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Mechanisms involved in the loss of excitatory post-stimulus responses by inflammation
Inge Depoortere1, Theo Thijs, Leen Thielemans
1Department of Pathophysiology, Center for Gastroenterological Research, University of Leuven, Gasthuisberg O and N, 3000 Leuven, Belgium. inge.depoortere@med.kuleuven.ac.be
Aim:
Electrical stimulation of colonic muscles elicits a response during the stimulation period, and a transient excitation after the stimulus. Post-stimulus or "rebound" excitation has been linked to pathways involving inhibitory neurotransmitters, prostaglandins and substance P but the mechanism is incompletely understood. Because rabbit colitis is characterized by a loss of inhibitory neurotransmission we hypothesized it might affect the rebound response. Therefore we characterized rebound responses in non-inflamed and inflamed tissue by comparing the effect of antagonists/blockers of putative (nitric oxide [NO], ATP, substance P, prostaglandins) and new (serotonin) neurotransmitters.
Methods:
Strips from rabbits with colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) were subjected to electrical field stimulation. Because rebound responses are more prominent under nonadrenergic noncholinergic (NANC) conditions, the effect of specific antagonists (N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin, SR140333, methiothepin) on the rebound response was compared under normal and NANC conditions.
Results:
NANC-conditions increased rebound responses in non-inflamed strips, but this effect was reduced or abolished in inflamed strips. Rebound responses were reduced by pretreatment with the NO-synthase inhibitor, L-NAME, under NANC conditions in non-inflamed strips but not affected in inflamed tissue. In contrast, the P(2) purine receptor antagonist, suramin, did not affect rebound responses in inflamed and non-inflamed strips. The effect of the cyclo-oxygenase inhibitor (COX), indomethacin, on rebound responses was reversed from excitatory to inhibitory by inflammation. Under NANC conditions rebound contractions were also reduced by the neurokinin-1 (NK(1)) antagonist, SR140333, both in normal and inflamed strips. The most pronounced reduction in rebound responses in inflamed and non-inflamed strips under normal conditions was observed with the 5-hydroxytryptamin (1,2) (5-HT(1,2)) antagonist, methiothepin.
Conclusion:
Rebound responses are mainly non-cholinergic and involve NO, substance P, serotonin and inhibitory prostaglandins. In inflamed tissue the nitrergic pathway is absent, excitatory prostaglandins prevail and the cholinergic and tachykinergic components are relatively more important. However there remains an important serotonergic contribution. Our data suggest that inflammation damages different neural pathways to a different extent and is most selective for nitrergic pathways.
Insights
Colitis alters colonic muscle rebound responses, diminishing nitric oxide pathways while enhancing others. Serotonin remains a key contributor in both inflamed and non-inflamed tissues, indicating selective neural damage during inflammation.
Area of Science:
- Gastroenterology
- Neurogastroenterology
- Pharmacology
Background:
- Electrical stimulation of colonic muscles causes transient post-stimulus excitation, known as rebound response.
- Rebound excitation mechanisms involve neurotransmitters like nitric oxide (NO), prostaglandins, and substance P, but are not fully understood.
- Colitis is associated with impaired inhibitory neurotransmission, potentially affecting rebound responses.
Purpose of the Study:
- To investigate the role of various neurotransmitters in colonic rebound responses in both non-inflamed and inflamed rabbit tissue.
- To compare the effects of antagonists for nitric oxide (NO), ATP, substance P, prostaglandins, and serotonin on rebound responses.
- To determine if colitis-induced changes in neurotransmission affect the rebound response characteristics.
Main Methods:
- Colitis was induced in rabbits using 2,4,6-trinitrobenzenesulfonic acid (TNBS).
- Colonic muscle strips from normal and TNBS-treated rabbits were subjected to electrical field stimulation.
- The effects of specific antagonists (L-NAME for NO, indomethacin for prostaglandins, SR140333 for substance P, methiothepin for serotonin) were assessed under normal and non-adrenergic, non-cholinergic (NANC) conditions.
Main Results:
- Non-adrenergic, non-cholinergic (NANC) conditions enhanced rebound responses in non-inflamed tissue but not in inflamed tissue.
- Nitric oxide (NO) synthase inhibition (L-NAME) reduced rebound responses in non-inflamed tissue under NANC conditions, with no effect in inflamed tissue.
- Prostaglandin inhibition (indomethacin) reversed its effect from excitatory to inhibitory in inflamed tissue. Serotonin (5-HT) antagonism (methiothepin) caused the most significant reduction in rebound responses in both tissue types.
Conclusions:
- Colonic rebound responses involve non-cholinergic pathways including NO, substance P, serotonin, and prostaglandins.
- Inflammation selectively damages neural pathways, notably the nitrergic pathway, while promoting excitatory prostaglandins.
- Serotonergic pathways play a significant role in colonic rebound responses, even in inflamed conditions.