Introduction to the Autonomic Nervous System

Professor John A. Peters

E-mail j.a.peters@dundee.ac.uk

“The autonomic nervous system consists of nerve cells and nerve fibres, by means of

which efferent impulses pass to tissues other than multi-nuclear striated muscle” [John

Newport Langley in his classic text ‘The Autonomic Nervous System’ (1921)]. He was

also a pioneer of the receptor theory, postulating the existence of ‘receptive substances’

as early as 1905.

John Newport Langley

Neuroeffector junctions between a

postganglionic fibre (N) and

intestinal smooth muscle cells (S)

(Burnstock, 1988)

N

S

3 μm

Learning ObjectivesFollowing this lecture and further study students should be able to:

Appreciate that the autonomic nervous system (ANS) is essential to life due its

fundamental roles in homeostasis

Describe the anatomy of the motor ANS utilizing the terms, pre- and post-ganglionic

fibre, ganglia, paravertebral ganglia and prevertebral ganglia

Name the ‘classical’ neurotransmitters synthesised and released by pre- and post-

ganglionic fibres in the sympathetic and parasympathetic divisions of the ANS and the

receptors that they act upon understanding the meaning of the terms cholinergic,

cholinoceptor, adrenergic, adrenoceptor and non-adrenergic , non-cholinergic (NANC)

State the effect of sympathetic and parasympathetic stimulation upon selected targets

noting their frequently reciprocal, but in some instances unopposed, effects

Provide a simple description of neurochemical transmission in the sympathetic and

parasympathetic divisions of the ANS noting subtypes of cholinoceptor, adrenoceptor,

their exemplar organ distribution and physiological actions

Recommended reading:• Boron WF, Boulpaep EL (2017). ‘Medical Physiology’ (3rd. ed.). Chapter 14, pp. 334 –

347.

• Naish J, Syndercombe Court D (2014). ‘Medical Sciences’ (2nd. ed.). Chapter 4, pp.

125 - 130 and 138 - 147.

• Koeppen BM, and Stanton BA (2018). ‘Berne and Levy Physiology’ (7th. ed.). Chapter

11.

• Neal MJ (2016). ‘Medical Pharmacology at a Glance’ (8th. ed.). Chapter 7.

• Rang HP, Ritter JM, Flower RJ, Henderson G (2016). ‘Rang and Dale’s Pharmacology’

(8th. ed.). Chapter 12.

Introduction to the Autonomic Nervous System

The entire nervous system can be divided broadly into the Central Nervous

System (CNS) and Peripheral Nervous System (PNS) and their subdivisions.

The Autonomic Nervous System (ANS) has both central and peripheral

components

PNS

CNS (Brain and Spinal Cord)

Somatic afferent(i.e. sensory fibres, from

skin and skeletal muscle)

Somatic efferent(i.e. motor fibres to

skeletal muscle)

Enteric

(ENS)

Sympathetic

division

Parasympathetic

division

Afferent signals

(towards the

CNS)

Efferent signals

(away from the

CNS)

Autonomic (ANS)(motor and sensory

components)

The Overall Functions of the ANSThe motor autonomic nervous system (ANS) mediates output from the

CNS to the whole of the body, with the exception of skeletal (voluntary)

muscle. Output is modulated by external and internal sensory input, often

via reflexes involving negative feedback loops within PNS and the CNS

• contraction and relaxation of vascular and visceral smooth muscle

• the heartbeat (including rate and force)

• all exocrine and certain endocrine secretions

• aspects of metabolism (particularly in liver and skeletal muscle)

• modulation of the processes of the immune system

• is subdivided anatomically into sympathetic and parasympatheticdivisions (and, debatably, the enteric nervous system also)

regulates functions essential to human health and life that do not require conscious effort (e.g. whilst asleep) and that are largely involuntary, e.g.

The ANS:

training allows a degree of conscious influence over the execution of some

ANS reflexes (e.g., micturition, defecation via voluntary control of skeletal muscle

external sphincters of the urethra and anus commanded by somatic efferents).

