Organization and neurochemistry of vagal preganglionic neurons innervating the lower esophageal sphincter in ferrets

Abstract

The motor control of the lower esophageal sphincter (LES) is critical for normal swallowing and emesis, as well as for the prevention of gastroesophageal reflux. However, there are surprisingly few data on the central organization and neurochemistry of LES-projecting preganglionic neurons. There are no such data in ferrets, which are increasingly being used to study LES relaxation. Therefore, we determined the location of preganglionic neurons innervating the ferret LES, with special attention to their relationship with gastric fundus-projecting neurons. The neurochemistry of LES-projecting neurons was also investigated using two markers of "nontraditional" neurotransmitters in vagal preganglionic neurons, nitric oxide synthase (NOS), and dopamine (tyrosine hydroxylase: TH). Injection of cholera toxin B subunit (CTB)-horseradish peroxidase (HRP) into the muscular wall of the LES-labeled profiles throughout the rostrocaudal extent of the dorsal motor nucleus of the vagus (DMN) The relative numbers of profiles in three regions of the DMN from caudal to rostral are, 43 +/- 5, 67 +/- 11, and 113 +/- 30). A similar rostrocaudal distribution occurred after injection into the gastric fundus. When CTB conjugated with different fluorescent tags was injected into the LES and fundus both labels were noted in 56 +/- 3% of LES-labeled profiles overall. This finding suggests an extensive coinnervation of both regions by vagal motor neurons. There were significantly fewer LES-labeled profiles that innervated the antrum (16 +/- 9%). In the rostral DMN, 15 +/- 4% of LES-projecting neurons also contained NADPH-diaphorase activity; however, TH immunoreactivity was never identified in LES-projecting neurons. This finding suggests that NO, but not catecholamine (probably dopamine), is synthesized by a population of LES-projecting neurons. We conclude that there are striking similarities between LES- and fundic-projecting preganglionic neurons in terms of their organization in the DMN, presence of NOS activity and absence of TH immunoreactivity. Coinnervation of the LES and gastric fundus is logical, because the LES has similar functions to the fundus, which relaxes to accommodate food during ingestion and preceding emesis, but has quite different functions from the antrum, which provides mixing and propulsion of contents for gastric emptying. The presence of NOS in some LES-projecting neurons may contribute to LES relaxation, as it does in the case of fundic relaxation. The neurologic linkage of vagal fundic and LES relaxation may have clinical relevance, because it helps explain why motor disorders of the LES and fundus frequently occur together.

Central Nervous System Control of Gastrointestinal Motility and Secretion and Modulation of Gastrointestinal Functions

“…Several morphological and functional studies have suggested, however, that most enteric neurons receive inputs from vagal fibers and that individual vagal fibers contact many enteric neurons (432, 526) suggesting that the role of the vagus is a more generalized modulation of existing activity levels within enteric neural circuits. Neurotransmitters other than acetylcholine have also been identified within vagal preganglionic neurons within the brainstem, including catecholamines and NO (207, 242, 256, 551); vagal neurotransmission is essentially prevented by nicotinic acetylcholine receptor antagonists, however, suggesting that these noncholinergic neurotransmitters play a modulatory role in cholinergic vagal transmission (432). …”

Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease

“…43 Signals from the DMV to the LOS originate from two functional areas inside the DMV known as the rostral and caudal area. 44,45 By assessing the function of both regions, it was observed that stimulation of the caudal DMV resulted in decreased LOS pressure, whereas stimulation of the rostral DMV resulted in increased LOS pressure. 44,46 Although central modulation of LOS relaxation in response to gastric distension has been investigated extensively, central modulation of the crural diaphragm has received somewhat less attention.…”

Expression of NADPH-d in the vagal nuclei of the chronic esophagitis model in rats

“…The esophagus and the LES receive inhibitory input from the caudal neurons and excitatory input from the rostral neurons (4,20,(22)(23)(24). The excitation is provided by the preganglionic cholinergic projections onto cholinergic neurons, while the inhibition is provided by nitrergic enteric neurons (4,(25)(26)(27).…”

“…The excitation is provided by the preganglionic cholinergic projections onto cholinergic neurons, while the inhibition is provided by nitrergic enteric neurons (4,(25)(26)(27). The activation of the intrinsic nitrergic inhibitory neurons by the preganglionic vagal efferents in the caudal DMV leads to LES relaxation during deglutition (4,20,22,23) (5) emphasized the effect of DMV, NTS, and NA on the esophageal motility. The proposed mechanism was that the acid-pepsin exposure to the lower part of the esophagus stimulates the mucosal receptors, which in turn activate the neurons of the NTS through the vagal afferents and finally the neurons in DMV and NA to modulate the esophageal peristalsis.…”