Download The Autonomic Nervous System

The Autonomic Nervous
System
2. Physiology
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Carlo Capelli, MD
Department of Neurological, Neuropsychological, Morphological and
Movement Sciences, University of Verona, Italy
The Autonomic Nervous
System
Goals
- General organization
- Specific organization: sympathetic and parasympathetic divisions, ENS
- Synaptic physiology and pharmacology:
Preganglionic synapses (nicotinic receptors)
Parasympathetic Postganglionic synapses (muscarinic receptors)
Sympathetic Postganglionic synapses (noradrenergic receptors)
- Divergence and Convergence
- Functions of ANS: closed feedback control loop and control in ANS
Integrated function
• Sympathetic anc Parasympathetic
divisions act sinergistically on several
organs and/or systems
• A good example of this behaviour is the
integrated action on the cardiovascular
system
Sympathetic and Parasympathetic Effects in the
Cardiovascular System
Sympathetic input to the heart
•  Cardiac nerves form a plexus that innervates atria, SA node, ventricula
•  Effects: tachicardia (right cardiac nerve) and increase of contractility (left cardiac nerve)
•  β1 receptors
Parasympathetic input to the heart
•  Right vagus (inhibit SA node) and left vagus (inhibit conduction of AV node), myocardial
tissue
•  Effects: bradycardia, decrease AV conduction speed, less contractility
Sympathetic input to the blood vessel
•  Vasocostriction or vasodilatation:
•  Which agonist is released ?
•  Which adrenoreceptor that agonist bindes to ?
•  Receptor occupancy causes vasoconstriction or vasodilation ?
•  Which type of receptor subtypes is present or prevail on the target organ ?
Sympathetic and Parasympathetic Effects in the
Cardiovascular System
Sympathetic input to the blood vessel
•  NA has greater activity on and binds with greater affinity to α receptor
•  A has greatest activity on and binds with greater affinity to β receptor
•  However, NA can also activate β receptor: β1 has about the same affinity for NA and A; β2
has a higher affinity for A than for NA
•  However, A can also activate α receptor
•  Vasoconstriction is an α1 effect
•  Vasodilation is a β2 effect
•  Many blood vessels are populated with a mixture of α and β receptor subtypes. The
response depends on the relative dominance of one of the subtypes
•  Therefore, the ultimate outcome in the target tissue depends on the heterogeneous
mixutures of agonists and of types of receptors
•  Example: - blood vessel of the skin have only α1: only vasocostriction
- coronary blood vessels: β2 > α: dilatation prevails.
Sympathetic and Parasympathetic Effects in the
Cardiovascular System
Paraympathetic input to the blood vessel
•  Parasympathetic vasodilator fibers (releasing ACh) are far less common than vasoconstrictor
sympathetic fibers
•  They supply salivary glands, some GI glands and erectile tissue
•  They indirectly cause vasodilation binding to M receptor on neighboring cells
•  ACh binds to M2 receptors of postgnalgionic sympathetic neurons decreasing [cAMP] and
inhibiting the release of NA
•  in erectile tissue ACh binds to M3 receptors on entothelial cells, IP3 is released and [Ca++]
increases stimulating nitric oxyde synthase to produce NO, wich diffuses to the smooth
muscel cells, activates soluble guanyl ciclase with cGMP production and activation of
protein kinase G. The subseqent phosphorilation of MLCK causes relaxation.
•  in salivary glands ACh stimulates the production of callicreine that clivates kininogenes to
vasodialting kinines (bradykinin)
ANS and Control Systems
•  ANS monitors, controls and maintains within an optimal range
several physiological paramaters by means of a series of
properly damped feedback control loops
Error signal
Setpoint
+
E (s)
-
G (s)
H (s) Y (s)
CNS resetting
mechanisms
Output
H (s)
Y (s)
Perturbations
Feedback
•  The internal environment has to be monitored (feedback)
and compared to some set point (SP) and an output
produced to reduce the error signal (ER)
Afferent Limb of Visceral Control System
•  Viscera are also innervated by afferent fibers that monitor nociceptive
mechanical (stretch, arterial pressure, bladder distension), thermal and
physiological chemical (PO2, PCO2, pH, glucose) or noxious
chemical stimuli
•  Many of these unmyelinated fibers
travel in sympathetic nerves, most with
parasympathetic fibers
•  Their cell bodies are located in the
dorsal root ganglia
•  The largest concentration of VA is
found in the vagus nerve that carries
non-nociceptive mechanical and
chemical afferent input from all the
viscera (gastric distension) of thorax
and abdomen
•  Cell bodies of these afferents are
located in the nodose ganglion
Afferent Limb of Visceral Control System
•  Some of these afferents origin from specialised receptors (baroreceptors,
chemoreceptors); others can monitor local chemical (glucose, pH, K+),
