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 alphabeta-methylene-
ATP and
ADPbetaS. The inhibitory effect of
adenosine on contractions to EFS was lost after prolonged (90 min) treatment of control ileum with methyladenosine (100 micro M). 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.