Neuro-Endocrine Regulation of GI Flashcards

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Submucosal Plexus

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  • layer of nerves found beneath the mucosa
  • nerves within this plexus send out processes which synapse on other nerves within the plexus (inter-neurons), as well as, effecter cells (secretory, endocrine) located within the mucosa and submucosa, and also smooth muscle cells in the circular muscle layer.
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Myenteric Plexus

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  • nerves reside between the circular and longitudinal layers of smooth muscle
  • Output from these nerves primarily regulate and coordinate the contractility of the muscle layers. The innervation of muscle layers can either inhibit or stimulate muscle activity dependent on the neurotransmitter released. However, visceral smooth muscle contractility is generally under inhibitory control.
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5
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Inputs to the Enetric (Intrinsic) Neuronal Plexi

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  • CNS - sympathetic and parasympathetic autonomics
  • walls of the alimentary canal itself - proprio- and chemo receptors located within the mucosa and submucosa
  • neurons within wach plexus communicate via interneurons - reflex arcs
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6
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Outputs from the Enteric (Intrinsic) Neuronal Plexi

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  • Outputs from the neuronal plexi regulate all functions of the alimentary canal, and modulate function of the pancreas, gall bladder, as well as, provide information to the central nervous system.
  • Interneurons within the plexi coordinate activities along the canal.
  • Cholinergic neurons (acetylcholine) located in the submucosal plexus regulate secretory cell activity while cells in the circular muscle layer are regulated by neurons located within both plexi. This is particularly true for the sphincter regions, which are thickenings of the circular layer.
  • On the other hand, the longitudinal muscle layers that drive movements along the canal are regulated primarily by neurons whose cell bodies are located in the myenteric plexus.
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7
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Extrinsic Regulation - Sympathetic Innervation

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  • The Salivary glands are innervated by fibers originating in the superior cervical ganglia.
  • Thoracic and lumbar cord segments extend neurons to the celiac, superior and inferior mesenteric and hypogastric plexuses (the Sympathetic Chain).
  • These ganglia send out axons that innervate the enteric plexi via adrenergic (norepinephrine) synapses, and directly innervate the pancreas, liver, gall bladder and vascular smooth muscle of feed arterioles.
  • The primary consequence of sympathetic stimulation is a general inhibition of motor and secretory function that includes enhanced contraction of the alimentary sphincters via activation through the submucosal plexus.

***Possibly the most important response to sympathetic output is vasoconstriction through the direct innervation of blood vessels.

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Extrinsic Regulation - Parasympathetic Innervation

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  • The 7th and 9th cranial nerves innervate the salivary glands.
  • Vagal branches innervate from the esophagus through the ascending colon, and include the liver, pancreas and gall bladder.
  • The descending colon to anus is innervated by pelvic nerves.
  • All parasympathetic fibers synapse on neurons within the enteric plexi. The response to parasympathetic stimulation is a general increase in motor and secretory function within the alimentary canal, and ancillary organs.
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9
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Extrinsic Regulation - Central Afferents

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•Afferents to the spinal cord travel primarily in vagus nerves, with fewer in sympathetic tracts.

-However, visceral pain signals, originating in nerve endings (receptors) located in the wall of the alimentary canal, are carried via sympathetic nerve fibers whose cell bodies reside in the “sympathetic chain” ganglia.

  • Most afferent signals arise from proprio- and chemo-receptors located in the mucosa with their cell bodies located in the myenteric and submucosal plexi.
  • Afferent signals are transmitted from the plexi to either the sympathetic chain or spinal cord where these signals are assimilated. Thus afferent sensory signals can elicit local responses within segments of the canal via direct enteric reflex, and can coordinate responses between different segments of the canal via long central reflex arcs.
  • In addition, parasympathetic afferent fibers provide information to hypothalamus regarding moment-to-moment feeding behavior.
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10
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Reflex Arcs

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  • In general, reflex arcs are described by their point of origin and termination.
  • For example, an enteric reflex that initiates in the intestine to regulate gastric acid secretion is referred to an entero-gastric (or -oxyntic) reflex.
  • A classic reflex that originates from stretch of the stomach to enhance motility of the colon is called the gastro-colic reflex. This reflex travels from the stomach via the vagus nerve to the spinal cord, then back to the colon also via the vagus. Therefore, this is in the general class of a vago-vagal reflex.
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11
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Intergration of Signals

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Signal integration occurs primarily within the enteric nervous system, but also through long reflexes coordinated in prevertebral ganglia and spinal cord.

