Constitutively Active 5-HT Receptors: An Explanation of How 5-HT Antagonists Inhibit Gut Motility in Species Where 5-HT is Not an Enteric Neurotransmitter?

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.

Keywords: 5-HT; colon; colonic transit; enteric nervous system; migrating motor complex; peristalsis; serotonin.

Figure 1

(A) Immunohistochemical staining of a myenteric ganglion with antibodies against 5-HT. Varicose 5-HT immunoreactive nerve axons ramify within myenteric ganglia and internodal strands.(B) Distension-evoked peristalsis elicited by insertion of an artificial fecal pellet. (C) After injection of reserpine into conscious guinea-pigs, all 5-HT is depleted from enteric ganglia. (D) Despite removal of all the mucosa and submucosal plexus and depletion of 5-HT from myenteric ganglia, distension-evoked peristalsis still reliably occurs.

Figure 2

Repetitive peristaltic contractions evoked by maintained colonic distension with a fixed artificial fecal pellet are only temporarily inhibited by 5-HT3 and 5-HT4 antagonists in isolated guinea-pig distal colon. (A) Shows that increasing concentrations of ondansetron and SDZ-205-557 have only temporary effects on inhibiting distension-evoked peristaltic contractions in control distal colon. (B) Shows 5-HT is present in varicose nerve axons of myenteric ganglia. (C) In reserpine-treated guinea-pigs to deplete neuronal 5-HT and which also have their mucosa and submucosal plexus removed, maintained colonic distension by a fecal pellet continues to evoke repetitive peristaltic contractions. Simultaneous addition of increasing concentrations of ondansetron and SDZ-205-557 temporarily inhibited peristaltic contractions, which recovered in the continued presence of both antagonists. The two black arrows indicated when peristaltic contractions recover in the presence of both antagonists when applied at 3 μM and then 5 μM. (D) Reserpine treatment depleted all neuronal 5-HT from this specimen.