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PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 1

MAJOR DIVISIONS OF THE NERVOUS SYSTEM

Somatic Nervous System: Voluntary involved largely with the control of skeletal muscles.

Autonomic Nervous System: Autonomous, involved with the involuntary control of most physiological functions
necessary for life. Functions to maintain "homeostasis" or constancy of the internal environment. Consists of two
major branches known as the sympathetic and parasympathetic.

Enteric Nervous System: Also autonomous, but more specifically involved with the control of the gastrointestinal
system.

EFFERENT VS. AFFERENT NERVES

going inward

going
Away

Afferent neuron: information going from peripheral to CNS

efferent neuron: information going away form CNS to peripheral

Descending pathway from motor cortex to control

volunteering movement

if you want to move ur arm or walk or

whatever, your motor cortex of your brain
sends information down activate alpha motor
neuron, it sends signal to skeletal muscle by
efferent motor neuron that intimate
contraction.

somatic motor nerves consist of a single neuron whose cell body is in the ventral horn and which synapses in skeletal muscle

1 actual neuron that control movement of skeletal muscle are cells body's in ventral horn. cell body's of somatic efferent nerves
projected in continues axon and synapse in skeletal muscle at neuron muscular. this neuron is continues, it is not intermediate.
it is myelinated and it is fast, soJ.W.
it gives precious motorofcontrol.
Regan/Department this neuron
Pharmacology because use neuron
& Toxicology/University oftransmitter
Arizona acetylcholine call
cholinergic nerve and it release acetylcholine ACh as neurotransmitter @ synapse btw efferent motor nerve and effecter organ
@ organ we have nicotinic cholinergic receptor (Nm) {N=nicotinic, m=muscle}
 -
brain spinal cord

Peripheral Nervous system

Somatic
Enteric
( gut )
Autonomic
nervous system

a
Yaresymtethet
Sympathetic ,

Esfihtiflight
,
f
Rest I
digest
Response

middle part that is gray is cell

body and white part is axons
that are myelinated so that is
why it looks white
 in case of somatic nervous system we have neurons that have afferent sensory neurons that pick up sensory
information form receptor that are present in bone, joints, muscle, and sending information through continuous
neuron that call dorsal root

information from afferent nervous system travels through dorsal roots. there are synapses on inner neurons at
level of spinal cord where it comes in and information sends in ascending dorsal pathway that project to the
somatic sensory cortex which is in top of your brain which image your body position.

efferent motor neuron that we have descending pathways

from motor cortex that controls voluntary movement. these
descending neurons come to synapse on cell body of the
efferent what is called alpha motor nerve.

cell body ofnerve

cholinergic somatic: isefferent
containsnerves
neuronlocated at ventral horn
no intermediate. it is
and continueand
myelinated in project
is fast soaxon in synapse
it gives in skeletal
it precious motor muscle
control.at
neuron skeleton muscle
use neurotransmitters acetylcholine.
release acetylcholine ACH as neurotransmitter at synapse
between efferent motor nerve and effective organ that we
have cholinergic receptor
 Ps P

Ps
ps p p

Ps P Ps P

PS=pre-synaptic
P=postsynaptic
ganglion contain cell bodies & synapses
in somatic nervous system we have presynaptic nerve but postsynaptic structure is effector organ not a nerve

oA#h%en
0=7
cholinergic Actylcheline AS Hoh)
sympathy
make
,
=
neurotransmitter
and

one
Nicotinic
Reqptor
colinergic Vn)
short cell body synapses with 20-260 post-ganglionic neuron, it is not strictly 1 to 1

n=heuro:
we named the neuron by transmitter that release. post ganglionic in sympathetic release NE so we called it adrenergic
neuron however it has nicotinic receptor

post ganglionic fibers are in sympathetic nervous system are mostly adrenergic

post ganglionic in parasympathetic system are cholinergic

receptor on organ is adrenergic receptor because activated by NE, adrenalin, ....

