5 Neuromuscular Physiology of GI Tract / Enteric Nervous System Flashcards
1
Q
Enteric nervous system (ENS) (p.2)
- The “brain-in-the-gut” analogy
- Origin
A
-
The “brain-in-the-gut” analogy
- the ganglia in ENS are more like the interconnected processes in the brain and have mechanisms for integrating and processing information.
- There are more neurons in the ENS than external efferent neurons innervating the gut.
- these mechanisms are regulated and mediated by the same broad spectrum of transmitters as the brain.
-
Origin
- ENS neurons are neural crest cells that migrate into the developing gut with oral-to anal progression.
2
Q
Enteric nervous system (ENS) organization (p.2-3)
- Myenteric plexus
- Submucosal plexus
- Interstitial cells of Cajal (ICC)
A
-
Myenteric plexus,
- between the longitudinal and circular smooth muscle layers,
- regulates contractions.
-
Submucosal plexus,
- contacts the mucosal cells to gather sensory information and regulate secretions.
- more prominent in small and large intestine,
- less active in stomach,
- mostly absent in esophagus.
-
Interstitial cells of Cajal (ICC)
- specialized cells of mesenchymal origin that act as the pacemakers for gut smooth muscle.
3
Q
Enteric nervous system (ENS) organization (p.4-5)
- Afferent Sensory Neurons to the ENS in the mucosa
- Extrinsic primary afferent neurons (EPAN)
- Intrinsic primary afferent neurons (IPAN)
A
-
Afferent Sensory Neurons to the ENS in the mucosa
- sense mechanical, chemical, thermal, and possibly painful stimuli (e.g. distension, satiety, and abdominal pain) to stimulate the ENS and CNS.
-
Extrinsic primary afferent neurons (EPAN)
- have cell bodies in the nodose ganglia
- provide signals to vagal centers in the medulla oblongata.
-
Intrinsic primary afferent neurons (IPAN)
- have cell bodies in the submucosal plexus
- synapse with ENS interneurons and ganglia in the myenteric and submucosal plexuses.
4
Q
Enteric nervous system (ENS) organization (p.6)
- Excitatory motor neurons
- evoke/
- Project/
- Voltage gated L-type calcium channels/
- Inhibitory motor neurons
- generate/
- project/
- release/
- Innervation is in/
- Inhibitory neurons/
- There is spontaneous/
A
-
Excitatory motor neurons
- evoke excitatory junctional potentials (EJP) for smooth muscle cell contraction and secretion from mucosal glands.
- Project orally from the ganglia to promote contraction and move food anally.
-
Voltage gated L-type calcium channels are essential for full firing of action potentials that drive muscle contraction
- pharmaceuticals that inhibit L-type Ca++ channels (e.g. cardiac calcium blockers) can cause nausea and constipation.
-
Inhibitory motor neurons
- generate inhibitory junctional potentials (IJP) that suppress contraction of smooth muscle.
- project anally from ganglia
- release nitric oxide (NO) and VIP.
- Innervation is in circular muscle of the stomach, intestine, gallbladder, and various sphincters.
- Inhibitory neurons dominate the tone of circular smooth muscle to limit the range of muscle contraction to areas that are near the peak of slow wave potential
- There is spontaneous firing of inhibitory neurons in all intestinal states (feeding and interdigestive).
5
Q
Enteric nervous system (ENS) organization (p.7)
- Secretomotor neurons
- innervate/
- release/
- Excess stimulation of secretomotor neurons/
- Suppression of neuronal excitability/
A
-
Secretomotor neurons
- innervate mucosal secretory glands and epithelial cells.
- release acetylcholine to promote secretion.
- Excess stimulation of secretomotor neurons (excess histamine in mast cell release during allergic response; cholinesterase inhibitors) causes neurogenic secretory diarrhea.
- Suppression of neuronal excitability (opioids) inhibits secretion to promote constipation.
