neurokinin-a and Inflammatory-Bowel-Diseases

The tachykinins substance P and neurokinin A participate in the regulation of gastrointestinal motility, secretion, vascular permeability and pain sensitivity. Advances made during the past two years corroborate a causal involvement of tachykinins in inflammation-induced disturbances of gut function, such as dysmotility, secretory diarrhoea, oedema and hyperalgesia. It would therefore appear that tachykinin receptors, which in the digestive system are expressed in a cell-specific manner, represent attractive targets for novel therapeutics in gastroenterology.

Topics: Animals; Colonic Diseases, Functional; Digestive System; Digestive System Physiological Phenomena; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Inflammatory Bowel Diseases; Neurokinin A; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Receptors, Tachykinin; Substance P

Inflammatory bowel disease (IBD) is associated with altered sensory and motor function in the human colon. The aim of the present study was to compare neuromuscular function in normal and IBD-affected colon in vitro, with emphasis on inhibitory enteric nerves, sensory neuropeptides and stimulation of axon collaterals.. Strips of longitudinal and circular muscle were prepared following colectomy from six patients with intestinal carcinoma (mean age 64.2 +/- 4.8 years) and six patients with IBD (Crohn's disease, n = 3; ulcerative colitis, n = 3: mean age 35.8 +/- 5.7 years). Responses were measured to electrical field stimulation, potassium chloride, 1,1-dimethyl-4-phenylpiperazinium iodide, isoprenaline, calcitonin gene-related peptide (CGRP), capsaicin and neurokinin (NK)-1 and -2 receptor subtype-specific agonists, alone or after muscle precontraction.. The NK-1 and CGRP receptor-mediated relaxation was reduced in the circular (by 44%, P < 0.05) and longitudinal (by 61%, P < 0.05) muscle from IBD-affected colon, respectively. Maximal NK-2 receptor-mediated contraction was also significantly decreased in both longitudinal (71%, P < 0.001) and circular (51%, P < 0.01) muscle. Capsaicin evoked relaxation in precontracted colonic longitudinal and circular muscle; this was significantly diminished in the IBD-affected colon (by 63%, P < 0.001 and 76%, P < 0.01, respectively). Responses evoked by stimulation of enteric inhibitory nerves were not significantly altered.. Colonic muscle strips from patients with IBD exhibited impaired CGRP and NK-1 receptor-mediated relaxation and NK-2 receptor-mediated contraction. Capsaicin-activated relaxation of colonic smooth muscle is deficient in IBD-affected colon. These results suggest a discrete effect of IBD on sensory-motor coupling and tachykinin-mediated effects on colonic motility.

Topics: Adult; Aged; Aged, 80 and over; Capsaicin; Case-Control Studies; Colon; Electric Stimulation; Gastrointestinal Motility; Humans; Inflammatory Bowel Diseases; Middle Aged; Neurokinin A; Neuromuscular Junction; Peptide Fragments; Stimulation, Chemical; Synaptic Transmission; Tissue Culture Techniques

1. This in vitro study was designed to determine the potential use of the NK(1) antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimuli on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated. 2. Submucosal and sensory nerve fibre stimulation using electrical field stimulation (1 ms/7 Hz/7 V) and capsaicin (50 microM) respectively, mast cell activation by anti-IgE (1/250 dilution) and granulocyte stimulation using fMLP (50 microM) each released SP and evoked a secretory response. 3. SP and the NK(1) selective agonist, Sar-SP (0.1 - 1000 nM) stimulated an increase in colonic secretion which was antagonized by SR140333 (pD'(2)=6.7 and 7.25 versus SP and Sar-SP respectively). 4. SR140333, at a concentration that blocked NK(1)-mediated secretion (500 nM), also reduced the secretory response to both alphaIgE and capsaicin. This suggests a pathophysiologic role for NK(1) receptors. 5. Capsaicin evoked SP release was increased in tissue taken from Crohn's disease but not ulcerative colitis patients. The response to SP was however reduced by 70 and 89% respectively. 6. Mast cells and sensory afferents contribute to allergic diarrhoea. Since SR140333 reduced the secretory response to mast cell and afferent stimulation this compound may be particularly useful in reducing the symptoms of food allergy.

Topics: Animals; Antidiarrheals; Capsaicin; Colitis, Ulcerative; Colon; Crohn Disease; Epithelial Cells; Food Hypersensitivity; Guinea Pigs; Humans; Immunoglobulin E; Inflammatory Bowel Diseases; Male; Mast Cells; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Receptors, Neurokinin-1; Species Specificity; Substance P; Tachykinins