thermal (cold, heat) local and/or blood conditions
•  Other afferents encode exteroceptive
informations that can initiate an
autonomic response
Baroreceptors
Autonomic Reflexes and Anticipatory Behaviour
1.  Feedback loop mechanism Arterial pressure control
•  Afferent fibers (IX and X cranial nerves)
respond to elevation of AP with increased
activity as a result of activation of
baroreceptors and carry these informations
to brainstem
•  The level of AP is compared to a reference Brain
AP value (SP)
Stem
•  reciprocal actions in the brainstem are
initiated in proportion to ER= AP- SP
i) inhibition of sympathetic
Autonomic
cardioacceleratory and vasocostrictive
Output
nerves
ii) excitation of parasympathetic
vagus nerve
•  HR is slowed, the arterioles vasodilate and
AP is lowered
•  The behaviour of this system can be
modified by resettin the SP value by CNS
(PS)
(S - A Node)
Autonomic Reflexes and Anticipatory Behaviour
1.  Anticipatory Mechanisms
•  ANS system also anticipates the future needs of behaviour of
the individuals
•  F.I., efferents from motor or premotor cortical areas are
irradiated at the early beginning of (or even before) exercise
and activate cardiovascular and respiratory control areas in
the brainstem: Central Command
•  Because of this anticipatory, feedforward stimulation, HR
and V’A can promptly increase at the beginning of exercise
and AP set point is reset
Brainstem Nuclei and Forebrain Structures
involved in ANS functions
“ …the word autonomic suggest a much greater degree of
independence of the central nervous system than in fact exists”
•  Indeed, it was soon realised that ANS is under the control of centers
in the brain
1.  A variety of brainstem structures/nuclei are involved in visceral
control.
- Nucles Tractus Solitarius (NTS), ventrolaterla medulla,
medullary raphe, reticular formation, locus coerules,
parabrachial nucleus, nuclei of the cranial nerves
- They may play a well-defined role or they are linked to multiple
autonomic functions
Brainstem Nuclei - NTS
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NTS is one of the most important strucure, located in the medulla
It integrates multiple inputs from visceral afferents and exerts control
over autonomic output
it is the major lower brainstem command center for visceral control
•  It contains second-order sensory
neurons and receives
baroreceptors, chemoreceptor
and visceral non-nociceptive
afferents (tractus solitarius)
from organs of thorax and
abdomen
•  Subnuclei devoted to
cardiovascualr, respiratory,
gustatory and GI input and
control
•  Outputs to several parts of CNS
(SC)
•  NTS
CONNECTIONS TO/FROM NTS
Receive inputs from
Vagus n. (peripheral chemoreceptors/aortic bodies, baroreceptors, nonnociceptive afferent input from every organ of thorax and abdomen
Connections of NTS
Glossopharyngeal N. (taste and peripheral chemoreceptors/carotid
bodies,carotid baroreceptors)
Facial n. (taste)
Trigeminal n. (teeth, sinuxes)
Ventrolateral medulla
Medullary raphe
Area postrema
Periacqueductal gray
Prabrachial nucleus
Hypothalamus
Cerebral cortex
Send Outputs to
Intermediolateral cell column, sacral parasympathetic neurons
Preganglionic sympathetic neurons
Dorsal motor nucleus of vagus
Preganglionic parasympathetic neurons
Nucles ambiguus
Ventrolateral medulla
Medullary raphe
Area postrema
Prabrachial nuclei
Reticular formation
Forebrain nuclei
Phrenic motor nucles and other respiratory output pathways
Hypothalamus
Forebrain
Several regions of the forebrain play a role in coordinating and
modulating the activities of the lower centers of ANS
Hypothalamus: paraventicular nucleus
it projects to parabrabrachial nucleus, medullary raphe,
NTS, central grey matter, ILC of spinal cord
it coordinates autonomyc function with
feeding,thermoregulation, circadian rythms, water
balance,emotions, sexual drive, reproduction
Limbic system: includes the majority of the forebrain regions
involved in this modulation
Neocortex: Minimal conscious control of ANS, but emotions,
mood, anxiety, stress and fear cal alter ANS functions and
responses
Afferent limb and Referred Pain
•  In the CNS (spinal cord and brain stem) the visceral pain is mapped
viscerotopically
•  The visceral afferents terminate in laminae I and V of the dorsal horn of
spinal cord
•  In spinal cord there is a large class of cells that respond both to visceral
and somatic afferent stimulation, i.e. thare is a substantial divergence in
the afferent input
•  The nociceptive fibers travel with sympathetic fibers and enter the spinal
cord at a specific segmental level
•  Viscerotopic mapping is lost at the level of the cerebral cortex
•  Thus, awareness of visceral pain is not localized to a specific organ,but it
is referred to the dermatome (delimited kjin area) innervated by the
same spinal nerve.
•  This is called referred pain.