there are 9 adrenergic receptor in human body, that called IAKIBKD

XZA , XZBKZC
13,1132/13 }
Acetylcholine
exception of sympathetic system M3 => muscarinic receptor

AKS
kidneys went
O=eA
Not Ademg
Adrenal
...
:c

Felines
eccrine sweat gland (control body heat) M3
one

M3 apocrine sweat gland (associated w/ stress) 91 Receptor

post ganglionic call cholinergic here and release Ach and receptor on organ is muscarinic recptor

adrenal gland activate by pre ganglionic and when it activated it relese 20% NE

Gratifies
and 80% epinephrine then NE & Epinephrine go to blood and everywhere in
body and activate all alpha1b,alpha2b,and beta receptors through body so this is
a global activation of adrenergic nervous system which is part of fight and
flight. when you scared you release NE, and E in blood adrenergic receptors in

the
tch
all body activated.

#se Dopamine ,

OT
0
Dapaminajc neuron d,
Receptor on kidney
parasympathetic

)
( Always

_#9ItchjA#
liners i c

he

NN

Ach that release from post ganglionic neuron act on muscarinic receptor (M1-M5)

pre-occupied:
M2 located on heart and activation of this cause heart slow down heart rate contraction
but in sympathetic heart receptor is beta which increase heart rate contraction

M3 present on most glands

sympathetic and parasympathetic work opposite of each other

for example in heart when NE release activate beta 1 adrenergic receptor in heart to increase heart rate force and contraction in
parasympathetic system activation of parasympathetic nerves cause activation of M2 muscrinic receptor in hear cause slow heart
rate and contraction
 PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 2

we have nerve that called visceral

sensory neuron that have receptor
located in visceral (heart, eye,
intestine, lung,...) these carry sensory
information back into nervous
system.

it project to inner neuron in dorsal

horn of spinal cord. on motor side we
have visceral efferent motor nerve.

cell body's in ventral horn; in somatic system cell body's of alpha motor neuron located through spinal cord but in autonomic nervous system the
cell body's in sympathetic branch are in thoracic & lumbar region and parasympathetic neurons are in cervical and sacral
ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM

J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona

they have short pre-ganglionic fiber that
synapses chain of ganglia that close to cord,
that make diff btw sympathetic and
parasympathetic
Spotlight Figure 137

Peripheral Distribution of Spinal Nerves

SENSORY INFORMATION
A spinal nerve collects sensory information from peripheral
structures and delivers it to sensory nuclei in the thoracic or
superior lumbar segments of the spinal cord. The dorsal, ventral,
and white rami also contain sensory fibers.

From interoceptors From exteroceptors,

of back proprioceptors of back 4 The dorsal root of each
spinal nerve carries
sensory information to
3 The dorsal ramus carries sensory the spinal cord.
information from the skin and
skeletal muscles of the back.
Somatic
sensory nuclei

2 The ventral ramus carries sensory

information from the ventrolateral
body surface, structures in the
body wall, and the limbs.

Dorsal
root
From exteroceptors, ganglion
proprioceptors of
body wall, limbs

From interoceptors
of body wall, limbs
Rami
communicantes
Visceral
Ventral sensory nuclei
root
= Somatic
sensations
= Visceral 1 The sympathetic nerve
sensations
carries sensory information From interoceptors
from the visceral organs. of visceral organs

426
 MOTOR COMMANDS
A spinal nerve distributes motor commands that originate in motor
nuclei of the thoracic or superior lumbar segments of the spinal cord.

To skeletal Postganglionic fibers to

muscles of smooth muscles,
back glands, etc., of back

2 The spinal nerve forms just

lateral to the intervertebral
3 The dorsal ramus contains
foramen, where the dorsal
somatic motor and visceral motor
and ventral roots unite.
fibers that innervate the skin and
Dorsal root
Dorsal root skeletal muscles of the back.
ganglion

4 The axons in the relatively large

ventral ramus supply the
1 The ventral root of each spinal
ventrolateral body surface,
nerve contains the axons of structures in the body wall, and
somatic motor and visceral the limbs.
motor neurons.

