PERIPHERAL NERVOUS SYSTEM

Essentials and Pharmacological

 Peripheral Nervous System
Handles the CNS’s input and output.
Contains all the portions of the NS
outside the brain and spinal cord.
Contains sensory nerves and motor
nerves
Divided into autonomic nervous system
and somatic nervous system.
 Peripheral Nervous System

Sensory Nerves Motor Nerves

(to the brain) (from the brain)
Carry messages from Carry orders from CNS
receptors in the skin, to muscles, glands to
muscles, and other contract and produce
internal and external chemical messengers
sense organs to the
spinal cord and then to
the brain
The ANS is part of the peripheral nervous system
and it controls many organs and muscles within
the body.
In most situations, we are unaware of the
workings of the ANS because it functions in an
involuntary, reflexive manner.
For example, we do not notice when blood
vessels change size or when our heart beats faster.
However, some people can be trained to control
some functions of the ANS such as heart rate or
blood pressure.
The ANS is most important in two situations:

1-In emergencies that cause stress and

require us to "fight" or take "flight"
(run away).

2- In no emergencies that allow us to

"rest" and "digest".
It is usual to divide the nervous system
into somatic, autonomic and integrated
systems.
The somatic nervous system provides
voluntary motor control of skeletal
muscle.
The autonomic nervous system provides
an involuntary control of internal
environment and the viscera.
The two systems are
anatomically separated form
each other, but functionally
they cannot perform their work
independently, and they work
with each other in an integrated
manner
Peripheral Nervous System
Autonomic NS
Somatic NS
Consists of nerves Permits the
connected to Involuntary functions
sensory receptors of blood vessels,
and skeletal Glands and
muscles internal organs e.g.:-
Permits voluntary the bladder
action (writing stomach
your name)
heart
 Characteristic Somatic nervous Autonomic N.
system system
Effectors Voluntary muscle Cardiac muscle
glands, s. muscle
General functions Adjustment to Adjustment within
external environment internal environment
Numbers of neurons 1 2

Ganglia outside the ------------ Chain ganglia,

CNS collateral ganglia or
terminal ganglia
Neurotransmitter acetylcholine Acetylcholine,
adrenaline,
noradrenaline
Center Anterior Horn cells Lateral Horn cells
Comparison of Autonomic and
Somatic Motor Systems
Autonomic nervous system
◦ Chain of two motor neurons
 Preganglionic neuron
 Postganglionic neuron
◦ Conduction is slower due to thinly or
unmyelinated axons

Pre-ganglionic Post-ganglionic

Ganglion
 Sympathetic N.S. Parasympathetic N.S.

Like the accelerator of Like the brakes in your car

your car Slows the body down to
keep its rhythm

Mobilized the body for Enables the body to

action conserve and store energy
Preganglionic: short, synapse Preganglionic: long, synapse
within the lateral & collateral within the terminal ganglia
ganglia

Postganglionic: long Postganglionic: short

Has a wide distributions Has a restricted distributions

• Often work in
Autonomic Nervous System
opposition
• Cooperate to fine-
tune homeostasis
• Regulated by the
brain;
hypothalamus, pons
and medulla
• Can also be
regulated by spinal
reflexes; no higher
order input
• Pathways both
consist of a two
neuron system
Preganglionic neuron autonomic ganglion postganglionic neuron target
from CNS outside CNS
Fig. 45.34(TE Art)
Hypothalamus activates
sympathetic division of
nervous system
Heart rate, blood pressure,
and respiration increase
Adrenal medulla
secretes
epinephrine and
norepinephrine

