Gastrointestinal Systems

9.1 Introduction, 284

9.2 The intrinsic innervation of the gut, 285

9.2.1 Identification of neuronal types, 285

9.2.2 Functional classes of enteric neurones, 289

Motor neurones, 289 Interneurones, 290 Sensory neurones, 291

9.3 The extrinsic innervation of the gut, 291

9.3.1 The sympathetic system, 291 Structure, 291 Functions, 291

9.3.2 The parasympathetic system, 293

Structure, 293 Functions, 293

9.4 Myogenic activity of the smooth muscles, 294

9.5 The role of the autonomic nervous system in gut motility, 297

9.5.1 Oesophagus, 297

9.5.2 Stomach, 297

9.5.3 Small intestine, 299 Segmentation and pendular activity, 299

Peristalsis, 301

9.5.4 Gall-bladder and sphincter of Oddi, 302

9.5.5 Large intestine, 304 Ileocaecal junction, 304 Proximal large bowel, 306 Transverse and descending colon, 306

9.5.6 Defecation, 307

9.5.7 Vomiting, 309

9.5.8 Migrating motor complex, 310

9.6 The role of the autonomic nervous system in glandular and epithelial secretion and absorption, 311

9.6.1 Mechanisms, 311

9.6.2 Mucous secretion, 312

9.6.3 Mucosal endocrine secretion, 313

9.6.4 Salivary glands, 314

9.6.5 Gastric secretions, 314

9.6.6 Pancreatic secretion, 317

9.6.7 Gall-bladder, 318

9.6.8 Intestinal secretion and absorption, 319

9.7 Relevant pharmacology, 321

9.7.1 Drugs reducing gastric acid secretion, 321

9.7.2 Emetics and anti-emetic drugs, 322

9.7.3 Drugs affecting intestinal motility, 323

9.1 Introduction

The autonomic innervation of the gut is extremely complicated. The intrinsic neurones of the enteric nervous system (the nerve plexuses in the gut wall) are as numerous as the neurones in the cerebellum, and of sufficient complexity to ensure that the gut can perform the vast majority of its functions in a co-ordinated manner totally independent of the central nervous system. The central nervous system can, however, influence the enteric nervous system, and it does this through the other divisions of the autonomic nervous system, the parasympathetic and sympathetic systems, which supply what could be called the 'extrinsic' as opposed to the 'intrin- chapter 9

sic' innervation of the gut (see Figs 2.15-2.18, pp. 35-7). The extrinsic control Gastrointestinal of the gut is concerned with such things as the preparation of the gut for the Systems receipt of food, the evacuation of the faeces at a convenient time and place, and the shutting down of the activity of the gut when the body has more important demands on its energy resources.

We will deal first here with the general properties of the enteric nervous system and the extrinsic control of the gut by the sympathetic and parasympathetic systems. We will then examine in more detail the role of the autonomic nervous system in the motility and secretory/absorptive activity of the individual regions of the gut.

9.2 The intrinsic innervation of the gut

The enteric nervous system controls motility of the gut and the transport of water and electrolytes across the gut wall. It also modulates blood flow to the gut, and plays a role in the secretion of some gastrointestinal hormones, gastric acid secretion and mucous production.

Most of the intrinsic innervation is found in two networks of interconnected ganglia, the myenteric plexus (Auerbach's plexus) and the submucous plexus (Meissner's plexus), the details of which are given in Chapter 2. The neurones in these plexuses make up complex reflex pathways containing sensory neurones, interneurones and motor neurones within the gut. Figures 9.1-9.3 show some details of the structure. The axons of some neurones run between the two plexuses, interconnecting them, and axons of the motor neurones extensively innervate the smooth muscle layers and the mucosa, often forming separate but non-ganglionated plexuses. The sensory neurones may also project out of the gut and interconnect with the prevertebral ganglia as part of entero-enteric reflex pathways that can influence more distal and proximal parts of the gut, and yet bypass the central nervous system (Fig. 9.4).

The myenteric plexus is found between the longitudinal and circular muscle layers throughout the gut, from the oesophagus to the anal canal. It is a continuous network surrounding the gut circumferentially (Fig. 2.17, p. 37). The submucous plexus is only fully developed in the small and large intestines. Scattered ganglia may occur near the mucosa of other organs.

