Metabotropic 5-HT receptor-mediated effects in the human submucous plexus.

Background: Serotonin (5-HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5-HT receptors. The ionotropic 5-HT ₃ receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5-HT _1P , 5-HT ₄ , and 5-HT ₇ receptors to activate human submucous neurons.
Methods: Neuroimaging using the voltage sensitive dye Di-8-ANEPPS was performed in submucous plexus preparations from human surgical specimens of the small and large intestine. We synthesized a new, stable 5-HT _1P agonist, 5-benzyloxyhydrazonoindalpine (5-BOHIP).
Key Results: 5-HT evoked a fast and late-onset spike discharge in enteric neurons. The fast component was blocked by the 5-HT ₃ receptor antagonist cilansetron, while the remaining sustained response was significantly reduced by the 5-HT _1P receptor antagonist 5-hydroxytryptophanyl-5-hydroxytryptophan amide (5-HTP-DP). The newly synthesized 5-HT _1P agonist 5-BOHIP induced a slowly developing, long-lasting activation of submucous neurons, which was blocked by 5-HTP-DP. We could not demonstrate any 5-HT ₇ receptor-induced spike discharge based on the lack of response to 5-carboxamidotryptamine. Similarly, the 5-HT ₄ agonists 5-methoxytryptamine and prucalopride evoked no immediate or late-onset spike discharge.
Conclusions & Inferences: Our work demonstrated for the first time the presence of functional 5-HT _1P receptors on human submucous neurons. Furthermore, we found no evidence for a role of 5-HT ₄ or 5-HT ₇ receptors in the postsynaptic activation of human submucous neurons by 5-HT.
(© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)