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NEURAL CONTROL OF GI FUNCTION

Nerves and neurotransmitters play an important role in regulating the function of the GI tract. In its simplest form, neural regulation occurs when a neurotransmitter is released from a nerve terminal located in the GI tract and the neurotransmitter has an effect on the cell that is innervated. However, in some cases there are no synapses between motor nerves and effector cells in the GI tract. This neural regulation of the GI tract is surprisingly complex. The gut is innervated by 2 sets of nerves---1) The extrinsic nervous system is defined as nerves that innervate the gut, with cell bodies located outside the gut wall; these are actually part of the autonomic nervous system (ANS) 2) The intrinsic nervous system, aka enteric nervous system (ENS), consists of nerves that innervate the gut, with cell bodies located within the gut wall ; these include the submucosal and myenteric plexuses). ***Some GI functions are highly dependent on the extrinsic nervous system, yet others can take place independently of the extrinsic nervous system and are mediated entirely by the ENS. However, extrinsic nerves can often modulate the function of intrinsic nervous system. This extrinsic and intrinsic components--- innervating the gut, are sometimes collectively referred to as the "brain-gut axis."

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Hierarchical neural control of GI function. Stimuli to the GI tract from the meal (e.g., chemical, mechanical, osmotic) will activate both the intrinsic and extrinsic sensory (afferent) pathways, which in turn will activate the extrinsic and intrinsic neural reflex pathways.

INTRINSIC NERVOUS SYSTEMThe ENS is made up of two major neural networks, which are collections of nerve cell bodies (ganglia) and their fibres, all originating in the gut wall - beginning in the oesophagus & extending all the way to the anus : 1) The Auerbachs myenteric plexus (lies between the outer longitudinal and inner circular muscle layers) 2) The Meissners submucosal plexus (lying within the submucosa, i.e. b/w the mucosa & inner circular muscle layer)

Neurons in the two plexuses are linked by interganglionic strands. Neurons in the ENS are characterized functionally as afferent neurons, interneurons, & efferent neurons, similar to the neurons in the extrinsic part of the ANS. Thus, all components of a reflex pathway can be contained within the highly developed ENS. Stimuli in the gut wall are detected by afferent neurons, which activate interneurons and then efferent neurons to alter function.

In this way the ENS can act autonomously from extrinsic innervation. However, as neurons in the ENS are innervated by extrinsic neurons, the function of these reflex pathways can be greatly modulated by the extrinsic nervous system.

The number of neurons in the ENS is about 100 million-- as many as are found in the whole spinal cord , and the system is probably best viewed as a displaced part of the CNS that is concerned with the regulation of GI function. Apart from this , as the ENS is capable of performing its own integrative functions and complex reflex activities -- it is sometimes referred to as the "little brain in the gut" .

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In an attempt to better understand the multiple functions of the ENS, different neurotransmitter substances have been identified ,which are released by the nerve endings of different types of enteric neurons. Two of them with which we are already familiar are (1) Acetylcholine and (2) Norepinephrine ; (6)GABA, (7)NO, (8) CO ;

Others are (3) ATP, (4) Serotonin, (5) Dopamine,

Including certain peptides like (9) CCK, (10) substance P, (11) VIP , (12)

Somatostatin, (14)Endothelin-2 , (17) Neurotensin, bombesin.

(13) Enkephalins ( leu-enkephalin (18) Neuropeptide Y,

& met-enkephalin), (19) Peptide YY , (20) Galanin , (23)

(15) CGRP (Calcitonin Gene Related Peptide) , (16) GRP ,

(21) PACAP (Pituitary Adenylate Cyclase Activating Peptide) , (22) TRH , &

Some of these peptides also act in a paracrine fashion, and some enter the bloodstream,

becoming hormones. Not surprisingly, most of them are also found in the brain. These mediators and regulatory peptides are thus referred to as "brain-gut peptides" . Acetylcholine most often excites GI activity. Norepinephrine almost always inhibits

gastrointestinal activity. This is also true of Epinephrine, which reaches the gastrointestinal tract mainly by way of the blood after it is secreted by the adrenal medullae into the circulation. The other aforementioned transmitter substances are a mixture of excitatory and inhibitory agents, but the specific functions of many of these are not known clearly till date.

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Neural connections of the gut wall, showing (1) the myenteric & submucosal plexuses (black fibers); (2) extrinsic control of these plexuses by the sympathetic & parasympathetic nervous systems (red fibers); (3) sensory fibers passing from the luminal epithelium & gut wall to the enteric plexuses, then to the prevertebral ganglia of the spinal cord and directly to the spinal cord and brain stem (dashed fibers)

Comparison Between the Myenteric and Submucosal Plexuses : Myenteric Plexus Innervates the longitudinal and circular smooth muscle layers and is concerned primarily with the motor activity along the length of the gut. When this plexus is stimulated, its principal effects are --(1)increased tonic contraction, or tone of the Submucosal plexus Innervates the glandular epithelium, intestinal endocrine cells, and submucosal blood vessels and is primarily involved in controlling the function within the inner wall of each minute segment of the intestine.