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12
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Extrinsic Intergration

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  • Afferents signals originating from enteric receptors are relayed through the enteric neuronal network then feed into the parasympathetic and sympathetic arms of the ANS.
  • These fibers synapse centrally where they integrate with incoming signals from other areas of the alimentary canal, as well as, with higher centers.
  • The summation of signals at this level modifies subsequent feedback to the digestive tract. Since the pancreas and biliary tract receive no direct innervation from the alimentary canal, all sensory feedback is via these “spinal reflexes.”
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13
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Intrinsic Integration

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  • Integration within the canal is coordinated through enteric neurons.
  • The strongest input comes from local alimentary receptors, but these intrinsic signals are influenced by long reflexes from central autonomics.
  • When food resides in a specific region of the tract, local signals to the enteric plexi to drive local alimentary function.
  • Long reflexes coordinate activity, but rarely are strong enough to override strong local signals such as distension or lumenal acidity.
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14
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Hormone

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Chemical messenger produced and secreted by a specialized gland, released into the blood where it “circulates” to distant organs to elicit a physiological response. Effects are exerted relatively slowly, but for prolonged periods The GI tract is the largest endocrine organ in the body. It produces a wide variety of hormones and biologically active peptides

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15
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Gastrin Family

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  • Increases Intracellular Ca2+
  • Gastrin
  • CCK (neurotransmitter and hormone)
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16
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Secretin Family

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  • Activates adenylate cyclase, increasing cAMP
  • Secretin
  • VIP (neurotransmitter and hormone)
  • GIP
  • Glucagon
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Gastrin

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  • Gastrin is released by G-cells located primarily in the pyloric antrum portion of the stomach in response to vagal (neural) stimulation, peptides in the stomach, and stretch of the stomach.
  • Gastrin’s primary actions are to stimulate HCl secretion from oxyntic glands and stimulate growth of mucosa in the stomach and pancreas.
  • At high levels gastrin stimulates contractility (mixing) of the stomach and closure of the pyloric sphincter.
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Secretin

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  • Secretin is secreted by duodenal and jejunal S-cells in response to increased H+ (pH < 4) and to lesser degree free fatty acids in the small intestine.
  • Secretin stimulates secretion of bicarbonate and water by the pancreas and biliary tract
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CCK

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  • Cholecystokinin (also called Pancreozymin CCK–PZ); is secreted by duodenal and jejunal I-cells.
  • CCK release is stimulated by certain essential amino acids and long-chain fatty acids in the small intestine.
  • CCK stimulates pancreatic secretion of enzymes and gall bladder contraction.
  • CCK also promotes growth of pancreatic acinar cells.
  • hormone and a neurotransmitter (NANC)
  • At high levels CCK, like Gastrin, activates motility of the stomach and closure of the pyloric sphincter.
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GIP and Glucagon

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  • The ‘Incretin’s’ Glucose-dependent insulinotropic peptide (GIP) and Glucagon like peptide-1 (GLP-1).
  • These peptides are released from duodenal K-cell and L-cells respectively, primarily in response to luminal glucose, and their primary action(s) is to enhance secretion of insulin from Beta-cells and reduce glucagon secretion from alpha-cells of the pancreas.
  • Glucose in the small intestine (with subsequent absorption to blood) elicits a much greater release of insulin than does injection of glucose intravenously due to incretin release from the intestine by the alimentary glucose load.
  • At physiological levels, GLP-1 also inhibits gastric emptying, and has significant satiety effects.
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Distribution of Cells that Secrete GI Hormones

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  • Mucosal endocrine cells distributed throughout the mucosa and at the base of the crypts of the intestine and distal stomach.
  • The mucosal endocrine cells structurally resemble mucosal epithelial cells involved in digestion and absorption in having brush borders. These cells contain “receptors’ for digestive products or other lumenal factors which promote the release of GI hormones, though little is known about the mechanisms for sensing nutrients.
  • Since these cells reside within the canal itself, and their secretion is stimulated by factors within the lumen, the rate of secretion of a hormone is dependent upon the length of small intestine lumen that contains the stimulatory factor; i.e.; the length of lumen that is active.