Uniquely, accommodation in the eye (focus of the lens, for near vision) can be

voluntarily controlled, despite it being an autonomic function

Sympathetic and parasympathetic divisions of the ANS often work

simultaneously in a reciprocal and complementary manner maintaining

homeostasis

Basic Organisation of the Motor ANS (1)

Inside

CNS

Autonomic

ganglion

Preganglionic

neurone

Postganglionic

neurone

Eff

ec

tor

ce

lls

Chemical synaptic

transmission in the

ganglia

e.g

., c

ard

iac’

sm

oo

th m

uscle

, o

r secre

tory

ce

lls

Outside CNS

Chemical transmission

at the neuroeffector

junction

The motor (efferent) component comprises two neurones in series:

preganglionic and postganglionic fibres

Parasympathetic ANS

• regulates many functions, some

of which are restorative and

energy conserving ‘rest and

digest’

Sympathetic ANS

• orchestrates the stress response and

energy consumption associated with

‘fight or flight’ reactions, but also has

very important ongoing activity

‘Fight or flight’ and ‘rest and digest’, although memorable, are simplistic

descriptions of the extremes of sympathetic and parasympathetic activity

Basic Organisation of the Motor ANS (2)The transmitter of the preganglionic neurones, sympathetic and parasympathetic,

is always acetylcholine (ACh) acting via excitatory nicotinic cholinoceptors, but

the classical transmitters of the postganglionic neurones are different [i.e.

noradrenaline (NA), aka norepinephrine (NE)] and ACh, respectively

Th

ora

colu

mb

ar o

utf

low

fro

m s

pin

al c

ord

Preganglionic neurone (cholinergic,

synthesises and releases ACh as

transmitter)

Postganglionic neurone (usually

adrenergic, synthesises and

releases NA as transmitter)

Sympathetic divisionacetylcholine (ACh) usually noradrenaline (NA)

Eff

ecto

r cells

(ac

tio

n v

ia

ad

ren

oc

ep

tors

)

Cra

nio

sacr

al o

utf

low

fro

m b

rain

stem

an

d s

pin

al

cord

Preganglionic

neurone (cholinergic)

Postganglionic

neurone (cholinergic)

Parasympathetic division Acetylcholine

(ACh)

Eff

ecto

r cells

(ac

tio

n v

iam

us

ca

rin

ic

ch

oli

no

ce

po

rs)

Basic Organisation of the Motor ANS (3) Sympathetic preganglionic neurones synapse with postganglionic neurones in

either (i) paravertebral ganglia, or (ii) prevertebral ganglia (see next slide), both

of which are close to the spinal cord. Their axons (fibres) are typically short

Sympathetic postganglionic neurones innervate effector cells in organs distant

to the sympathetic ganglia. Their axons (fibres) are generally long

Parasympathetic preganglionic neurones synapse with postganglionic

neurones in terminal ganglia that are distant to the CNS and often located in

the walls of the target organ. Their axons (fibres) are thus long.

Correspondingly, the fibres of the postganglionic neurones are short

Typically, preganglionic fibres, both sympathetic and parasympathetic are

myelinated (see lecture upon the action potential) and are termed motor B-

fibres. They give a white appearance. By contrast, postganglionic fibres are

largely unmyelinated and appear grey and are termed motor C-fibres

Sympathetic preganglionic fibres branch extensively to synapse with many

postganglionic neurones located in one, or several, pre- or para-vertebral

ganglia. The effect of sympathetic stimulation may sometimes be widespread

(as in the ‘fight or flight’ reaction)

Postganglionic neurone

– usually releases NA

L2, or L3, spinal

nerve

Thoraco-

lumbar

outflow

Sympathetic chain

Paravertebral ganglia:

pre- and post-ganglionic

neurones synapse here at

segmental, or more

rostral/caudal locations

T1 spinal nerve

The Sympathetic Outflow (1)

Preganglionic neurone

– releases ACh: note the

‘anatomical logic’ of the

segment of the cord at

which the preganglionic

neurone cell bodies are

located in relation to the

location of the target

tissue/organ

Prevertebral ganglia:

pre- and post-ganglionic

neurones synapse here

Adrenal gland – note the

innervation is pre

ganglionic and the

transmitter is ACh, not NA.