Visceral motor nuclei

To skeletal muscles
of body wall, limbs
Somatic motor nuclei
Rami
communicantes Postganglionic fibers to
smooth muscles, glands,
= Somatic motor etc., of body wall, limbs
commands
Sympathetic
= Visceral motor ganglion
commands 5 The white ramus is the first branch from the
spinal nerve and carries visceral motor fibers to
a nearby sympathetic ganglion. Because these
Postganglionic fibers to
preganglionic axons are myelinated, this branch
smooth muscles,
glands, visceral organs has a light color and is therefore known as the
in thoracic cavity white ramus.
7 A sympathetic nerve
6 The gray ramus contains postganglionic fibers
contains preganglionic and
postganglionic fibers that innervate glands and smooth muscles in the
Preganglionic fibers to
sympathetic ganglia innervating structures in the body wall or limbs. These fibers are unmyelin-
innervating thoracic cavity. ated and have a dark gray color.
abdominopelvic viscera
Together, the white and gray rami are known as
the rami communicantes (R-m ko-m-
ni-KAN-tz), or communicating branches
(singular, ramus communicans).

427
 PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 3
Sympathetic Nervous System (SNS)

A. Cells of origin: thoracic and lumbar cord (thoracolumbar).

B. One-pre-ganglionic fiber innervates about 20 post-ganglionic fibers.
C. Innervation and neurotransmitters:

Parasympathetic Nervous System (PNS)

A. Cells of origin - Cranial and sacral cord (i.e., craniosacral).

B. One pre-ganglionic fiber innervates about 1 post-ganglionic fiber.
C. PNS innervates most organs/tissues that the SNS innervates, EXCEPT resistance blood
vessels (arterioles), skin and mucosa.
D. Innervation and Neurotransmitters:

sympathetic input cause shut the gut down and parasympathetic influence in gut rest and digest , these are in higher level work cuz gut has its
own nervous system.

Enteric Nervous System part of autonomic nervous system

control movement of gut

A. Cells of origin: intramural plexuses (myenteric and submucosal)

of the wall of the intestine.
B. Complex innervation, also receives input from postganglionic
sympathetic and preganglionic parasympathetic fibers. Regulate
blood
C. Utilizes a number of neuropeptide (e.g., substance P) and other Circulation
transmitters, such as 5-hydroxytryptamine (serotonin).
I secretion of
D. Controls gut motility and secretion.
food into the lumen I
lumen where the food is beneath of mucosa there is submucosal has a lot of blood vessels that are responsible for take nutrition out of gut it control
J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona blood flaw
outside of submucosa there is 2 muscle layers which are circular muscle layer and longitudinal muscle layer
circular muscle layer: mash stuff 4 Reabsorption
longitudinal muscle:
PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 4
Summary of Somatic Nervous System:

A. Cells of origin throughout the spinal cord.

B. No intermediate ganglions.

C. Neurons are cholinergic and released ACH binds to nicotinic cholinergic receptors at
neuromuscular end plate in skeletal muscle.

D. Under voluntary control.

Summary of Autonomic Nervous System:

A. Consists of the sympathetic and parasympathetic divisions.

B. Cholinergic neurons liberate ACH.

C. Adrenergic neurons liberate NE.

D. All pre-ganglionic neurons are cholinergic.

E. All post-ganglionic parasympathetic neurons are cholinergic.

F. Most post-ganglionic sympathetic neurons are adrenergic (except those innervating sweat
glands).

G. Adrenal medulla is an adrenergic organ (liberates NE & EPI in blood).

H. Functions autonomously as a homeostatic mechanism.

1. Frequently opposing (e.g., heart rate, bladder), but not always. For example
innvervation of the sweat glands and most blood vessels is only sympathetic and sometimes
effects are similar, for example on the salivary glands.
2. Sympathetic: tonically active, more widespread and can be discharged as a unit as in
the fight or flight response.
3. Parasympathetic: Generally more discrete and localized (bladder control). Tends to
function during periods of lowered activity (rest and digest).