6
Q
Enteric nervous system (ENS) organization:
Transmitters (p.8)
- Multiple chemical transmitters stimulate/
- Serotonin (5-HT)
- Acetylcholine
- Nitric oxide (NO) and vasoactive intestinal peptide/
- NO
- Multiple transmitters, such as norepinephrine from sympathetic neurons or chemicals, regulate/modulate/
A
- Multiple chemical transmitters stimulate afferent and efferent receptors for synaptic transmission.
-
Serotonin (5-HT)
- the main transmitter of afferent neurons
- sense mechanical changes, transmit information to the CNS, and regulate presynaptic transmitter release from ENS interneurons.
-
Acetylcholine
- the main transmitter in parasympathetic and sympathetic ganglia, interneuron junctions, and at post-synaptic excitatory motor neurons.
-
Nitric oxide (NO) and vasoactive intestinal peptide are the main transmitters of inhibitory motor neurons.
- NO is a lipid soluble gas generated by neuronal nitric oxide synthetase (nNOS).
- Multiple transmitters, such as norepinephrine from sympathetic neurons or chemicals, regulate/modulate transmitter release from the ENS interneurons.
7
Q
CNS centers integrate sensory inputs to regulate GI motor functions (p.8)
- The main integrative regulation is from/
- CNS inputs are from/
- Cranial nerve IX/
- CNS inputs are from /
- Cranial nerve IX/
- Chemical trigger zone (area postrema) (CTZ) responds to/
- Anti-nausea drugs/
- Opioids/
- Cranial nerve VIII
- Muscarinic or histamine antagonists/
- Some classes of motility drugs target the CNS regulatory centers rather than direct motility regulation in the gut/
A
-
The main integrative regulation is from
- the dorsal vagal complex in medulla oblongata (consists of the dorsal motor nucleus, nucleus tractus solitarius, area postreama, and nucleus ambiguous)
- pelvic nerves from sacral region of the spinal cord.
-
CNS inputs are from
- gut wall irritation and distension (vagal afferents, EPAN)
- cognition, visual disturbance, and other sensory sensations (also involved in vagal stimulation of digestion; e.g. cephalic phase).
- Cranial nerve IX senses pharyngeal activity and contributes to gag response.
-
Chemical trigger zone (area postrema) (CTZ) responds to chemicals sensed from blood (low blood brain barrier) and GI.
- Anti-nausea drugs, such as ondansetron (Zofran), block 5-HT3 receptors in the CTZ and the solitary tract nucleus (STN; vomiting center).
- Opioids cause nausea by both a complex action involving visual disturbance in the CNS and direct action on presynaptic receptors in the ENS.
-
Cranial nerve VIII from vestibular apparatus
- enriched in muscarinic (M1) and histamine (H1) receptors
- transmits motion detection, creating the potential for GI manifestation as motion sickness.
- Muscarinic antagonists (scopolamine) or histamine antagonists (Dramamine) block motion sickness.
- Some classes of motility drugs target the CNS regulatory centers rather than direct motility regulation in the gut (e.g. dopamine antagonist metaclopramide).
8
Q
Parasympathetic regulation of the GI (p.9)
- Opposite of flight or fight
- Transmission is through/
- efferent vagal nerve fibers
- Efferent pelvic nerve fibers
- The main functions of the muscarinic system in gut pharmacology
- All end organ actions are blocked by/
A
-
Opposite of flight or fight:
- relax, secrete, digest, and move along slowly.
-
Transmission is through acetylcholine
- released at both ganglionic sites (nicotinic receptors) and effector sites (muscarinic receptors)
- The main parasympathetic drive comes from _efferent vagal nerve fibers _
- synapse with motor neurons of enteric nervous system (ENS) in the esophagus, stomach, small intestine, and colon, in addition to the gallbladder and pancreas (e.g. within the myenteric and submucosal plexuses).
- Efferent pelvic nerve fibers synapse with ganglia on the serosal surface of the colon and the ENS in the wall of the large intestine.
-
The main functions of the muscarinic system in gut pharmacology
- stimulation of motor neurons, smooth muscle contraction, peristalsis, sphincter control, and promoting secretions.
- All end organ actions are blocked by atropine-like drugs.