The medulla of the gland

releases adrenaline (A) and

NA as hormones

Higher centres in the

brainstem regulate

sympathetic outflow

Cervical ganglia (superior, middle

and inferior)

1

2

3

1, coeliac; 2,

aorticorticorenal, 3,

superior mesenteric and 4,

inferior mesenteric

prevertebral ganglia

Modified from Moore’s

Clinically Oriented

Anatomy (2006)

4

The Sympathetic Outflow (2) – further anatomical features

Preganglionic fibre cell bodies are located in the intermediolateral (IML) cell

column (lateral horn) of the spinal cord. Those controlling a particular organ

(e.g. the heart) may be spread over several segmental levels

Preganglionic fibres exit the cord

via the ventral (anterior) roots,

follow the spinal nerves and white

rami communicantes (at levels T1

to L2/3) and then synapse with

postganglionic cell bodies in

either:

• paravertebral sympathetic

ganglia, from which the

postganglionic fibres join the

peripheral nerves, via grey

rami communicantes, to travel

to their target organs in the

skin and blood vessels

or• prevertebral sympathetic

ganglia of the abdomen via

paravertebral ganglia (without

synapsing), and onwards in

splanchnic nerves to internal

organs/vessels From Koeppen and Stanton (2018)

Postganglionic fibres (sudomotor neurones) innervating the

thermoregulatory (eccrine) sweat glands, and a few blood vessels are

cholinergic: thus the transmitter is ACh, not NA. Correspondingly, the

receptors on the effector cells are muscarinic cholinoceptors, not

adrenoceptors. However, the postganglionic fibres innervating the stress

(apocrine) sweat glands are adrenergic and activate adrenoceptors

Preganglionic fibres also innervate neurones in the pelvic plexuses

Additional to the classical transmitter, NA, postganglionic fibres store and

release others [e.g. adenosine triphosphate (ATP) and neuropeptide Y (NPY)

(see later)]

The Sympathetic Outflow (3) – additions and exceptions to the

general rules

Preganglionic cholinergic fibres

innervate the adrenal medulla,

chromaffin cells specifically,

directly via splanchnic nerves.• Chromaffin cells are modified

postganglionic neurones that

secrete, primarily adrenaline (80%),

but also NA (20%) that enter the

capillary circulation as hormones

Cranial nerves (CN) III,

VII, IX & X X

The Parasympathetic Outflow (1)

Preganglionic neurone

– releases ACh

Postganglionic neurone

– releases ACh

Parasympathetic are usually

in the target organs (discrete

ganglia in head and neck and

some plexuses in the pelvis)

IX

VII

III

Sacral spinal nerves

(S2-S4)

Modified from Moore’s

Clinically Oriented

Anatomy (2006)

Origin and CN Ganglion Postganglionic fibre target

Midbrain

CN III (oculomotor)

Ciliary Eye (pupillary constrictor and ciliary body)

Pons

CN VII (facial)

Pterygopalatine

Submandibular

Lacrimal gland, glands of nasal cavity

Submandibular and sublingual salivary glands

Medulla oblongata

CN IX (glossopharyngeal)

CN X (vagus)

Otic

Widespread, diffuse

Parotid salivary glands

Bronchial tree, heart, liver, pancreas, upper G.I. tract

Preganglionic fibres of the sacral outflow course in the sacral nerves (nervi

erigentes) synapsing upon postganglionic neurones in the walls of visceral

organs in the abdominal and pelvic cavities

Preganglionic fibre cell bodies are located in:• the brainstem (cranial outflow) comprising the

midbrain, pons and medulla oblongata

or• sacral segments (S2-S4) of the spinal cord

The Parasympathetic Outflow (2) – further anatomical

features and additions

Preganglionic fibres of the cranial outflow follow

cranial nerves (CN) and synapse upon postganglionic

neurones as tabulated below:

Additional to the classical transmitter, ACh, postganglionic fibres release

others [e.g. nitric oxide (NO) and vasoactive intestinal peptide (VIP) (see later)]

Chemical Transmission in the ANS (1)

Sympathetic division

Ca2+ Ca2+

Eff

ecto

r cell

noradrenaline activates G-protein-coupled adrenoceptors in the effector

cell membrane to cause a cellular response via ion channels/enzymes

ACh binds to and opens ligand-gated ion channels (nicotinic ACh receptors) in

the postganglionic neurone, causing depolarization and the initiation of action

potentials that propagate to the presynaptic terminal of the neurone, triggering

Ca2+ entry and the release, usually, of noradrenaline

Action potential originating in the CNS

travels to the presynaptic terminal of the preganglionic neurone triggering Ca2+

entry through voltage-gated, calcium selective, ion channels and the release of

ACh by exocytosis

Chemical Transmission in the ANS (2)

Parasympathetic division

Ca2+

Eff

ecto

r cell

Ca2+

Ca2+

The process is very similar to that described for the sympathetic division, with

the important exceptions that:

ACh activates G-protein- coupled muscarinic acetylcholine receptors

in the effector cell membrane to cause a cellular response via ion channels/

enzymes

ACh is always the classical transmitter used by postganglionic neurones

Chemical Transmission in the ANS (3) ACh and NA are not the only transmitters released from sympathetic

and parasympathetic postganglionic fibres• in some instances, the transmitter is neither NA, nor ACh, which is known

as non-adrenergic, non-cholinergic (NANC) transmission

• far more frequently, NA or ACh are co-released with a NANC co-transmitter

(or modulator), the best studied substances being:

o adenosine triphosphate (ATP) and neuropeptide Y (NPY) from

sympathetic fibres

o nitric oxide (NO) and vasoactive intestinal peptide (VIP) from

parasympathetic fibres

Parasympathetic Sympathetic

Rapid response

Intermediate response

Slow response

Tissue response

ACh

NO

VIP

ATP

NA

NPY

Ten

sio

n o

f vascu

lar

sm

oo

th m

usc

le

Time

An Example of Chemical Co-Transmission in the ANS –regulation of vascular smooth muscle tone

Electrical stimulation of postganglionic

sympathetic fibre to vessel

1 2 3 1. ATP produces a fast

contraction of the smooth

muscle

2. Noradrenaline produces a

moderately fast response

3. Neuropeptide Y produces a

slow response

Ten

sio

n o

f vascu

lar

sm

oo

th m

uscle

Time

Electrical stimulation of postganglionic

parasympathetic fibre to vessel

1 2

1. Acetylcholine and nitric

oxide produce a rapid

relaxation

2. Vasoactive intestinal

peptide can produce a

slow, delayed response

Based on Boron and Boulpaep (2017)

Classical Receptor Classes of the Ganglia and Effector Cells (Cholinoceptors)

ACh is the endogenous agonist of cholinoceptors that are nicotinic, or

muscarinic

• Nicotinic ACh receptors of the ganglia are:

o Ligand-gated ion channels (LGICs), selectively activated by the plant alkaloid,

nicotine

o Structurally and pharmacologically distinct

from nicotinic receptors at the skeletal

neuromuscular junction, or in the CNSTobacco plant

Nicotiana tabacum• Muscarinic ACh receptors of the effector

cells are:

o G-protein-coupled receptors (GPCRs), selectively activated by the plant alkaloid,

muscarine

o Structurally and pharmacologically defined

as five subtypes: M1, M2, M3, M4 and M5 that

are differentially expressed across

tissues/organs, M1-3 being most important

in the ANS

Fly Agaric

Amanita muscaria

NA and adrenaline (A) are the endogenous agonists of a family of

adrenoceptors that are all GPCRs:

o Fundamentally classified, originally on the basis of the rank order of

potency of agonists (Ahlquist, 1948), as α-, or β-adrenoceptors• α-adrenoceptor: noradrenaline > adrenaline > isoprenaline (for α1 – see below)

• β-adrenoceptor: isoprenaline > adrenaline > noradrenaline (for β2 - see below)

Classical Receptor Classes of the Ganglia and Effector Cells (Adrenoceptors)

o Clinically important subclasses of adrenoceptors, with differing tissue

locations, have been characterised structurally and pharmacologically as

α1, α2, β1, β2 and β3, all of which are selectively targeted by current

therapeutic agents• α1- and α2-adrenoceptors are further characterised as α1A, α1B, α1D, α2A, α2B and

α2C. It is not essential to elaborate upon this here!