9.2.1 Identification of neuronal types

Recent histological techniques have enabled the layout of the various plexuses to be seen in whole-mount preparations (Fig. 2.18, p. 37), and in any one species the networks have characteristic patterns in each segment of the gut (Fig. 9.5).

The anatomical details of the innervation of the small intestine of the guinea-pig are being studied in exquisite detail in Australia by J.B. Furness,

Fig. 9.1 This figure shows the three components of the myenteric plexus in the guinea-pig small intestine. The primary plexus (1) consists of the ganglia and the internodal strands. The secondary component (2) consists of nerve bundles that arise from the primary plexus and run parallel to the circular smooth muscle, between it and the internodal strands. These nerve fibres supply the circular smooth muscle. The third component (3) is a network of small nerve fibres running between the primary meshes at the interface between longitudinal and circular smooth muscle. Adapted from Furness & Costa (1987). Scale bar: 100 nm.

M. Costa and their co-workers. It turns out that populations of neurones with similar structures, anatomical positions and functions usually contain antigenic proteins in combinations that are unique to each type. The antigens provide precise markers for populations of neurones, and their visualisation can be achieved using specific antibodies coupled to various labels. These immunohistochemical techniques are thus a powerful tool for identifying classes of neurones, and have enabled many interesting experiments to be designed that have thrown light on the physiological properties and functions of each class.

Initially, the antibodies used were raised against enzymes known to participate in either the synthesis or breakdown of established classical neurotransmitters, such as choline acetyltransferase (the enzyme synthesising acetylcholine) or tyrosine hydroxylase (involved in the synthesis of catecholamines). Later, antibodies raised against a host of biologically active peptides have been utilised. Multiple staining of the same cells with several antibodies linked to different fluorescent labels has shown that many neuronal classes can be uniquely identified by the expression of a group of antigens, many of which are located on neuropeptides that have been shown to have either a neurotransmitter or neuromodulator function. For example, in

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Fig. 9.2 Enzymatic digestion followed by fixation and scanning electron microscopy reveals details of the intermuscular layer between the longitudinal and circular smooth muscles of the guinea-pig small intestine. The meshes of the myenteric plexus are seen covered with a dense network of connective tissue cells. The ganglia are exposed at intervals, for instance at the arrow. This layer also contains blood vessels and lymphatic vessels (one of which (Iv) runs across the figure from top to bottom on the right). Bar: 100 um. From Baluka & Gabella (1987).

Fig. 9.3 Scanning electron micrograph of the submucosa of the guinea-pig duodenum. Elements visible are the ganglia and connecting strands of the submucous plexus (smp), the grape-like clusters of Brunner's glands (Bg), blood vessels (bv), smooth muscle cells of the muscularis mucosa (mm) and fine nerve fibres (n) innervating the latter three. Scale bar: 100 um. From Baluka & Gabella (1987).

Fig. 9.3 Scanning electron micrograph of the submucosa of the guinea-pig duodenum. Elements visible are the ganglia and connecting strands of the submucous plexus (smp), the grape-like clusters of Brunner's glands (Bg), blood vessels (bv), smooth muscle cells of the muscularis mucosa (mm) and fine nerve fibres (n) innervating the latter three. Scale bar: 100 um. From Baluka & Gabella (1987).

Lumbar spinal cord

Proximal colon

Intramural excitatory cholinergic neurone

Lumbar spinal cord

Proximal colon

Fig. 9.4 Diagram of sensory pathways. Sensory neurones in the submucous plexus leave the gut and synapse with neurones in the prevertebral ganglia, setting up local reflexes that do not involve the CNS. Other sensory neurones have their cell bodies in the dorsal root ganglia, and their axons enter the spinal cord, taking information to the CNS.

Fig. 9.4 Diagram of sensory pathways. Sensory neurones in the submucous plexus leave the gut and synapse with neurones in the prevertebral ganglia, setting up local reflexes that do not involve the CNS. Other sensory neurones have their cell bodies in the dorsal root ganglia, and their axons enter the spinal cord, taking information to the CNS.

the stibmucous ganglia in the guinea-pig small intestine, 54% of neLirones are putative cholinergic neurones, judged from the fact that they contain choline acetyl transferase (ChAT). However, these can be divided into three groups: some 29% also contain cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and somatostatin (SOM); some 11% also contain substance P (SP); and the rest contain ChAT alone of these substances.