Blood flow to Stomach

skeletal muscles contractions
increases are inhibited
 Sympathetic
Fight or Flight, Dealing with
stress, thoracolumber,
intermediolateral column,
T1 -L2
Parasympathetic
Rest and Digest,
Craniosacral S2-S4,
Sympathetic nerve endings also
activate the release of NE and E
from the adrenal medulla
Enhances effects of NE from
sympathetic nerve endings
Adds the effects of E to the overall
arousal (“fight or flight”) pattern
The Autonomic System
 Sympathetic
• Sometimes called the
“thoracolumbar” division
• Short preganglionic neurons;
long postganglionic neurons;
ganglia are called the chain
ganglia
• Preganglionic neurons secrete
Ach onto nicotinic receptors
• Postganglionic neurons
secrete NE on to a or b
receptors
• Target tissues are smooth
muscle, cardiac muscle,
endocrine glands, brown fat
Parasympathetic
• Sometimes called the
“cranio-sacral division
• Long preganglionic
neurons;
• short postganglionic
neurons (often in the
target organ)
• Preganglionic neurons
secrete Ach on to
nicotinic receptors
• Postganglionic neurons
secrete Ach on to
muscarinic receptors
• Target tissues are
smooth muscle,
cardiac muscle,
exocrine glands, brown
fat
Anatomical Differences in Sympathetic
and Parasympathetic Divisions
Anatomical Differences in Sympathetic
and Parasympathetic Divisions
 Similarities between Sympathetic & Parasympathetic

• Both are efferent (motor) systems: “visceromotor”

• Both involve regulation of the “internal” environment
generally outside of our conscious control:
“autonomous”
• Both involve 2 neurons that synapse in a peripheral
ganglion and Innervate glands, smooth muscle,
cardiac muscle
glands
CNS ganglion

smooth
muscle

cardiac
preganglionic postganglionic
muscle
neuron neuron
 Differences between Sympathetic & Parasympathetic

Location of Preganglionic Cell Bodies

Sympathetic Parasympathetic

Thoracolumbar Craniosacral
T1 – L2/L3 levels Brain: CN III, VII, IX, X
of the spinal cord Spinal cord: S2 – S4
 Differences between Sympathetic & Parasympathetic

Relative Lengths of Neurons

Sympathetic
ganglion target
CNS

short preganglionic long postganglionic

neuron neuron

Parasympathetic
ganglion target
CNS

long preganglionic short postganglionic

neuron neuron
 Overview of the Autonomic Nervous System
Differences between Sympathetic & Parasympathetic
Neurotransmitters
Sympathetic NE (ACh at sweat glands),
ACh, + + / -, α & ß receptors

• All preganglionics release acetylcholine (ACh) & are excitatory (+)

• Symp. postgangl. — norepinephrine (NE) & are excitatory (+) or inhibitory (-)
• Excitation or inhibition is a receptor-dependent & receptor-mediated response
Parasympathetic ACh, +

ACh, + / -
muscarinic receptors

• Parasymp. postgangl. — ACh & are excitatory (+) or inhibitory (-)

 Overview of the Autonomic Nervous System
Differences between Sympathetic & Parasympathetic
Target Tissues
Sympathetic Parasympathetic
• Organs of head, neck, • Organs of head, neck,
trunk, & external genitalia trunk, & external genitalia
• Adrenal medulla
• Sweat glands in skin
• Arrector muscles of hair
• ALL vascular smooth muscle

» Sympathetic system is distributed to essentially all

tissues (because of vascular smooth muscle)
» Parasympathetic system never reaches limbs or
body wall (except for external genitalia)
Overview of ANS
Functional Differences

Sympathetic
• “Fight or flight”
• Catabolic (expend energy)

Parasympathetic
• “Feed & breed”, “rest &
digest”
• Homeostasis

» Dual innervation of many

organs — having a brake
and an accelerator provides
more control
Chemical transmission

The traveling of signal in the nervous system between

different neurons is mediated by the effect of a
chemical substance released at the nerve terminal
called chemical transmitter.
In the sympathetic nervous system the chemical
transmitter is adrenaline, noradrenaline or sometimes
acetylcholine.
When the chemical transmitter is adrenaline the nerve
fiber is called adrenergic, but when the chemical
transmitter is acetylcholine, the nerve fiber is called
cholinergic.
 Nerves Contact Other Cells at Synapses
The synapse is the relay point where information is
conveyed from neuron to neuron by chemical transmitters.
 At a synapse the axon usually enlarges to from a button '
which is the information delivering part of the junction.
The terminal button contains tiny spherical structures called
synaptic vesicles, each of which can hold several thousand
molecules of chemical transmitter.
On the arrival of a nerve impulse at the terminal button,
some the vesicles discharge their contents into the narrow
cleft that separates the membrane of another cell's dendrite,
which is designated to receive the chemical message.
Chemical transmitters carry the signal across
synapses
Chemical transmitters are made and stored in
the presynaptic terminal
The transmitter diffuses across the synaptic
gap and binds to a receptor in the postsynaptic
membrane.
Binding of the Transmitter Produces an
excitatory postsynaptic potential EPSP or
inhibitory postsynaptic potential IPSP
The Transmitter is Broken down and
Recycled
Once the signal has been delivered the
transmitter must be removed so that new
signals may be received
In some cases the transmitter is broken down
by an enzyme in the synapse
In other cases the transmitter is recycled- it is
transported back into the presynaptic nerve
In still other cases these 2 methods are
combined
 Acetylcholine

