Alteration of the purinergic modulation of enteric neurotransmission in the mouse ileum during chronic intestinal inflammation

Abstract

1 The effect of chronic intestinal inflammation on the purinergic modulation of cholinergic neurotransmission was studied in the mouse ileum. Chronic intestinal inflammation was induced by infection of mice with the parasite Schistosoma mansoni during 16 weeks. 2 S. mansoni infection induced a chronic inflammatory response in the small intestine, which was characterised by intestinal granuloma formation, increased intestinal wall thickness, blunted mucosal villi and an enhanced activity of myeloperoxidase. 3 In control ileum and in chronically inflamed ileum, electrical field stimulation (EFS) of longitudinal muscle strips induced frequency-dependent contractions that were abolished by tetrodotoxin (TTX) and atropine. Carbachol induced dose-dependent contractions that were not affected by TTX but abolished by atropine. 4 In control ileum, adenosine and ATP dose-dependently inhibited the contractions to EFS. Theophylline and 8-phenyltheophylline, P 1 and A 1 receptor antagonists respectively, prevented this inhibitory effect of adenosine and ATP. PPADS, DMPX and MRS 1220, antagonists of P 2 , A 2 and A 3 receptors, respectively, did not prevent this inhibitory effect of adenosine and ATP. Adenosine and ATP did not affect the contractions to carbachol. 5 The inhibitory effect of adenosine and ATP on contractions to EFS in control ileum was mimicked by the stable adenosine analogue methyladenosine and by the A 1 -receptor agonist N(6)-cyclohexyladenosine, but not by the A3 receptor agonist 2-Cl IB-MECA or by the ATP analogues ab-methylene-ATP and ADPbS. The inhibitory effect of adenosine on contractions to EFS was lost after prolonged (90 min) treatment of control ileum with methyladenosine (100 mM). 6 In chronically inflamed ileum, adenosine, methyladenosine, N(6)-cyclohexyladenosine and ATP all failed to inhibit the cholinergic nerve-mediated contractions to EFS. Also theophylline, 8-phenyltheophylline, PPADS, DMPX and MRS 1220 had no effect on the contractions to EFS and carbachol. The loss of effect of adenosine and ATP was still evident after 52 weeks of infection. 7 These results indicate that in physiological conditions neuronal adenosine A 1 receptors modulate cholinergic nerve activity in the mouse ileum. However, during chronic intestinal inflammation, this purinergic modulation of cholinergic nerve activity is impaired. This suggests that chronic intestinal inflammation leads to a dysfunction of specific neuronal regulatory mechanisms in the enteric nervous system.

P2X ion channel receptors and inflammation

“…ATP release from injured cells enhances the inflammatory response through increased synthesis of prostaglandin E 2 (PGE 2 ) [4] via P2X7 receptors [5]. P2X receptor involvement in inflammation also occurs in irritable bowel syndrome [6,7], lung injury and fibrosis [8,9], systemic inflammation [10], arthritis [11], fever [12], and rhinosinusitis [13]. Purinergic signalling in different inflammatory cells involves purinoceptor responses in immune cells (see [14]).…”

Proliferative enteropathy (PPE)-induced changes in the expression of DBH, VAChT and NOS in the neurons of intramural ganglia of the porcine ileum

“…The release of acetylcholine from cholinergic nerve terminals is under wellregulated presynaptic control, involving specific neuronal receptors. Among them are purinergic P1 and P2 receptors, which, upon activation, enhance or inhibit the release of acetylcholine, depending upon the receptor subtype involved (Moody and Burnstock, 1982;De Man et al, 2003). Interestingly, there is some evidence that adenosine and ATP, which are natural ligands of P1 and P2 receptors, respectively, are generated at sites of inflammation (for a review see Cronstein, 1994).…”

Activation of adenosine low-affinity A3 receptors inhibits the enteric short interplexus neural circuit triggered by histamine

“…Expression of A1 or A3 receptors or mRNA has been shown to be sensitive to intestinal inflammation in a rabbit ileitis-Crohn's disease model (61) or human IBD (50) and adenosine A1 receptor (ADOA1R) downregulation leads to disruption of neurotransmission (28).…”