With reference to the neurochemistry of the enteric neurones, the fact that the cell bodies contain neuropeptides does not, of course, mean that they necessarily release them at their nerve terminals - it is equally possible that the cell bodies may take up neuropeptides released by axons innervating them. Nevertheless, pharmacological studies of the response of neurones and smooth muscle cells to the stimulation of intrinsic nerves and application of putative neurotransmitters and neuromodulators have identified more than 20 substances that could be potential neurotransmitters. A list of the more important of these is given in Table 9.1. It is clear that there is a very considerable degree of complexity of this system, reminiscent of the

Duodenum

Duodenum

Rectum

Fig. 9.5 Patterns of the myenteric plexus from various parts of the guinea-pig intestine. Kindly supplied by G. Gabella.

Fig. 9.5 Patterns of the myenteric plexus from various parts of the guinea-pig intestine. Kindly supplied by G. Gabella.

situation in the central nervous system. In fact, the enteric nervous system is often used for experiments that can shed important light on the functions of the central nervous system, and a large number of the important central transmitters have first been discovered in the enteric nervous system.

9.2.2 Functional classes of enteric neurones

Motor neurones

Excitatory muscle motor neurones. These innervate the longitudinal and

Table 9.1 Potential transmitters and neuromodulators in the enteric nervous system.

Excitatory motor neurones Inhibitory motor neurones

Secretomotor neurones

Interneurones

Acetylcholine* Substance P* Neurokinin A Neuropeptide 7 Neuropeptide k Dynorphin Enkephalin

Nitric oxide*

Vasoactive intestinal polypeptide* ATP

Dynorphin Galinin

Neuropeptide Y Gastrin-releasing peptide

Acetylcholine*

Vasoactive intestinal polypeptide*

Dynorphin

Galinin

Neuromedin U

Cholecystokinin

Calcitonin gene-related peptide

Somatostatin

Neuropeptide Y

Gastrin-releasing peptide

Acetylcholine* Serotonin* Substance P* At least 15 peptides

There are several subclasses of neurones in each group, each of which contains a primary transmitter and a subset of peptides.

* There is evidence that these substances are primary transmitters.

circular muscles, and the muscularis mucosa (the muscle layer under the mucosa). The principal transmitter is acetylcholine, acting through muscarinic receptors. Several peptides are also released from these neurones, and may have longer term actions than acetylcholine. These are principally the tachykinins (substance P and neurokinin A).

Inhibitory muscle motor neurones. These innervate circular and longitudinal smooth muscles. The neurotransmitters vary between regions and species, but it is becoming clear that an important inhibitory transmitter is nitric oxide (NO). Vasoactive intestinal polypeptide (VIP) is also released from several inhibitory neurones, and it is possible that adenosine triphosphate (ATP) may be involved in inhibitory transmission, but this is not well established.

Secretomotor neurones. These enhance the secretion of salts and water across the gut wall into the lumen. There are two classes: cholinergic neurones, which act through muscarinic receptors, and non-adrenergic, non-cholinergic (NANC) neurones, which probably act by releasing VIP, with a similar effect. Another class of cholinergic neurones act on the parietal cells of the gastric mucosa and play a role in gastric acid secretion.

Vasodilator neurones. These act as inhibitory motor neurones on vascular smooth muscle, and probably release VIP

Interneurones

These act in reflex pathways, and may be ascending or descending. They [290]

may be excitatory or inhibitory. Some are cholinergic, some non-cholinergic. chapter 9

Some may use 5-hydroxytryptamine (5-HT) as a transmitter. Gastrointestinal

Systems

Sensory neurones

These may have their cell bodies in the submucosa or in the myenteric plexus. They may be cholinergic or NANC (the transmitters are unknown, but substance P and CGRP are probably important).

9.3 The extrinsic innervation of the gut 9.3.1 The sympathetic system

Structure

The extrinsic sympathetic nerves enter the gut mostly from the prevertebral ganglia and plexuses. The postganglionic axons usually run into the gut wall along with the blood vessels. These fibres form varicose nerve endings, which innervate several different elements in the gut wall.

1 The myenteric plexus contains large numbers of sympathetic axons, with nerve terminals forming synapses on intrinsic neurones. Some cholinergic neurones in particular receive a dense sympathetic input (Fig. 9.6).

2 The submucosal plexus also has a moderately dense sympathetic input, with synaptic connections to some specific neurones.