Important neurotransmitter in central and

peripheral nervous systems.
Acetylcholine is synthesized in the nerve
terminal.
1- Acetyl-coenzyme A (AcCoA) is
manufacured in mitochondria.
2- Choline is accumulated in the teminals by
active uptake from interstitial fluid.
3- AcCoA + choline = acetylcholine.
Acetylcholine storage

 Acetylcholine is stored in vesciles in the verve terminal after

its synthesis, each vesicle contains approximatly 104 Ach
molecules, which are released as a single packet.

Acetylcholine release
The arrival of the action potential to the nerve terminal, it leads
to increase in the permeability of the terminal to Ca++ influx.
 Ca++ recat with synapsin that bind the vesciles, which on its
unbinding the vesciles sweeps to attach to the presynaptic
membrane.
 The vesciles rupture and the acetylcholine released to the
synaptic cleft.
 Acetylcholine act on its specific receptors on the postsynaptic
membrane.
 Acetylcholine release sites

1-Preganglionic nerve fibres of both

sympathetic and parasympathetic divisions
of the autonomic nervous system.
2-Postganglionic nerves of the
parasympathetic division.
3- The sympathetic innervation of sweet
glands.
4- Neuromuscular junction.
5- Autonomic ganglion to the adrenal gland.
Neurotransmitter release sites
 Acetylcholine inactivation
In synaptic cleft, Acetylcholinesterase
breaks it down into acetate and choline.
50% of choline then re up taken into
presynaptic neuron.
 Acetylcholine receptors

Acetylcholine effects on the tissue are the result of its

action on the receptor present in the membrane of the
effector cells.
Several types of Ach receptors have been characterized by
their sensetivity to agonists (which mimic the action of
Ach) or antagonists (which specifically block the action
of Ach).
Two types of cholinergic receptors are well known:
Nicotinic receptors which are easily activated by agonist
molocule such as nicotine and
Muscarinic receptors: which are sensitive to muscarine.
 Cholinergic receptors
Nicotinic receptors Muscarinic receptors
(Central) (peripheral )
Types Two types:- M1, M2 (cardiac), M3
Ganglionic (glandular&smooth
Neruomuscular muscle) M4
(brain).M5,M6 and M7.
Stimulated Nicotine in small Muscarine, Ach,
by doses, Ach, carbarcholine
metacholine
Blocked by Nicoitin in large doses- Atropine
decameyhonium scopolamine
d-tubourarine-
site Autonomic ganglia Parasympathetic
M.E.P (pre-postganglionic)
Adrenal medulla Sympathetic
Preganglionic neuron. postganglionic nerve
endings (sweat glands
& skeletal muscle).
Nicotinic Receptors
Located in the ganglia of both the
PSNS and SNS
Named “nicotinic” because can be
stimulated by the alkaloid nicotine
Muscarinic Receptors
Located postsynaptically:
◦ Smooth muscle
◦ Cardiac muscle
◦ Glands of parasympathetic fibers
◦ Effector organs of cholinergic sympathetic
fibers
Named “muscarinic” because can be
stimulated by the alkaloid muscarine
Parasympathetic (Cholinergic) Drugs
 Subdivisions of the Autonomic Nervous System

Sympathetic Parasympathetic

Primary norepinephrine
acetylcholine
Neurotransmitter epinephrine (~20%)

Receptors Adrenergic GPCRs Muscarinic GPCRs

& 1 – IP3/DAG, [Ca2+]i PKC M1 – IP3/DAG, [Ca2+]i PKC
Second 2 - cAMP/PKA M2 – cAMP/PKA, PI(3)K
Messenger M3 – cAMP/PKA,
Systems 1 - cAMP/PKA IP3/DAG, [Ca2+]i PKC
2 - cAMP/PKA M4 –
3 - cAMP/PKA M5 – IP3/DAG, [Ca2+]i PKC

