Download The Autonomic Nervous System

The Autonomic Nervous System
1. Anatomy and general organisation
• 
• 
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
Hystoric Remarks
The autonomic nervous system was described at the
beginning of the twentieth century by Langley and coworkers
an the term “Autonomic Nervous System was first used by
Langley in 1921
As defined, ANS is a motor system
“The ANS consists of nerve cells and nerve fibres, by
means of which efferent impulses pass to tissues other than
striated muscles”
Functions
• ANS is responsible for controlling our internal
environment through “autonomic” processes
(metabolic, cardiopulmonary, hormonal, visceral)
that never stop and continue independently of our
awakeness
• This is in contrast with those parts and functions
of our CNS involved, f.i., in voluntary movements,
voluntary cognitive processes
General Organisation
1.  Somatic motor neurons (soma located in CNS, excitatory,
monosynaptic link with the target, i.e striated muscle)
2.  Autonomic motor neurons: innervate organs, blood
vessel, adipose tissue, components of the skin and also
organs of the immune system
•  ANS has three Divisions
1.  Sympathetic
2.  Parasympathetic
They can function independently, but they often work
sinergistically
3. 
Enteric (located within the wall of gastrointestinal tract; a network - plexus - of
afferent neurons, interneurons an motor neurons) that can function independently
from other parts of ANS
Sympathetic and Parasympatehic
Divisions
General organization
•  Two-synapse pathways
•  Cell bodies in the CNS:
preganglionic neurons
•  Outside CNS they make
synapses with
postganglionic neurons
in peripheral ganglia
•  Axons from
postganglionic neurons
project to target organs
Sympathetic Division-Preganglionic Neurons
Thoracolumbar Division
Preganglionic Neurons
•  Soma in the thoracic and
upper lumbar spinal cord
between T1 and L3
•  They lie in the so called
intermediolateral cell
column (lateral horn)
•  Axons exit the spinal cord
through the ventral roots
along with the somatic motor
neurons.
•  After entering the spinal
nerves, they enter the white
rami
(myelinated)communicantes
and enter the nearest
paravertebral ganglion
Sympathetic Division-Paravertebral ganglia
1
3
2
Paravertebral Ganglia
•  The chain extends from the neck to
the coccyx
•  Superior cervical ganglion (C1 C4): head, neck
•  Middle (C5, C6) and Inferior
(C7,C8) fused with the first thoracic
to form Stellate ganglion, which,
together with upper thoracic and
middle cervical, innervates, heart,
lungs and bronchi
Sympathetic Division-Prevertebral ganglia
Prevertebral Ganglia
•  They form the prevertebral
plexus
•  This organisation is possible as a
preganlgionic fiber synapses on
many postganglionic neurons
located within one or several
nearby ganglia
Sympathetic Division-Postganglionic
Neurons
Postganglionic neurons
•  Axons from paravertebral ganglia
via the gray (unmyelinated) rami
communicantes (from C2 to
coccyx)
•  Postganglionic neurons of
prevertebral ganglia: axons travel
within other nerves or along blood
vessels
•  They are rather long
Parasympathetic Division-Pre/Postganglionic
Neurons
Preganglionic Neurons
•  Soma of preganglionic neurons:
medulla, pons and midbrain
and S2-S4 level of spinal cord
•  Craniosacral Division
•  Preganglionic fibers of the brain
stem: they distribute with four
cranial nerves (III, VII, IX, X)
•  Preganglionic fibers S2-S4:
pelvic splachnic nerves to
terminal ganglia of descending
colon, rectum, bladder
Postganglionic Neurons
•  Located at the periphery and
widely distributed within the
walls of their target organs
•  Postganlgionic fibers are short
Parasympathetic Division - III, VII, IX and X Cranial Nerves
III: Edinger-Westphal Nucleus
•  Preganglionic fibers via
the Oculomotor Nerve
•  They synapse in the
Ciliary Ganglion
•  Postganglionic fibers:
papillary constrictor
smooth muscle, smooth
muscle of the ciliary body
Parasympathetic Division - III, VII, IX and X Cranial Nerves
VII: Superior Salivatory Nucleus
•  Preganglionic fibers via
the Facial Nerve
•  They synapse:
1. in the Pterygopalatin
Ganglion
•  Postganglionic fibers:
lacrimal glands
2. In the Submandibular
Ganglion
•  Postganglionic fibers:
submandibular and
sublingual glands
Parasympathetic Division - III, VII, IX and X Cranial Nerves
X: Dorsal Motor
Nucleus Vagi
(DMN), Nucleus
Ambiguus (NA)
and IX
•  Preganglionic fibers via the Vagus
Nerve (viscera of thorax and
abdomen between pharynx and
distal colon)
•  They synapse in the esophageal,
pulmonary, cardiac plexuses with
ganglia located within the target
organs
•  DMN: gastric, insulin, glucagon
secretions
•  NA: striated muscle of pharynx,
larynx, esophagus, bradycardia
Convergence and Divergence
•  Convergence: Many preganglionic axons may synapse on a single
postganglionic neurons (4-15 pre to one post)