Summary of Enteric Nervous System:

A. Cells of origin are in the walls of the intestine (myenteric and submucosal plexuses).

B. Receives input from both divisions of the autonomic nervous system.

C. Neurons utilize a variety of neurotransmitters.

D. Functions in the control of the gastrointestinal tract, even after denervation of the autonomic
innervation.
J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona
PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 5

Control of Micturition: An Example of Autonomic Integration with Voluntary Function

there is a tonic activation of sympathetic post ganglionic fibers that

origanate form cell bodies. post ganglionic release NE and activate
alpha 1 receptor which is present on smooth muscle on internal
sphincters and keep that sphincters contracted and close. tonic
activity you do not have to think about cuz it is autonomic

-
consciously as bladder fills with fluid U get sensory activation of sensory
afferent nerve, activation of sensory afferent contracted by
conscious activation of somatic nervous system. so when it gets
worse and worse you are consciously and it is not autonomic
anymore activating somatic efferent nerve to keep external
sphincters close

sensory afferent says stop and pee and somatic try to keep system
shut down

Cholinergic Receptor Sites (examples):

Cardiac muscle Muscarinic Receptors (M-2)
Exocrine glands Muscarinic Receptors (M-3)
Smooth muscle Muscarinic Receptors (M-3)
Ganglia (PNS & SNS) & Adrenal Medulla Nicotinic Receptors (N-neuronal) Nn
Skeletal Muscle End Plate Nicotinic Receptors (N-muscle) Nm
Sweat Glands (Sympathetic NS) Muscarinic Receptors (M-3)
Brain & spinal Cord Muscarinic (M-1), Nicotinic (N-neuronal)

Adrenergic Receptor Sites (examples):

Resistance Blood Vessels (arterioles) Alpha-1
Capacitance Blood Vessels (venules) Alpha-1
Smooth Muscle of Most Organs Alpha-1
Post-Ganglionic Adrenergic Neurons Alpha-2
Cardiac Muscle Beta-1 (predominantly)
Respiratory Smooth Muscle Beta-2
Blood Vessels in Skeletal Muscle Beta-2
Skeletal Muscle (not innervated) Beta-2
Smooth Muscle of GI Tract Alpha-1
Urinary Tract Alpha 1 & Beta-2
Fat Cells Beta-3
Renal/Mesenteric Blood Vessels D-1

J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona

 PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 6

2. after acetylcholine generated it transport

to vesicle that is responsible for fusing with @ choline transporter is responsible for bringing
presynaptic membrane to release @ choline in
neurotransmitter called ?
choline acetyl transferase add acetyl group to
there is VAT (vesicular acetylcholine choline to generate acetylcholine
transporter) that is responsible for moving
acetylcholine form cytoplasm in to vesicle
2
that stored
autoreceptor activated by whatever
neurotransmitter release by neuron
3
upon activation, depolarization of post and this autorecptor has to cholinergic
ganglionic neuron, this vesicle fuses with receptor cuz neuron release Ach
presynaptic membrane and release content
of vesicle, so acetylcholine release to the if neuron was adrenergic, NE would
synapse release so autoreceptor has to
3
adrenergic so it is usually alpha 2
adrenergic
this presynaptic neuron could have M3
cholinergic receptor so this presynaptic
if presynaptic release neurotransmitter a
receptor called heteroreceptor cuz it is
lot it would bind to autoreceptor and
t
different with neurotransmitter that
you get inhibition. they are inhibitory.
neuron has
this is presynaptic inhibition.