Adrenal Medulla
(epi:norepi::80:20)
Comparison of sympathetic and
Parasympathetic Pathways

Neurotransmitters
Receptors
 Drugs Affecting the
Autonomic Nervous System
Parasympathomimetic drugs:
These are drugs which exert an action similar to acetylcholine
and there are two types:-
- Drugs directly stimulate cholinergic receptors - Drugs inhibit
cholinesterase enzyme.
Parasympatholytic Drugs:
These drugs antagonize the action of acetylcholine.
Cholinergic Agents

Drugs that stimulate the parasympathetic

nervous system (PSNS).
Drugs that mimic the effects of the PSNS
neurotransmitter
Acetylcholine (ACh)
 Parasympathomimetic drugs

These are drugs which exert an action

similar to the action of acetylcholine
and it is divided into two groups:
(A) Drugs that directly stimulate the
cholinergic receptors: These include
Ach derivatives that not hydrolyzed
rapidly by cholinesterase e.g.
metacholine, carbachol,
poiolocarpine and muscarine.
(B) Drugs that inhibit the cholinesterase enzyme: These
drugs preserve the action of Ach by preventing the action
of cholinesterase enzyme and they are two types:-
(1) Drugs which has a reversible effect i.e. their action is
temporary e.g. eserine (phyostigmine) and prostigmine
(neostigmine).
 - Eserine: is a generalized drugs which causes generalized
blocking allover the body, thus we use it locally as an eye drops in
treatment of glaucoma otherwise it will cause generalized
parasympathetic effect.
 - Neostigmine:It was used in treatment of myasthenia gravis due to
its direct action on the motor end plate.
(2) Drugs which have irreversible effect i.e. their action
are prolonged e.g. parathion (an insecticide) and
D.F.P. (Diisopropyflurophosphate), which is a toxic
nerve gas.
Parasympatholytic Drugs
These drugs which antagonize the action of
Ach by one of the following mechanisms:-
Competitive inhibition: These drugs occupy
the Ach receptors and present its action.
Persistent depolarization: These drugs cause
prolonged depolarization of Ach receptor thus
they prevent the excitation of the receptor by
the released Ach.
 Parasympatholytic drugs
Muscarinic like action Ganglion blockers Neuromuscular blocker
blockers
These drugs block the These drugs block the These drugs block the
action of Ach at action of Ach at nicotinic nicotinic like action of Ach
cholinergic receptors by recpotors at neuromuscular junction.
blocking the action of
Ach at muscarinic
receptors
e.g.- e.g. e.g.
AtropineHomatropine -Nicotine in large doses. - curare
Hyoscine - Arfonad
- Hexamethonium
Mechanism of action- Competitive inhibition. Competitive inhibition.
competitive inhibition -Persistent depolarization

Clinical use: - Ganglion blocker used - Curare is used as a

Atropine used for:-- for blocking conduction in muscle relaxant
dilation of pupil- relive sympathetic ganglion of
spasm- prevent hypertension.
bronchial secretion
Sympathetic (Adrenergic) Drugs
 NADP+
NADPH
from phe, diet, or protein
breakdown DHBR

BH4 BH2
1
Tyrosine L-Dopa
Tyrosine hydroxylase 2 Dopa
(rate-determining step) H O decarboxylase
O2 2
pyridoxal
H2O 3 O2 CO
DPN OHase in neuro-
2
phosphate
scretory granules ascorbate
Norepinephrine Dopamine
Dopamine hydroxylase
Parkinson’s disease: local
PNMT
Epinephrine deficiency of dopamine
SAM from
synthesis; L-dopa boosts
metabolism of 4 PNMT specific to production
Met adrenal medulla
SAM SAH

Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin; DHBR,

dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH3 transferase; SAH, S-
adenosylhomocysteine; SAM, S-adenosylmethionine
Regulation of the release of Stress
catecholamines and synthesis of Chronic
Hypothalamus
epinephrine in the adrenal regulation
medulla chromaffin cell. ACTH
from adrenal
Cortisol cortex via intra-
Tyrosine adrenal portal
system
Acute L-Dopa DPN
regulation
induction
granule DPN

..............
Neuron 
..
..
Ca2+ NE
PNMT
Epinephrine
NE
 E E E
neuro-
acetylcholine promotes NE E
exocytosis secretory
Adrenal Medulla granules
Chromaffin Cell E E
EEE E NE
EE
NE
 Epinephrine COMT + MAO
Vanillylmandelic acid
Norepinephrine

COMT + MAO
Dopamine Homovanillic acid

Neuronal re-uptake and degradation of catecholamines quickly

terminates hormonal or neurotransmitter activity.
Cocaine binds to dopamine receptor to block re-uptake of dopamine
Dopamine continues to stimulate receptors of the postsynaptic nerve.

