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ACh: acetylcholine

ANS: autonomic nervous system

CCK: cholecystokinin

CFTR: cystic fibrosis transmembrane conductance regulator

CTZ: chemoreceptor trigger zone

CYP: cytochrome P450

DOR: delta opioid receptor

ECG: electrocardiogram

ENaC: epithelial sodium channel

ENS: enteric nervous system

FDA: U.S. Food and Drug Administration

GC: guanyl cyclase

GERD: gastroesophageal reflux disease

GI: gastrointestinal

GLP: glucagon-like peptide

GPCR: G protein-coupled receptor

HIV: human immunodeficiency virus

5HT: serotonin, 5-hydroxytryptamine

IBS: irritable bowel syndrome

KOR: kappa opioid receptor

MOR: mu opioid receptor

NEP: neutral endopeptidase

NHE: Na+-H+ exchanger

NK: neurokinin

NO: nitric oxide

NTS: nucleus of the solitary tract

OTC: over-the-counter

PEG: polyethylene glycol

Pgp: P-glycoprotein (MDR1, ABCB1)

PK: protein kinase (e.g., PKA, PKC)

PONV: postoperative nausea and vomiting

QT: ECG interval (duration of ventricular depolarization and repolarization)

SLC: solute carrier transporter

SSRI: selective serotonin reuptake inhibitor

SST: somatostatin

TMEM: transmembrane protein

USP: U.S. Pharmacopeia

VIP: vasoactive intestinal peptide


The gastrointestinal (GI) tract is in a continuous contractile, absorptive, and secretory state. The control of this state is complex, with contributions by the muscle and epithelium, the enteric nervous system (ENS), the autonomic nervous system (ANS), microbial mediators, innate and adaptive immune cells and their mediators, and local enteroendocrine and circulating hormones. Of these, the master regulator of physiological gut function is the ENS (Figure 54–1) (Fung and Vanden Berghe, 2020; Furness, 2012; Sharkey et al., 2018; Spencer and Hu, 2020).

Figure 54–1

The neuronal network that initiates and generates peristalsis Mucosal stimulation leads to the release of serotonin by enterochromaffin cells (8), which excites the intrinsic primary afferent neurons (1), which then communicate with ascending (2) and descending (3) interneurons in the local reflex pathways. The reflex results in contraction at the oral end via the excitatory motor neuron (6) and aboral relaxation via the inhibitory motor neuron (5). The migratory myoelectric complex (see text) is shown here as being conducted by a different chain of interneurons (4). Another intrinsic primary afferent neuron with its cell body in the submucosa also is shown (7). CM, circular muscle; LM, longitudinal muscle; MP, myenteric plexus; Muc, mucosa; SM, submucosa.

The ENS is an extensive collection of nerves and glial cells that constitutes the third division of the ANS. It is the only part of the ANS that is truly capable of autonomous function if separated from the CNS. The ENS lies within the wall of the GI tract and is organized into two connected networks of neurons, nerve fibers, and glial cells: the myenteric (Auerbach) plexus, found between the circular and longitudinal muscle layers, and the submucosal (Meissner) plexus, located in the submucosa (Furness, 2012; Sharkey, 2015). The former is largely responsible for motor control, whereas the latter regulates secretion, ion and fluid transport, and blood ...

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