Disturbance of the prejunctional modulation of cholinergic neurotransmission during chronic granulomatous inflammation of the mouse ileum

1 The effect of chronic granulomatous inflammation of the intestine was studied on the prejunctional modulation of cholinergic nerve activity in the mouse ileum. 2 Contractions to carbachol(0.01-0.3 muM) and to electrical field stimulation (EFS, 0.25-8 Hz) of enteric neurons were higher in inflamed ileum as compared to control ileum. However, when the neurally-mediated contractions to EFS were expressed as percentage of the direct smooth muscle contraction to carbachol, the responses to EFS were similar in control and inflamed ileum. 3 Atropine (1 muM) abolished all contractions to EFS and carbachol in control and inflamed ileum. DMPP (3-30 muM), a nicotinic receptor agonist, induced concentration-dependent contractions that were more pronounced in inflamed ileum as compared to control ileum. Hexamethonium (100 muM), a nicotinic receptor blocker, significantly inhibited the contractions to EFS in inflamed ileum but not in control ileum. 4 In control ileum, histamine (10-100 muM) and the histamine Hl receptor agonist HTMT (3-10 muM) inhibited the contractions to EFS concentration-dependently without affecting the contractions to carbachol. The inhibitory effect of histamine and HTMT was prevented by the histamine III antagonist mepyramine (5-10 muM) but not by the H-2- and H-3-receptor antagonists cimetidine and thioperamide (both 10 muM) In chronically inflamed ileum however, histamine (10-100 muM) and HTMT (3-10 muM) failed to inhibit the contractions to EFS. The histamine H-2 and H-3 receptor agonists dimaprit and R(-)-alpha -methylhistamine did not affect the contractions to EFS in control and inflamed ileum. 5 The alpha (2)-receptor agonist UK 14.304 (0.01-0.1 muM) inhibited the contractions to EFS in control and inflamed ileum without affecting the contractions to carbachol. The effect of UK 14.304 was reversed by the alpha (2)-receptor antagonist yohimbine (1 muM). The inhibitory effect of UK 14.304 on contractions to EFS was of similar potency in control and inflamed ileum. 6 Our results suggest that the prejunctional modulation of cholinergic nerve activity by nicotinic and histaminic H-1 receptors is disturbed during chronic intestinal inflammation whereas the modulation by alpha (2)-receptors is preserved. Such a disturbance of cholinergic nerve activity may contribute to the motility disturbances that are often observed during chronic intestinal diseases in humans.