Degradation of epinephrine, norepinephrine and dopamine via

monoamine oxidase (MAO) and catechol‑O‑methyl-
transferase (COMT)
Table 1. Classification of Adrenergic Hormone Receptors

Second
Receptor Agonists G protein
Messenger
alpha1 (1) E>NE IP3/Ca2+; DAG Gq
alpha2 (2) NE>E  cyclic AMP Gi
beta1 (1) E=NE  cyclic AMP Gs
beta2 (2) E>>NE  cyclic AMP Gs
E = epinephrine; NE = norepinephrine
Synthetic agonists:
isoproterenol binds to beta receptors
phenylephrine binds to alpha receptors (nose spray action)

Synthetic antagonists:
propranolol binds to beta receptors
phentolamine binds to alpha receptors
 NH2

HOOC

Figure 4. Model for the structure of the 2-adrenergic receptor

 Table 2. Metabolic and muscle contraction responses to catecholamine binding to
various adrenergic receptors. Responses in italics indicate decreases of the indicated
process (i.e., decreased flux through a pathway or muscle relaxation)

1-receptor 2-receptor 1-receptor 2-receptor

Process
(IP3, DAG) ( cAMP) ( cAMP) ( cAMP)
liver/muscle
Carbohydrat glycogenolysis;
 liver
e No effect No effect
glycogenolysis  liver gluconeogenesis;
metabolism
 glycogenesis
Fat
No effect  lipolysis  lipolysis No effect
metabolism
Hormone  insulin  insulin and glucagon
No effect No effect
secretion secretion secretion
Smooth
Smooth Smooth muscle
muscle -
muscle - blood Myocardial relaxation - bronchi,
Muscle some
vessels, - rate, blood vessels,
contraction vascular;
genitourinary force GI tract, genitourinary
GI tract
tract tract
relaxation
 1 or 2 2 receptor
receptor

Gs Gi
s  i 
  
  
GTP GTP
i
s
GTP GTP
 
inactive
ACTIVE X inactive
adenylyl adenylyl
cyclase adenylyl
cyclase
cyclase
ATP cyclic AMP

Figure 5. Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity
 "FIGHT OR FLIGHT" RESPONSE

epinephrine/ norepinephrine major elements in the

"fight or flight" response
acute, integrated adjustment of many complex
processes in organs vital to the response (e.g.,
brain, muscles, cardiopulmonary system, liver)
occurs at the expense of other organs less
immediately involved (e.g., skin, GI).
epinephrine:
rapidly mobilizes fatty acids as the primary fuel for
muscle action
increases muscle glycogenolysis
mobilizes glucose for the brain by  hepatic
glycogenolysis/
gluconeogenesis
preserves glucose for CNS by  insulin release
leading to reduced glucose uptake by muscle/
adipose
increases cardiac output
norepinephrine elicits responses of the CV system - 
blood flow and  insulin
secretion.
Figure 6. Mechanisms for terminating the signal generated by epinephrine
binding to a -adrenergic receptor
epinephrine [1]
dissociation


[2]  GTP 
 GDP
[5] [3] [4]
GTPase
AC
degradation
to VMA OP OP OPOP
[6] OH OH
ATP cAMP AMP phosphorylation
phosphodiesterase of -receptor by binding of -arrestin
-ARK decreases further inactivates
activity even with receptor despite
activated PKA bound hormone bound hormone
phosphorylates
enzymes
insulin activation of protein
phosphatase to dephosphorylate
OH [7] OP enzymes
B1 found on heart muscle and in certain cells of the kidney
B2 found in certain blood vessels, smooth muscle of airways; found where sympathetic
neurons ARE NOT
A1 receptors are found most commonly in sympathetic target tissues
A2 receptors are found in the GI tract and pancreas (relaxation)