Divergent changes to muscarinic and serotonergic signalling following colitis

Ron W Wells ¹ and Michael G Blennerhassett ^1*

¹ Queen's University, Canada

^* To whom correspondence should be addressed. E-mail: mblen{at}meds.queensu.ca.

Accepted 21 June 2005

Abstract

The altered motility of the inflamed intestine derives in part from changes to the contractility of the intestinal smooth muscle cell. While modifications to the muscarinic receptor system are identified, changes to the 5-HT receptors that also mediate contraction are less well studied. In the TNBS model of rat colitis, we used receptor antagonists to identify changes in receptor utilization that accompany the selective reversal of the impaired contractile response to acetylcholine (ACh) and 5-HT during colitis [Day 4 (D4)] and following resolution of inflammation [Day 36 (D36)]. In isolated circular smooth muscle cells, challenged with ACh, the M₃R antagonists 4-DAMP and pF-HSD each showed a 50% decrease in antagonism on D4, while the M₂R antagonist methoctramine more than doubled its potency, showing a decreased role of M₃R and an increased role of M₂R respectively. These changes were fully reversed by D36. In contrast, the 5-HT₂R antagonist ketanserin was sharply decreased in effectiveness on D4, with further decrease by D36, when the contribution of the 5-HT_2AR was only 22% of control. There were no changes in response to the 5-HT₄R antagonist SDZ-205-557 at any time. Western blotting identified the decreased expression of 5-HT_2AR on D36 vs. control, further supporting the conclusion that the persistence of the impaired response to 5-HT was due to decreased expression of the excitatory 5-HT_2AR. Thus, the lasting decrease in receptor expression and resulting impairment of the contractile response will compromise the capacity for an appropriate response to 5-HT, which may contribute to the intestinal dysfunction seen in post- enteritis syndromes.

Keywords: acetylcholine, circular smooth muscle cell, contractility, intestine, serotonin

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