•  A single synaptic event is not sufficient to initiate an action potential in
the postganglionic neurons, but the summation of multiple events is
required to initiate it
•  Divergence: relatively few preganglionic neurons synapse with many
postganglionic neurons located within one or several nearby ganglia
(1:10; 1:100)
•  It allows for massive activation by few spinal centers of multiple
sympathetic targets under extreme conditions (flight or fight)
•  However, any impulse crosses a single synapse between pre and
postganglianic neurons
Synaptic physiology of ANS
General concepts
•  Many visceral targets receive both inhibitory and
excitatory synapses
•  These antagonistic synapses arise form the two divisions of
ANS
1. organs activated during exercise:
a. sympathetic: excitatory
b. parasympathetic: inhibitory
2. organs whose activity increases at rest
a. parasympathetic: excitatory
b. sympathetic: inhibitory
•  Exception: sweat glands, piloeroector muscles and most peripheral blood
vessels receive only sympathetic inputs
Synaptic physiology of ANS
Synapses of ANS
•  Rather than synaptic terminals, many postganglionic
autonomic neurons have varicosities distributed along their
axons within the target organs
•  Many varicosities form “en passant” synapses with the
target cells
Synapses of ANS with the target system shown in scanning electron micrograph
Preganglionic synapses
Ganglionic Transmission
•  Synaptic transmission between
pre- and post-ganglionic neurons
is mediated by acetylcholine
acting on nicotinic ionotropic
receptor N2
•  They are different from those
found at neuromuscular junction
(N1)
Pharmacology of
receptors
•  N2 stimulated by
tetramethylammonium
resistent to D-tubocurarine
•  N1 stimulated by
decamethonium
blocked by D-tubocurarine
Parasympathetic Postganglionic synapses
Postanglionic Transmission
•  Synaptic transmission
between post-ganglionic
neurons and target organs is
mediated by acetylcholine
acting on muscarinic
metabotropic receptor M
•  Activation can either
stimulate or inhibit the
function of the target cell
Muscarinic receptors
Physiology
• 
They are metabotropic receptors that interact with heterotrimetric G proteins
• 
Their actions are mediated by second messengers and are slow and prolonged
• 
The interactions occur by
1. 
Stimulating the hydrolysis of phosphoinositide (PIP2) and increase [CA++] and activate protein kinase
C
2. 
Inhibiting adenylate cyclase and decreasing the levels of cAMP
3. 
Directly modulating K+ channels via the G-protein βγ complex
Pharmacology
• 
Five different subtypes (M1 to M5) coded by five different genes
• 
They are stimulated by Ach and blocked by atropine
• 
M1, M3, M5: via the hydrolisis of PIP2
• 
M2, M4: inhibition of adenylate cyclase and decrease the levels of cAMP
• 
The five subtypes are heterogeneously distributed among tissues, they are found both pre
and postsynaptically, many smooth muscles coexpress multiple muscarinic receptors
Sympathetic Postganglionic synapses
Postanglionic Transmission
•  Synapses are noradrenergic
(noradenaline, NA)
•  A noticeable exception: sweat
glands, ACh
•  α and β metabotropic receptors
G-protein coupled
•  Each class has multiple
subtypes: α1, α2, β1, β2 and β3
•  α: greater affinity fo NA
•  β: greater affinity for A
•  Receptors have tissue-specific
distribution:
• α1 blood vessels
• α2, presynaptic
• β1, heart
• β2,bronchial muscle, lungs
• β3,adipose tissue
Sympathetic Postganglionic Synapses
Postanglionic Transmission
•  Synapses are noradrenergic
(noradenaline, NA)
•  A noticeable exception: sweat
glands, ACh
•  α and β metabotropic receptors
G-protein coupled
•  Each class has multiple
subtypes: α1, α2, β1, β2 and β3
•  α: greater affinity fo NA
•  β: greater affinity for A
•  Adrenal medulla: is a special adaptation of this division of ANS
•  homologous to a sympathetic ganglion
•  the postsynaptic targets are the chromaffin cells innervated
by pregangliar sympatehtic neurons (nicotinic Ach receptors)
•  chomaffin cells release epinephrine or adrenaline, A in
the blood stream causing generalized effects
•  Receptors have tissue-specific
distribution:
• α1 blood vessels
• α2, presynaptic
• β1, heart
• β2,bronchial muscle, lungs
• β3,adipose tissue
Sympathetic Postganglionic Synapses
Pharmacology
•  α1 agonists:
phenylephrine, methoxamine
•  α1 antagonists:
phentolamine prazosin (selective),
•  α2 agonists:
clonidine (reduces the NA release due to presynaptin hinibition,
bradycardia, hypotension)
•  α2 antagonists:
yohimbine
•  β1 agonists:
isoproterenol, dobutamine (heart failure)
•  β1 antagonists:
metoprolol, atenolol (beta blockers) (hypertension)
•  β2 agonists:
terbutaline, isoproterenol, salbutamol, formoterol (asthma)
•  β2 antagonists:
butoxamine, propanolol, (beta blockers)
•  β3 agonists:
amibegron, solabegron, isoproterenol
•  β3 antagonists:
SR 59230A
Receptor Distribution - A sinopsys
Target organs
Eye
Pupillar radial m.
