Abstract
Antagonists of 5-Hydroxytryptamine (5-HT) receptors are well known to inhibit gastrointestinal (GI)-motility and transit in a variety of mammals, including humans. Originally, these observations had been interpreted by many investigators (including us) as evidence that endogenous 5-HT plays a major role in GI motility. This seemed a logical assumption. However, the story changed dramatically after recent studies revealed that 5-HT antagonists still blocked major GI motility patterns (peristalsis and colonic migrating motor complexes) in segments of intestine depleted of all 5-HT. Then, these results were further supported by Dr. Gershons' laboratory, which showed that genetic deletion of all genes that synthesizes 5-HT had minor, or no inhibitory effects on GI transit in vivo. If 5-HT was essential for GI motility patterns and transit, then one would expect major disruptions in motility and transit when 5-HT synthesis was genetically ablated. This does not occur. The inhibitory effects of 5-HT antagonists on GI motility clearly occur independently of any 5-HT in the gut. Evidence now suggests that 5-HT antagonists act on 5-HT receptors in the gut which are constitutively active, and don't require 5-HT for their activation. This would explain a long-standing mystery of how 5-HT antagonists inhibit gut motility in species like mice, rats, and humans where 5-HT is not an enteric neurotransmitter. Studies are now increasingly demonstrating that the presence of a neurochemical in enteric neurons does not mean they function as neurotransmitters. Caution should be exercised when interpreting any inhibitory effects of 5-HT antagonists on GI motility.
Highlights
Antagonists of 5-Hydroxytryptamine (5-HT) receptors are well known to inhibit gastrointestinal (GI)-motility and transit in a variety of mammals, including humans
Evidence comes from the Constitutively Active 5-HT Receptors fact that (1) the largest quantity of serotonin in the body is synthesized in enterochromaffin cells in the mucosa (Erspamer, 1954), (2) high concentrations of 5-HT can be dynamically released from the mucosa (Bertrand, 2006; Keating and Spencer, 2010; Spencer et al, 2011) (3) exogenous 5-HT potently stimulates GI motility (Büllbring and Lin, 1957; Bülbring and Lin, 1958; Keating and Spencer, 2010; Spencer et al, 2011), and (4) numerous antagonists of 5-HT receptors can inhibit, or block peristalsis and reduce propulsion of contents (Grider et al, 1996; Kadowaki et al, 1996; Heredia et al, 2009), including rectal distension reflexes (Shimatani et al, 2003)
We studied colonic migrating motor complexes (CMMCs) and found that they were potently abolished by the selective 5-HT3 receptor antagonist alosetron, at physiologically relevant concentrations (Bush et al, 2001)
Summary
Antagonists of 5-Hydroxytryptamine (5-HT) receptors are well known to inhibit gastrointestinal (GI)-motility and transit in a variety of mammals, including humans. Evidence comes from the Constitutively Active 5-HT Receptors fact that (1) the largest quantity of serotonin in the body is synthesized in enterochromaffin cells in the mucosa (Erspamer, 1954), (2) high concentrations of 5-HT can be dynamically released from the mucosa (Bertrand, 2006; Keating and Spencer, 2010; Spencer et al, 2011) (3) exogenous 5-HT potently stimulates GI motility (Büllbring and Lin, 1957; Bülbring and Lin, 1958; Keating and Spencer, 2010; Spencer et al, 2011), and (4) numerous antagonists of 5-HT receptors can inhibit, or block peristalsis and reduce propulsion of contents (Grider et al, 1996; Kadowaki et al, 1996; Heredia et al, 2009), including rectal distension reflexes (Shimatani et al, 2003).
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