9
Q
Sympathetic regulation of the GI (p.10)
- response
- Preganglionic sympathetic neurons
- project from/
- release/
- Prevertebral ganglia
- Norepinephrine released from postganglionic sympathetic neurons stimulates /
- primary reason for decreased GI secretions.
- Secondary actions
A
- Fight or flight response:
-
Preganglionic sympathetic neurons
- project from the thoracic and upper lumber segments of the spinal cord,
- release acetylcholine at the synapses with the prevertebral ganglia.
-
Prevertebral ganglia
- the celiac, superior mesenteric, and inferior mesenteric.
- Norepinephrine released from postganglionic sympathetic neurons stimulates alpha-adrenergic vasoconstriction in splanchnic vessels to shunt flow to skeletal muscle.
-
primary reason for decreased GI secretions.
- Decreased blood flow in viscera
-
Secondary actions
- direct increase in sphincter tension, presynaptic inhibitory action to decrease transmitter release, postsynaptic inhibition of secretomotor neurons.
10
Q
Review of neurotransmission and modulation of cholinergic signaling (p.11-12)
- Neurotransmission is of particular importance because/
- Transmitter actions on post-synaptic excitable membranes (e.g. ganglionic) and some end organ actions result from/
- excitatory postsynaptic potential (EPSP).
- inhibitory postsynaptic potential (IPSP).
A
- Neurotransmission is of particular importance because pharmacologically active agents modulate the individual steps.
-
Transmitter actions on post-synaptic excitable membranes (e.g. ganglionic) and some end organ actions result from receptor mediated effects on ion channels.
- increases in the permeability to cations (Na+ or Ca++), results in a localized depolarization of the membrane to generate an excitatory postsynaptic potential (EPSP).
- Selective increase in permeability to anions (Cl-), stabilizes or hyperpolarizes the membrane to cause an inhibitory postsynaptic potential (IPSP).
- Increased permeability to K+ (outward current) hyperpolarizes and stabilizes of the membrane potential (IPSP) as Cl- enters.
11
Q
Review of neurotransmission and modulation of cholinergic signaling (p.12-14)
- Modulation is mediated by/
- Afferent nerves release/
- The modulation depends on/
- Many modern chemical therapeutics target/
- Neuromodulation is also the basis of/
- Presynaptic auto- and heteroreceptors are a source of/
- Presynaptic and post-synaptic heteroreceptors that inhibit cholinergic
transmission includes/- Opioid µ-type receptors/
- Opioids have a greater effect on/
A
- Modulation is mediated by a number of different neurotransmitters affecting receptors on pre- and post-synaptic membranes (ganglia and end organ).
- Afferent nerves release serotonin (5HT), histamine, dopamine, and other neurotransmitters at central and peripheral ganglia to increase or decrease cholinergic signaling.
-
The modulation depends on the receptor subtypes for the modulating transmitter, as well as their location (pre- or post-synaptic).
- Many modern chemical therapeutics target the modulating receptors and not the cholinergic receptors to regulate cholinergic physiology (e.g. gut motility drugs, antihistamines).
- Neuromodulation is also the basis of many toxic or adverse drug reactions (e.g morphine, cancer therapeutics, sleep aids).
- Presynaptic auto- and heteroreceptors are a source of both feedback regulation and cross regulation between the parasympathetic and sympathetic nervous systems.
-
Presynaptic and post-synaptic heteroreceptors that inhibit cholinergic
transmission includes receptors for opiates, dopamine, norepinephrine (alpha receptors), etc.- Opioid µ-type receptors populate myenteric neurons in the small intestine and block transmission of inhibitory contractile signals.
- Opioids have a greater effect on increasing contractility in upper GI, but decrease coordinated peristalsis or motility.
12
Q
Types of GI motion
- Major regulation is provided by/
- Slow waves/
- Propulsive, peristaltic reflex/
- Mixing/
- Migrating motor (myoelectric) complex (MMC)/
- Modulation is provided by/
A
-
Major regulation is provided by the enteric nervous system.
- Slow waves are the basal rhythm of the electrical waves through out the GI.