Pupillar constrictor m.
Cyliary m.
Heat
NSA
Atria
AVN, ventricular
condiction system
Cholynergic effectc
Myosis
Contraction for close vision
Badycardia
Decrease of contractility and velocity
of conduction
Decrease of velocity of conduction
Slight decrease of contractility
Receptors
2
1
1
1
1
Blood vessels
Coronaries
NS
Skin
Sletal muscle
NS
NS
CNS
Lungs
NS
NS
2
2
Splanchnic
NS
Salivare glands
NS
2
Adrenergic effects
Mydriasis
Relaxation for remote vision
Tachycardia
Increase of contractility
Increase of velocity of conduction
Increase of contractility
Increase of velocity of conduction
Increase of automaticity and frequency of
hydiopathic pacemakers
Constriction
Dilatation
Constriction
Constriction
Dilatation
Constriction
Constriction
Dilatation
Constriction
Dilatation
Constriction
Receptor Distribution - A sinospys
Target organs
Cholynergic effects
Kidney
Proximal tubuli
Renine release
NN
Receptprs
Aderenergic effects
Increased reabsorbtion of natrium
Increased release of renine
2
Lung
Bronchial smooth muscles
Bronchial glands
Contraction
Dilatation
Stomach
Motility and tone
Sphincters
Secretion
Increase
Relaxation
Stimulation
2,
2
Motility and tone
Sphincters
Secretion
Increase
Relaxation
Stimulation
2,
2
Gallbladder and ducts
Contraction
Relaxation
Uncertain
2
Decrease (normally)
Contraction (normally)
Inhibition (?)
GI
Urinary bladder
Detrusor urinae
Sphincter, trigone
Urether
Motility and tone
Sphincter, trigone
Utero
Contraction
Relaxation
Decrease (normally)
Contraction (normally)
Inhibition (?)
Relaxation
2
Relaxation (normally)
Contraction
Uncertain
Increase
Variable
Relaxation
Pregnancy: contraction
No pregnancy: relaxation
2
Signaling Pathways for Nicotinic, Muscarinic and Adrenergic Receptors
(Synopsis)
G PROTEIN
LINKED
ENZYME
2ND
MESSENGER
RECEPTOR TYPE
AGONISTS
ANTAGONISTS
N1 nicotinic, ACh
ACh, (nicotine
decamethonium)
D-Tubocurarine. αbungarotoxin
N2 nicotinic, ACh
ACh, (nicotine,
TMA)
Hexamethonium
M1/M3/M5 muscarinic,
ACh
ACH (muscarine)
Atropine,
pirenzepine (M1)
Gαq
PLC
IP3 and DAG
M2/M4 muscarinic, ACh
ACH (muscarine)
Atropine,
methoctramine (M2)
Gαi and Gαo
Adenylyl
ciclase
[cAMP]i
α1-adrenergic
NA>A
(phenilephrine)
Phentolamine
Gαq
PLC
IP3 and DAG
α2-adrenergic
NA>A (clonidine)
Yohimbine
Gαi
Adenylyl
ciclase
[cAMP]i
β1-adrenergic
A>NA
(dobutamine,
isproterenol)
Metoprolol
Gαs
Adenylyl
ciclase
[cAMP]i
β2-adrenergic
A>NA
(terbutaline,
isoproterenol)
Butoxamine
Gαs
Adenylyl
ciclase
[cAMP]i
β3-adrenergic
A>NA
(isoproterenol)
SR 59230A
Gαs
Adenylyl
ciclase
[cAMP]i
ACh: acetylcholine; cAMP, cyclic adenosine monophosphate; DAG, diacylglicerol; A, adrenaline; NA, noradrenaline; IP3,
inositol 1,4,5-triphosphate; PLC, phospholipase C,;TMA, tetramethylammonium
Bibliography
•  Boron WF, Boulpaep EL, Medical Physiology,
Saunders
•  Fisiologia dell’Uomo, autori vari, Edi.Ermes,
Milano
–  Capitolo 4: Il Sistema nervoso vegetativo