Generalized cholinergic synapse in the parasympathetic nervous system. Acetylcholine (Ach) is synthesized from choline
and acetyl-CoA by choline acetyltransferase, a cytosolic enzyme. The Ach is transported into the synaptic storage vesicle
where it is released into the synapse following nerve depolarization. The released Ach binds to N-nicotinic receptors in
ganglionic synapses and to muscarinic receptors at neuro-effector junctions. Ach is broken down by the actions of
acetylcholinesterase in the synapse (from Katzung 11th ed., figure 6-3).

4. final step is metabolism acetylcholine by esterase

which hydrolysis acetylcholine to choline & acetate
and terminate action of neurotransmitter
later this choline would take up by neuron for
biosynthesis

Generalized noradrenergic synapse in the sympathetic nervous system. As described in detail on the next page of this
handout, norepinephrine (NE) is synthesized in several steps starting from tyrosine. NE is transported into the synaptic
storage vesicle where it is released into the synapse following nerve depolarization. The released NE binds to postsynaptic
alpha-1, alpha-2 or beta-adrenergic receptors depending upon the tissue/organ. Some of NE is broken down by the actions
of a variety of enzymes as detailed on the next page and some is transported back into the presynaptic neuron and reused
(from Katzung 11th ed., figure 6-4).

J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona

drug inhibit transporter for choline so
this has inhibitory effect
drug interact with transporter and inhibit re-uptake so
less Ach in vesicle

Ach that does not take up in vesicle usually broken

down that is why it goes to vesicle to protected, to
stored and have it available for release
this is toxin that produce by bacteria that kill release of Ach
drugs can activate this receptors (agonist) will facilitate action so in
system parasympathomimetic drugs mimic the action of Ach that we
can also block by antagonist drugs that called parasympatholytic
we can inhibit acetylcholine esterase.
it is different with cholinergic system, there is specific
re-uptake system for NE. this is true for seratonin
which we have sertonin transporter and dopamin
trnsporter.

specific transporter re-uptake neurotransmitter, and this

go back to presynaptic neuron and take back to vesicle
it could metabolize as well
it would terminate too cuz we remove it form synapse
reuptake and metabolism terminate action of
transmitter
inhibit vesicular reuptake of dopamine to the vesicle then
there is not transmitter in vesicle when you fuse with
membrane you get diminished response cuz you donot
release enough neurotransmitter
 we can have drug that mimic action of catecholamines
like NE which is sympathomimetic 0

or we can give a drug that sit on receptor & block

neurotransmitter action
one difference between sympathetic & parasympathetic is neurotransmitter reuptake of neurotransmitter
in sympathetic nerves system there is reuptake of NE which there is a specific transporter and there is specific transporter for reuptake of
sertonin and other one for dopamine reuptake. these are important to target pharmacologically for example cocaine inhibit dopamine
reuptake system. this is facilitatory cuz neurotransmitter is not take back up is not available to activate receptor so there is more
neurotransmitter in synapse and you facilitate activation of the system. cocaine facilitate dopamine adrenergic neurotransmitter which is
part of pleasure pathway. antidepressants drug facilitate monoamine neurotransmission.
in parasympathetic system acetylcholine esterase enzyme is responsible for degradation of acetylcholine so by blocking this enzyme you
facilitate neurotransmitter cuz you have more neurotransmitter around

in sympathetic nervous system drugs block MAO and it prevent break down of catecholamines which is facilitate
 PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 7

nor=without
without methyl group

Pathway for the biosynthesis of dopamine, norepinephrine (noradrenalin) and epinephrine (adrenalin). The rate-limiting
enzyme in this pathway is tyrosine hydroxylase (TH) whose activity essentially controls the whole pathway. TH and DOPA
decarboxylase are cytosolic enzymes. Cytosolic dopamine is then transported into the synaptic storage vesicle where it is
converted to norepinephrine (NE) in noradrenergic neurons (in dopaminergic neurons it is the end product). In adrenergic
neurons, the NE is transported out of the storage vesicle and into the cytoplasm where it is converted to epinephrine (EPI)
by phenolethanolamine-N-methyltransferase. The EPI is then transported back into the storage vesicle.

