Vagal afferents innervating the gastrointestinal tract and CCKA‐receptor immunoreactivity

Abstract

A large body of evidence derived from electrophysiological recording and pharmacological/behavioral experiments suggests the presence of CCKA-receptors on vagal primary afferent fibers innervating the gastrointestinal tract. With the availability of antibodies specific for the CCKA-receptor, we wanted to demonstrate its presence and distribution on identified vagal afferent fibers and different types of terminals in the mucosa, myenteric plexus, and external muscle layers of the stomach and duodenum. In the duodenal mucosa, neither a C-terminal (Ab-1) nor an N-terminal (Ab-2) specific antibody produced any specific staining; in the myenteric plexus, non-vagal enteric neurons and their processes, but not vagal intraganglionic laminar endings (IGLEs), exhibited CCKAR-immunoreactivity. Similarly, in the gastric myenteric plexus, a population of enteric neurons and their processes, but not identified vagal IGLEs, were labeled by both antibodies. In both external muscle layers of the stomach, CCKAR-immunoreactive axons were in close register with labeled vagal afferent intramuscular arrays, but the two labels were not contained in the same varicosities. Ab-1 immunoreactivity was found in the cell membrane of vagal afferent perikarya in the nodose ganglia and in pancreatic acinar cells. The failure to detect CCKAR-immunoreactivity in peripheral vagal afferent terminals cannot be due to methodological problems because it was present in enteric neurons in the same sections, and because it did not stain structures resembling IGLEs in material without the potentially masking vagal afferent label. We conclude that CCKA-receptors on vagal afferent terminals: 1) are below the immunohistochemical detection threshold, 2) exhibit a conformation or affinity state inaccessible to the two antibodies, or 3) are not transported to the peripheral terminals. Anat Rec 266: 10 -20, 2002.

Cholecystokinin and Gastrin Receptors

“…A population of CCK1R-immunoreactive fibers, localized in the gastric mucosa, markedly decreased following subdiaphragmatic vagotomy, suggesting a vagal origin (501). However, expression of these receptors was not confirmed in other studies (369,370).…”

“…Furthermore, activation of these receptors is thought to initiate a vagovagal reflex inhibition of gastric motor function (175, 176). However, recent attempts to characterize CCK1R immunoreactivity yielded surprising and unexplained negative results in the duodenal mucosa with positive results in cell bodies from the nodose ganglia (369,501).…”

The vagus nerve, food intake and obesity

“…Double labeling with an antibody to CCK revealed the presence of close anatomical appositions between labeled vagal afferent fibers and CCK-ir enteroendocrine cells in the lamina propria of duodenum and jejunum (Berthoud and Patterson, 1996). Together with the demonstration that vagal afferents express CCK-1 receptor (Moriarty et al, 1997;Broberger et al, 1999;Patterson et al, 2002) and numerous functional studies, these findings strongly suggest that luminal nutrients, particularly lipids and proteins activate vagal afferents via release of CCK from adjacent enteroendocrine cells (Smith et al, 1985;Geary, 2004;Raybould et al, 2006).…”

Gut chemosensing mechanisms

“…Subsets of enteric neurons are also thought to express CCK1 and GLP2 receptors (142,143) and have additionally been found to contain Rxfp4, potentially mediating responses to the orexigenic gut hormone INSL5 (20). Whether these receptors are located in the same or in different individual neurons remains to be established.…”