in contractile activity, excised colon was suspended in organ baths and stimulated to evoke contractile response. Carbachol (500nM, 20 mins) was added to the bath to evoke a maximal response. No significant difference was observed between the strains (n=6). Thus, responses to IL-6 and/or CRF were normalised to the carbachol response. IL-6 stimulated a six-fold greater contractile response in mdx (172.6± 66.48%, n=6, p<0.05) as compared to WT (30.39± 6.512%, n=7) mice. Pre-incubation of the tissue with the Na+ channel blocker, tetrodotoxin (TTX, 250nM) attenuated this response in mdx mice (26.14±14.58%, n=5, p=0.05) but had no effect in the WT mice (24.68±3.078%, n=4, p>0.05). In both strains (n=6, p>0.05) the stimulation of contraction by IL-6 and/or CRF was similar. However, the neuronally-mediated effects of IL-6 in mdx mice was borne out by the inhibitory effects of TTX on IL-6 plus CRF in mdx mice only (1.681±0.6920%, n=6, p<0.01). Discussion: These data begin to elucidate the physiological GI changes in the dystrophin-deficient mdx mice which may contribute to altered function. From these studies it appears that neuronally regulated IL-6-induced muscular contraction is important in GI pathophysiology in this strain.