Phase II I
phase

final products can be measure in

urine and can diagnosis
pheochromocytoma

Pathways for the metabolism of norepinephrine and epinephrine. The enzymes responsible for each pathway are listed at
the end of the arrow. The larger the arrow, the more important the pathway. Compounds that are underlined can be
measured clinically and can be used for a diagnosis of pheochromocytoma, etc. Abbreviations: PMNT, phenolethanolamine-
N-methyltransferase; MAO, monoamine oxidase; COMT, catechol-O-methyltransferase; ADH, alcohol dehydrogenase; m-
PST, phenolsulfotransferase; DHGP, 3,4-dihydroxyphenylglycol; DHMA, 3,4-dihydroxymandelic acid; MHPG, 3-methoxy-4-
hydroxyphenylglycol; VMA, vanillylmandelic acid.

J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona

PCOL 871A/571A, Fall 2015 Introduction to Autonomic Pharmacology page 8
Direct Effects of Autonomic Nerve Activity on Organ Systems

Effect of

Sympathetic Parasympathetic
Organ System
Action Receptor1 Action Receptor1

Eye
Iris, radial muscle Contracts (mydriasis) 1 ... ...
Iris, circular muscle ... ... Contracts (miosis) M3
Ciliary muscle (Relaxes) 2 Contracts (accommodation) M3
Ciliary epithelium increase aqueous humor 2
decrease aqueous humor 2
Lacrimal gland ... ... secretion-tears M3

Heart
Sinoatrial node Accelerates 1 Decelerates M2
Ectopic pacemakers Accelerates 1 ... ...
Contractility Increases 1 Decreases (atria) M2

Vascular smooth muscle

Skin, splanchnic vessels Contracts 1 ... ...
Skeletal muscle vessels Relaxes 2 ... ...
Relaxes M2 ... ...

Vascular endothelium ... ... Releases NO M3 3

Bronchiolar smooth muscle Relaxes 2 Contracts M3

Bronchiolar glands ... ... Secretion M3

Gastrointestinal tract
Smooth muscle
Walls Relaxes peristalsis 24, 2 Contracts peristalsis M3
Sphincters Contracts 1 Relaxes M3
Secretion ... ... Increases M3
Myenteric plexus Inhibits 1 Activates M1

Genitourinary smooth muscle

Bladder wall Relaxes 2 Contracts M3
Sphincter Contracts 1 Relaxes M3
Uterus, pregnant Relaxes 2
Contracts 1 Contracts M3
Penis, seminal vesicles emission/ejaculation 1 Erection NO

Skin
Pilomotor (hair follicle) Contracts 1 ... ...
Sweat glands
Thermoregulatory (eccrine) Increases M ... ...
Stress (apocrine) Increases 1 ... ...

Salivary Glands Increases (viscous) 1 Increases (watery) M3

Metabolic functions
Liver Gluconeogenesis 1, 2 ... ...
Liver Glycogenolysis 1, 2 ... ...
Fat cells Lipolysis 3 ... ...
Kidney Renin release 1 ... ...

Presynaptic receptors
Sympathetic Decreases NE release 2 Decreases NE release M
Parasympathetic Decreases Ach release 2 Decreases Ach release M1
1
Specific receptor type: = alpha, = beta, M = muscarinic.
2
Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers.
3
The endothelium of most blood vessels releases nitric oxide (NO), which causes marked vasodilation, in response to
muscarinic stimuli. These muscarinic receptors, however, are not innervated by parasympathetic nerves and they respond
only to circulating muscarinic agonists and not to stimulation of the parasympathetic nerves.
4
Probably through presynaptic inhibition of parasympathetic activity.

J.W. Regan/Department of Pharmacology & Toxicology/University of Arizona