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gut wall, (2) increased intensity of the rhythmical contractions, (3) increased rate of the rhythm of contraction, & (4) increased velocity of conduction of excitatory waves along the gut wall, causing more rapid movementof the gut peristaltic waves.

For instance, many sensory signals originate from the GI epithelium and are then integrated in the submucosal plexus to help regulate ----(1) local intestinal secretion, (2) local absorption, & (3) local contraction of the submucosal muscle that causes various degrees of infolding of the gastrointestinal mucosa. (4) blood flow to the gut.

*** The myenteric plexus should not be considered entirely excitatory because some of its neurons are inhibitory; their fibre endings secrete an inhibitory transmitter, possibly VIP or some other inhibitory peptide. The resulting inhibitory signals are especially useful for inhibiting some of the intestinal sphincter muscles that impede the movement of food along successive segments of the GI tract, such as--(1) the pyloric sphincter, which controls emptying of the stomach into the duodenum, and (2)the sphincter of the ileocecal valve, which controls emptying of the small intestine into the cecum.

These two plexuses are interconnected with each other. In both the plexuses , the axons

branch profusely, so that stimulation of one region produces a widespread response in the GIT.

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EXTRINSIC NERVOUS SYSTEM

Extrinsic neural innervation to the gut is via the two major subdivisions of the ANS, namely, parasympathetic and sympathetic innervation .I)

Parasympathetic innervation to the gut is divided into two divisions ----

1) Cranial division : Except for a few parasympathetic fibres to the mouth and pharyngeal

regions of the alimentary tract, the cranial parasympathetic nerve fibres are almost entirely in the vagus nerves. These fibres innervate the esophagus, stomach, gallbladder, pancreas, first part of the intestine, cecum, and the first half of the large intestine.2) Sacral division : Originate in the S2 S4 segments of the spinal cord & pass through the

pelvic nerves to innervate the distal half of the large intestine and all the way to the anus.

*** Thus consistent with the typical organization of the parasympathetic nervous system, the

preganglionic nerve cell bodies lie in the brainstem (vagus) or the sacral spinal cord (pelvic). Axons from these neurons run in the nerves to the gut (vagus and pelvic nerves, respectively), where they synapse with postganglionic neurons in the wall of the organ, which in this case are mainly in the myenteric & submucosal plexuses. There is no direct innervation of these efferent nerves to effector cells within the gut wall ; the transmission pathway is always via a neuron in the ENS.

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Extrinsic innervation of the GI tract consisting of the parasympathetic subdivisions of ANS

Stimulation of these parasympathetic nerves causes general increase in activity of the entire ENS. This in turn enhances activity of most GI functions.

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Sympathetic innervation -----

The sympathetic fibers to the GIT originate in the T5 L2 spinal segments. Most of the preganglionic fibers that innervate the gut, after leaving the cord, enter the sympathetic chains that lie lateral to the spinal column, and many of these fibers then pass on through the chains to outlying ganglia such as to the celiac ganglion and various mesenteric ganglia. Most of the postganglionic sympathetic neuron bodies are in these ganglia, and postganglionic fibers then spread through postganglionic sympathetic nerves to all parts of the gut. The sympathetics innervate essentially all of the gastrointestinal tract, rather than being more extensive nearest the oral cavity and anus as is true of the parasympathetics.

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Extrinsic innervation of the GI tract consisting of the sympathetic subdivisions of ANS

*** Sympathetic innervation is supplied by cell bodies in the spinal cord and fibers that terminate in the prevertebral ganglia (celiac, superior, and inferior mesenteric ganglia); these are the preganglionic neurons. These nerve fibers synapse with postganglionic neurons in the ganglia, and the fibers leave the ganglia and reach the end organ along the major blood vessels and their branches. Rarely, there is a synapse in the paravertebral (chain) ganglia, as seen with sympathetic innervation of other organ systems. Some vasoconstrictor sympathetic fibers directly innervate blood vessels of the GI tract, and other sympathetic fibers innervate glandular structures in the wall of the gut.

In general, stimulation of the sympathetic nervous system inhibits activity of the GIT,

causing many effects opposite to those of the parasympathetic system. It exerts its effects in two ways: (1) to a slight extent by direct effect of secreted norepinephrine to inhibit intestinal tract smooth muscle (except the mucosal muscle, which it excites) and (2) to a major extent by an inhibitory effect of norepinephrine on the neurons of the entire enteric nervous system.