3 The mucosa receives sympathetic input, with synaptic connections to the mucosal glands.

4 There is a dense sympathetic innervation surrounding the intramural arteries.

There is little, if any, direct sympathetic innervation of the longitudinal smooth muscle cells in most areas of the gut wall, although there may be a sparse sympathetic input to the taeniae and the rectum. There is also only a sparse sympathetic innervation to the majority of circular smooth muscles, and to the smooth muscle in the stomach. Sympathetic relaxation is mediated by inhibition of the cholinergic motor neurones. The only gut smooth muscles that receive a dense sympathetic innervation are the sphincters, where the innervation is excitatory. These include the lower oesophageal sphincter, the pylorus of the stomach, the sphincter of Oddi, the ileocolic sphincter and the internal anal sphincter.

Functions

The main role of the extrinsic sympathetic nerves is inhibition of the activity of the gut. Motility is inhibited by constriction of the sphincters and relaxation of the longitudinal elements of the gut, and secretion is inhibited (with

Fig. 9.6 Electron micrograph of an axo-dendritic synapse in a myenteric ganglion in the guinea-pig. The nerve terminal contains small dense-cored vesicles characteristic of postganglionic sympathetic nerves, and is synapsing onto a dendrite of a myenteric neurone containing mitochondria and microtubules. Scale bar: 0.5 iim. Kindly supplied by G. Gabella.

Fig. 9.6 Electron micrograph of an axo-dendritic synapse in a myenteric ganglion in the guinea-pig. The nerve terminal contains small dense-cored vesicles characteristic of postganglionic sympathetic nerves, and is synapsing onto a dendrite of a myenteric neurone containing mitochondria and microtubules. Scale bar: 0.5 iim. Kindly supplied by G. Gabella.

enhanced reabsorption of fluids and electrolytes). Blood flow is reduced and blood is expelled from the splanchnic circulation.

Postganglionic adrenergic fibres inhibit cholinergic motor neurones in the myenteric plexus, reducing ongoing excitation of the smooth muscle. Inhibition may also occur through direct activation of a-adrenoceptors on the longitudinal smooth muscle cells, which hyperpolarise and inhibit these smooth muscles. Circulating adrenaline will activate a- and |3-adrenoceptors, both of which are inhibitory, and will also activate presynaptic receptors on cholinergic motor neurones, leading to a reduction in acetylcholine release. In the sphincters, tonic contraction is evoked through activation of excitatory a-adrenoceptors, preventing movement of the gut contents from one part to another.

Activating sympathetic nerves to the gut has profound effects on the blood vessels, due to their dense innervation. Arteries are constricted, increasing the resistance to flow, and veins are also constricted, reducing the volume of blood in the splanchnic vasculature. Since about 20% of the total blood volume of the body may be in the splanchnic circulation, and about 40% of this can be expelled by moderate sympathetic activity, this mecha-

nism can be of considerable use in enhancing blood flow to more important chapter 9

areas of the body in an emergency. Circulating adrenaline has a similar Gastrointestinal effect, suggesting that a-adrenoceptors mediating the contractile response Systems are more important in this part of the circulation than ^-adrenoceptors.

Sympathetic nerves inhibit the secretion of water and electrolytes from the mucosa of the small intestine and probably also the large intestine, and also enhance reabsorption. They exert tonic activity on the secretory mechanisms, so that sympathetic blockade results in a net secretory response of the gut. The sympathetic nerves have their effects mainly on the secretomo-tor neurones in the submucosal plexus, which they inhibit through activation of a-adrenoceptors. The epithelial mucosal cells are also directly inhibited by noradrenaline, again mainly through a-adrenoceptors. Reduced secretion and enhanced absorption in response to sympathetic activity and circulating catecholamines are clearly appropriate in many emergency situations, such as haemorrhage, or in heavy exercise, when replacement of body fluids and electrolytes is essential. It is interesting that blood vessels supplying the mucosa and secretory and absorptive cells may be dilated through neural and hormonal pathways independent of the catecholamine system, which is presumably necessary to ensure adequate perfusion for fluid absorption in spite of sympathetic vasoconstriction.

