Localization of the 5-hydroxytryptamine 4 receptor in equine enteric neurons and extrinsic sensory fibers

Background: Serotonin plays a pivotal role in regulating gut motility, visceral sensitivity, and fluid secretion via specific receptors. Among these receptors, 5-HT₄ exerts a prominent control on gut motor function. Although the prokinetic effect exerted by 5-HT₄ agonists is well known, the cellular sites of 5-HT₄ expression remain poorly understood in large mammals, e.g., horses. In this study, we evaluated the distribution of 5-HT₄ in the horse intestine and in foals with enteric aganglionosis, reminiscent of human Hirschsprung's disease.

Methods: The intestine and spinal ganglia were obtained from three healthy horses and two foals with hereditary ileocolonic aganglionosis. Tissues were processed for immunohistochemistry using a specific antibody to 5-HT₄ and a variety of neuronal markers. Myenteric and submucosal plexus 5-HT₄ -immunoreactive (IR) neurons were quantified as relative percentage (mean±SD) to the total number of neurons counted. Furthermore, the density of 5-HT₄ -IR nerve fibers was evaluated in the mucosa and tunica muscularis.

Key results: The 5-HT₄ immunoreactivity was localized to large percentages of myenteric neurons ranging from 28±9% (descending colon) to 63±19% (ileum), and submucosal neurons ranging from 54±6% (ileum) to 68±14% (duodenum). The 5-HT₄ -immunoreactivity was co-expressed by some substance P-IR (SP-IR) spinal ganglion neurons and extrinsic sensory fibers of aganglionic foals.

Conclusions & inferences: The presence of 5-HT₄ in many enteric and extrinsic sensory neurons and nerve fibers provides solid morphological evidence of the cellular sites of 5-HT₄ expression in horses. The evidence of SP-IR sensory neurons positive for 5-HT₄ suggests its role in visceral sensitivity.