- Propulsive, peristaltic reflex contraction during intermittent feeding for mixing.
- Mixing for digestion.
- Migrating motor (myoelectric) complex (MMC) during fasting for sweeping.
-
Modulation is provided by
- __local pharmacology of GI smooth muscle (tonic myogenic contraction and pacemaker)
- input from the CNS.
13
Q
Smooth Muscle Contraction Patterns:
Electrical slow waves establish patterns of smooth muscle contraction (p.16-19)
- The interstitial cells of Cajal (ICC)
- The slow waves/
- Muscle contraction frequency/
- Slow wave frequency varies in different parts of the GI.
- antrum
- duodenum
- colon
- Inhibitory neurons control/
- Action potentials are generated/
- Chemical inactivation of nerve conduction (tetrodotoxin) /
- The oral and aboral boundaries of a contracted segment reflect/
A
-
The interstitial cells of Cajal (ICC)
- the pacemakers of electrical slow wave generation
- continue at the same frequency without neural input.
-
The slow waves raise the threshold of electrical activity in the circular and longitudinal muscle layers.
- Muscle contraction frequency cannot exceed the frequency of the electrical slow waves, but can be less since not every slow wave elicits an action potential.
-
Slow wave frequency varies in different parts of the GI.
- 3/minute in antrum
- 11-12/minute in duodenum (decrease towards ileum).
- 2-13/ minute in colon depending on segment.
-
Inhibitory neurons control the number of action potentials, and therefore contractions, generated from electrical slow waves.
- Action potentials are generated when inhibitory neurons are inactive.
- Chemical inactivation of nerve conduction (tetrodotoxin) releases inhibition and every slow wave generates an action potential.
- The oral and aboral boundaries of a contracted segment reflect the transition zone from inactive to active inhibitory motor neurons.
14
Q
Smooth Muscle Contraction Patterns:
Peristalsis is the stereotypic propulsive motor reflex in feeding and digestive state (p.20-21)
- Peristaltic action potentials are generated by/
- Action potentials in excitatory neurons spread/
- Action potentials to inhibitory neurons spread/
- The peristaltic reflex circuit/
- Synaptic gates between blocks/
- emesis
- Physiological ileus
- Pathologic (paralytic ileus)
- Paralytic ileus
A
-
Peristaltic action potentials are generated by vagal stimulation in response to swallowing, distention, or feedback from mucosal brushing.
- Action potentials in excitatory neurons spread orally to block the inhibitory neurons and stimulate circular muscle contraction (propulsive).
- Action potentials to inhibitory neurons spread anally to relax circular muscle (receiving) producing physiological ileus.
-
The peristaltic reflex circuit is repeated along the GI with blocks of connected sensory-interneuron-motor neuron.
- Synaptic gates between blocks dictate how many blocks can be recruited in a peristaltic contraction (i.e. distance of the peristaltic wave).
- Peristaltic propulsion in the upper small intestine is reversed in emesis.
-
Physiological ileus is an active inhibitory state and is ablated when inhibitory neural control is lost (therefore, every slow wave will generate a contracting action potential).
- Pathologic (paralytic ileus) results when synaptic gates between segments are held shut.
- Paralytic ileus (e.g. following surgery) can be reversed with muscarinic stimulation (neostigmine).
15
Q
Smooth Muscle Contraction Patterns: Sphincter regulation (p.22)
- Sphincters are tonically kept closed by/
- Sympathetic stimulation/
- Sphincters open in response to/
- Spastic sphincters can be treated with/
- Achalasia
A
-
Sphincters are tonically kept closed by low level muscarinic-stimulated contraction of circular muscle.
- Sympathetic stimulation will enhance contraction and closure.
- Sphincters open in response to high level vagal activity and/or distension of the esophageal wall stimulating inhibitory neuron nitric oxide release.
- Spastic sphincters can be treated with antimuscarinics or Botox (acetylcholine release inhibitor) injections.
- Achalasia (swallowing difficulty due to an inability to relax the esophageal sphincter) is promoted by loss or absence of NO releasing inhibitory neurons in the sphincters.