9.3.2 The parasympathetic system

Structure

Extrinsic parasympathetic input to the gut comes through the facial and glossopharyngeal nerves (which supply salivary glands opening into the buccal cavity), the vagus, which supplies the upper part of the gut, and the sacral outflow, which controls the distal part of the gut. The vagal fibres enter the gut wall in the region of the stomach as preganglionic neurones. Some of these neurones run down into the small intestine in the myenteric plexus, but the vagal influence falls off with distance down the length of the gut. The sacral input runs through the pelvic plexus. It is not yet known whether the nerves entering the lower gut are preganglionic or postganglionic.

Functions

Vagal input causes receptive relaxation of the stomach, promotion of acid secretion, promotion of gastrin secretion, and enhanced peristalsis in the stomach and possibly also the proximal small bowel. It also enhances secretion in the small intestine. Input from the pelvic nerves enhances motility, secretion and blood flow in the distal colon and rectum. It is involved in the initiation of defecation, particularly causing the peristaltic contractions that evacuate the lower bowel. Preganglionic cholinergic fibres synapse on many of the motor neurones in the intrinsic nerve plexuses, and have excitatory effects, mainly through nicotinic receptors. There is evidence that some of the preganglionic neurones in the vagus may be non-cholinergic.

9.4 Myogenic activity of the smooth muscles

Although the enteric nervous system is essential for the generation of the complex motility patterns in the gut, the majority of the smooth muscles have an underlying myogenic activity, i.e. they possess mechanisms for the generation of rhythmic contractions. In most gut muscles, these are best studied with electrical recordings of the membrane potential, which undergoes regular depolarisations called slow waves (Fig. 9.7). If these are large enough, they can initiate contractions, either by themselves reaching a voltage at which net Ca2+ entry occurs, or by triggering action potentials that may both involve Ca2+ entry and cause Ca2+ release from internal stores (Fig. 9.8). In many parts of the gut, the slow waves may initially be produced by specialised pacemaker cells, the interstitial cells of Cajal, which lie just outside some of the muscle layers, and interconnect both with enteric nerves and with smooth muscle cells. These cells generate large slow waves by unknown mechanisms. They last between two and five seconds, and vary in frequency from three to 30 per minute, depending on the part of the gut and the species studied. Currents associated with the slow waves then spread through gap junctions into the adjacent smooth muscle layers, and activate voltage-sensitive ion channels, resulting in slow waves in the muscle cells with a configuration characteristic of the part of the gut they are recorded from. In Fig. 9.9 examples of electrical activity recorded from the interstitial cells are shown and from the adjacent smooth muscle cells when

Stomach

Jl_H

Small intestine

30 seconds

Fig. 9.7 Slow wave activity recorded with intracellular electrodes from the stomach, small intestine and colon of the dog. Although the resting potentials, frequencies and amplitudes of the slow waves differ, each consists of a rapid upstroke with a spike-like top, repolarizing to a plateau depolarization followed by rapid repolarization to the baseline. Adapted from Sanders (1992).

Fig. 9.8 The effects of acetylcholine on the slow waves (lower traces) and their evoked contractions (upper traces) recorded from the antrum of the dog stomach. In the lower trace, c labels the control slow wave, which did not evoke a mechanical response. Increasing concentrations of acetylcholine (traces 1-7) increased the amplitude and duration of the electrical slow waves, and from traces 3 onwards, a contractile response was evoked, which also increased with increasing acetylcholine concentration. Adapted from Szurszewski, (1975).

Fig. 9.8 The effects of acetylcholine on the slow waves (lower traces) and their evoked contractions (upper traces) recorded from the antrum of the dog stomach. In the lower trace, c labels the control slow wave, which did not evoke a mechanical response. Increasing concentrations of acetylcholine (traces 1-7) increased the amplitude and duration of the electrical slow waves, and from traces 3 onwards, a contractile response was evoked, which also increased with increasing acetylcholine concentration. Adapted from Szurszewski, (1975).

Fig. 9.9 Electrical activity recorded from isolated segments of the dog colon. On the right the cells are shown, (a) The muscle layers have been experimentally isolated from each other. Under these conditions the longitudinal smooth muscle (LM) shows spike-like activity, the circular smooth muscle (CM) is silent, and the interstitial cells of Cajal (ICC) produce large slow waves, (b) The CM layer remains attached to the ICC. Under these conditions the superficial cells of the CM show regular slow waves of the same rhythm as the ICC. Cells nearer to the ICC will show larger slow waves. Adapted from Liu & Huizinga (1993).

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