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Afferent Sensory Nerve Fibers from the Gut Many afferent sensory nerve fibers innervate the gut. Some of them have their cell bodies in the enteric nervous system itself and some in the dorsal root ganglia of the spinal cord.These sensory nerves can be stimulated by (1) irritation of the gut mucosa, (2) excessive distention of the gut, or (3) presence of specific chemical substances in the gut. Signals transmitted through the fibers can then cause excitation or,under other conditions, inhibition of intestinal movements or intestinal secretion.In addition, other sensory signals from the gut go all the way to multiple areas of the spinal cord and even the brain stem. For example, 80 per cent of the nerve fibers in the vagus nerves are afferent rather than efferent. These afferent fibers transmit sensory signals from the gastrointestinal tract into the brain medulla, which in turn initiates vagal reflex signals that return to the gastrointestinal tract to control many of its functions. *** The ANS, both parasympathetic and sympathetic, also carries the fibers of afferent (toward the central nervous system [CNS]) neurons; these are sensory in nature. The cell bodies for the vagal afferents are in the nodose ganglion. These neurons have a central projection terminating in the nucleus of the tractus solitarius in the brainstem and the other terminal in the gut wall. The cell bodies of the spinal afferent neurons that run with the sympathetic pathway are segmentally organized and are found in the dorsal root ganglia. Peripheral terminals of the spinal and vagal afferents are located in all layers of the gut wall, where they detect information about the state of the gut. Afferent neurons send this information to the CNS. Information sent to the CNS relays the nature of the luminal contents, such as acidity, nutrient content, and osmolality of the luminal contents, as well as the degree of stretch or contraction in smooth muscle. Afferent innervation is also responsible for transmitting painful stimuli to the CNS. Gastrointestinal Reflexes The anatomical arrangement of the enteric nervous system and its connections with the sympathetic and parasympathetic systems support three types of gastrointestinal reflexes that are essential to gastrointestinal control. They are the following:

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1. Reflexes that are integrated entirely within the gut wall enteric nervous system. These include reflexes that control much gastrointestinal secretion, peristalsis, mixing contractions, local inhibitory effects, and so forth. 2. Reflexes from the gut to the prevertebral sympathetic ganglia and then back to the gastrointestinal tract. These reflexes transmit signals long distances to other areas of the gastrointestinal tract, such as signals from the stomach to cause evacuation of the colon (the gastrocolic reflex), signals from the colon and small intestine to inhibit stomach motility and stomach secretion (the enterogastric reflexes), and reflexes from the colon to inhibit emptying of ileal contents into the colon (the colonoileal reflex). 3. Reflexes from the gut to the spinal cord or brainstem and then back to the gastrointestinal tract.These include especially (1) reflexes from the stomach and duodenum to the brain stem and back to the stomachby way of the vagus nervesto control gastric motor and secretory activity; (2) pain reflexes that cause general inhibition of the entire gastrointestinal tract; and (3) defecation reflexes that travel from the colon and rectum to the spinal cord and back again to produce the powerful colonic, rectal, and abdominal contractions required for defecation (the defecation reflexes).

*** The components of a reflex pathway-afferents, interneurons, and efferent neurons-exist within the extrinsic innervation to the GI tract. These reflexes can be mediated entirely via the vagus nerve (termed a vagovagal reflex), which has both afferent and efferent fibers. The vagal afferents send sensory information to the CNS, where they synapse with an interneuron, which then drives activity in the efferent motor neuron. These extrinsic reflexes are very important in the regulation of GI function after the ingestion of a meal. An example of an important vagovagal reflex is the gastric receptive relaxation reflex, in which distention of the stomach results in relaxation of the smooth muscle in the stomach; this allows filling of the stomach to occur without an increase in intraluminal pressure. $#$# In general, as with other visceral organ systems, the parasympathetic and sympathetic nervous systems tend to work in opposition. However, this is not as simple as in the

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cardiovascular system, for example. Activation of the parasympathetic nervous system is important in the integrative response to a meal, and we will look at many examples of this in the following chapters. The parasympathetic nervous system generally results in the activation of physiological processes in the gut wall, although there are notable exceptions. In contrast, the sympathetic nervous system tends to be inhibitory to GI function and is more frequently activated in pathophysiological circumstances. Overall, sympathetic activation inhibits smooth muscle function; the exception to this is the sympathetic innervation of GI sphincters, in which sympathetic activation tends to induce contraction of smooth muscle. Moreover, the sympathetic nervous system is notably important in regulation of blood flow in the GI tract. )