-Full secretory rates are observed only when the entire proximal small intestine is active, and wanes as the chyme is moved distally.

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Other (Candidate) Hormones

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  • There are several peptides that regulate specific GI functions, which may be considered as GI hormones, however either the mechanism of action or stimulus for release of these peptides is not known.
  • Pancreatic Polypeptide
  • Ghrelin
  • Motilin
  • Enteroglucagon (GLP-1)
  • Entero-oxyntin
  • Enteropastrone
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Pancreatic Polypeptide

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  • Candidate hormone
  • produced in pancreas islets of Langerhans, and its release is likely stimulated by nutrients in the intestine.
  • PP inhibits pancreatic enzyme and HCO3 - secretion, and may act as a “break” on secretion, since maximal secretory rates are rarely observed.
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Motilin

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  • Candidate hormone
  • Motilin clearly plays a physiological role, since there is a direct correlation between elevated blood motilin and onset of a pattern of alimentary motility during periods of fasting.
  • However, the stimulus for motilin release and its mechanism of action are not known, so it is considered a “candidate hormone”
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Ghrelin

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  • Candidate hormone
  • Ghrelin is secreted from the gastric mucosa, which stimulates hunger during inter-digestive periods.
  • Stomach resection leads to decreased blood ghrelin that may be related to “loss of appetite” in these individuals.
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Enterogastrone and Entero-oxyntin

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  • Candidate hormone
  • There are two other purported hormones, which have been observed only through functional studies- no structural information exists. Both peptides are secreted from the small intestine and feed back onto the acid secreting glands to either stimulate or inhibit gastric acid secretion. Since little is known about these peptides, they are given generic names of enterogastrone (inhibitor of gastric secretion) and entero-oxyntin (stimulator of gastric secretion).
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Not Adrenergic Nor Cholinergic Transmitters - Peptide Modulators of GI Function

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  • VIP and Guanylin
  • GRP or bombesin
  • Enkephalins
  • Substance P
  • CCK
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Peptide Modulators of GI Function

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Many peptides are active modulators of GI function. These peptides can exert their actions in several ways.

1) They can act in an endocrine fashion by being released into the general circulation and acting at sites remote from their site of release.
2) They can function in a paracrine fashion by acting at sites near their site of release.
3) They can serve as neurotransmitters by being released from nerve endings

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Paracrine Peptide Modulators of GI Function

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  • Somatostatin
  • Histamine
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VIP and Guanylin

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  • NANC
  • mucosa and muscle of gut, colon
  • Relaxation of smooth muscle. Elevates cAMP in intestinal mucosa, activates NaCl and water secretion.
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GRP or bombesin

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  • NANC
  • gastric mucosa
  • gastrin release
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Enkephalins

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  • NANC
  • mucosa and muscle of gut
  • sphincter muscle contraction
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Substance P

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  • NANC
  • salivary glands
  • secretion, blood flow enhanced
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Somatostatin

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  • Paracrine
  • Released by cells within the submucosa where they directly regulate function of adjacent cells; blood levels are not significantly elevated.
  • decreases gastrin secretion
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Histamine

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  • Paracrine
  • Released by cells within the submucosa where they directly regulate function of adjacent cells; blood levels are not significantly elevated.
  • Stimulates acid secretion (secreted from “Enterochromaffin cells”) Activates crypt fluid secretion in intestine and colon (originating from Mast cells?)
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Regulation of Gastrin Secretion

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  • The primary regulator of Acid Secretion is the hormone gastrin.
  • Secretion of gastrin into the blood is also closely regulated.
  • Described here are the primary mechanisms for regulating the release of Gastrin from the G cells located within glands residing in the sub-mucosa of the pyloric region of the distal stomach.
  • G cells have receptors on their lumenal surface, which can sample the contents of the gastric lumen (amino acids).
  • In addition to this primary sensory information, Gastrin secretion is modulated by somatostatin released from cells located within the pyloric glands (paracellular regulation), as well as, neural input from the submucosal plexus.