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

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.

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.

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.

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.