More complications: Nicotinic and Muscarinic
Receptors on Postganglionic Neurons
•  Some sympathetic and parasympathetic postganglionic neurons have muscarinic
in addition to nicotinic receptors
•  This means that the release of ACh from preganglionic neurons may induce both
muscarinic and nicotinic effects
•  Multiphasic response:
- fast EPSP, nicotinic
- slow EPSP, muscarinic
More complications: Nicotinic and Muscarinic
Receptors on Postganglionic Neurons
•  Muscarinic neurotransmission inhibits
specific K+ current, M current
•  At baseline M current is active, thereby
producing a slight depolarization
•  Electrical stimulus of the neurons produces
only a single spike
•  With muscarinic stimulation M current is
turned off leading to a small depolarization
•  If stimulation is repated, repetitive spikes
appear
•  Muscarinic receptors modulates the
repetitive firing properties and enhance the
ability of ANS to control visceral activity
More complications: non Classic Neuromediators
may be Released at Each Level of ANS
•  Some neurotransmissions in the ANS involves neither
adrenergic nor cholinergicpathways
•  Many neuronal synapses use more that a single
neurotransmitter - cotransmission
•  Several different neurotransmitter may be found within some
neurons - colocolization
•  Non noradrenergic non cholinergic transimmiters may be
found at every level of ANS, especially in the ENS
•  It is not clear what controls the release of each of the many
neurotransmitters, but the proportions of released
neurotransmitters are controlled by firing frequences.
Neurotransmitters and Neuromodulators in the ENS
NEUROTRANSMITTERS AND
NEUROMODULATORS IN ENS
Acetylcholine (Ach)
Noradrenaline (NA)
Serotonin (5-HT)
Dopamine
Tachykinines (substance P, neurokinin A, neuropetide K,
neuropeptide γ)
Nitric Oxide (NO)
Adenosine triphosphate (ATP)
Vasoactive intestinal polypeptide (VIP)
γ-Aminobutyric acid (GABA)
Chlecystokinin (CCK)
Somatostatin
Gastrin-releasing peptide (GRP)
Enkephalines
Dynorphin
Calcitonin gene-related peptide (CGRP)
Neurotensin
Galanin
Neurotransmitters Present Within the ANS
NEUROTRANSMITTERS PRESENT WITHIN THE ANS
SYNAPSE
TRANSMITTERS
Presynaptic
Postsynaptic
CNS neurons
Preganglionic autonomic neurons
Glutamate
Glycine
Substance P
Serotonin
Noradrenaline
TRH
Enkephalines
Neuropeptide γ
Neurotensin
Neurophysin II
Oxytocin
Somatostatin
Preganglionic autonomic neurons
Postganglionic autonomic neurons
Acetylcholine
Substance P
CGRP
Postganglionic autonomic neurons
Target cell
Noradrenaline
Acetylcholine
NO
Neuropeptide γ
Galanin
Somatostatin
VIP
Opioid peptides
Visceral afferents
Neurons in autonomic ganglia or spinal cord
Substance P
CGRP
Interneurons
Peripheral autonomic ganglia and ENS
Dopamine
Enkephalines
Nonclassic Transmitter - ATP
•  Postganglionic sympathetic
vasoconstrictor neurons
•  Purinoreceptors (P2x,
ionotropic, P2γ, P2u,
metabotropic)
•  Vasoconstriction
•  Cotransmission: ATP, NPY
and NA
• P2x receptors in smooth muscles have a
relative high C++ permeability; rapid
depolarisation and contraction followed by a
second, slower phase
Nonclassic Transmitter - NO
NO (nitric oxide)
•  A short lived, vasodilating gas
produced locally from L-Arginine
by the enzyme nitrico oxide
synthase (NOS)
•  Activated by shear stress on
endothelial cells
Nonclassic Transmitter - NO
•  NOS is found also in pre
and postganglionic
sympathetic and
parasympathetic neurons
•  A parasympathetic
neurons, f.i, may release at
the same time
(cotransmission) Ach, NO
and VIP and potentiate
smooth muscel relaxation.
Enteric Nervous Sytem (ENS)
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A collection of nerve and sensory, motor and inter-neurons foming plexus that
surround the GI tract
Myenteric plexus: between external longitudinal and deeper circular smoothmuscle layers - motility controlo
Submucosal plexus (Auerbach): between circular muscle and muscolaris
mucosae- secretion control
They receive:
1.  Preganglionic parasympathetic fibers
2.  Postganglionic sympathetic fibers
Postganglionic
Sympathetic
Afferents
Preganglionic
Parasympathetic
Auerbac
Meissner
Scanning electron micrograph
Enteric Nervous Sytem (ENS)
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ANS modulates the activity of ENS, but it can by and large function
normally without extrinsic control
SNC
Sensory neurons
Chemoreceptors
Interneurons
Motor neurons
Reflex circuits
Inhibitory
Mechanoreceptors
Chemoreceptors
Epitelium
Muscles
Motor programs
Excitatory
Blood vessels
Bibliography
•  Boron WF, Boulpaep EL, Medical Physiology,
Saunders
•  Fisiologia dell’Uomo, autori vari, Edi.Ermes,
Milano
–  Capitolo 4: Il Sistema nervoso vegetativo