No

rad

ren

ali

ne a

ka

no

rep

ine

ph

rin

e

Ad

ren

ali

ne

ak

a

ep

ine

ph

rin

e

Iso

pre

na

lin

eaka

iso

pro

tore

no

l

CH3

CH3

CH3

Isoprenaline is

a synthetic

agonist

Selected Activities of the ANS

Decreases heart rate (M2) and force

(M2) in atria

Increases heart rate (β1)

Increases force of contraction

in atria and ventricles (β1)

Sympathetic stimulation (via

adrenoceptors, mostly)

Constricts bronchi (M3)

Stimulates mucus production (M3)

(airway resistance)

Relaxes bronchi (β2)

Decreases mucus production (β2)

(airway resistance)

Parasympathetic stimulation (via muscarinic cholinoceptors, mostly)

No effectRelease of adrenaline from adrenal

medulla (nicotinic AChR)

Increases intestinal motility and

secretions (M3)

Relaxes sphincters (NO, M3)

Reduces intestinal motility (α1, α2, β2)

Constricts sphincters (α1, α2, β2)

Constricts vasculature in most

locations (α1), but relaxes in skeletal

muscle (β2)

Largely no effect, but relaxes

vasculature in a few locations (e.g.

penis, salivary glands, pancreas (NO,

M3)

Ejaculation (α1) Penile erection (NO, M3)

Relaxes wall (detrusor) of

bladder (β2/β3), constricts

internal urethral sphincter (α1)

Contracts wall of bladder (M3),

relaxes internal urethral sphincter

(NO)

An Example of the Co-ordinated Activity of the Sympathetic and Parasympathetic Divisions of the ANS – the Micturition Reflex

The urinary bladder is a temporary store for urine, until it is convenient to void.

At a simple level, it comprises: (i) a smooth muscle wall (the detrusor) and (ii) a

trigone where urine enters from the ureters and leaves via the smooth muscle

internal urethral sphincter (at the junction between the bladder and urethra)

During filling, sympathetic activity

predominates:• the detrusor is relaxed by the release of

NA (NE) that activates β2/β3-adrenoceptors

• the internal urethral sphincter is

constricted by the release of NA that

activates α1-adrenoceptors

During voiding, parasympathetic

activity predominates:• the detrusor is contracted by the

release of ACh that activates M3-

muscarinic ACh receptors

• the internal urinary sphincter is relaxed

by the release of NO that stimulates the

production of cGMP (a relaxant) in

smooth muscle cells

With training, voluntary control is exerted by somatic efferents that release

ACh to contract the skeletal muscle external urethral sphincter surrounding

the urethra via nicotinic ACh receptors

From Hill, WG (2015). Clin J Am Soc

Nephrol, 10, 480-492

Common Misconceptions Regarding the ANS (1)

The phrases ‘fight, or flight’ and ‘rest and digest’ foster the idea that

sympathetic activity is predominantly short-lived (i.e. phasic) whilst

parasympathetic activity is largely ongoing (i.e. tonic’). However,

‘‘…this whole concept is simply wrong.’’ (Gibbins, 2013). Phasic and

tonic activity is common in both divisions of the ANS (see next slide)

The sympathetic and parasympathetic divisions are activated ‘en

masse’. This is untrue, the activity of the autonomic output to

individual organs and tissues is closely adjusted to match

physiological demand which, or course, varies with the external and

internal environments over time

The two divisions of the ANS are in opposition to each other. ‘‘This

quite the wrong idea. Autonomic nerves, whatever their anatomical

origin, act in concert to control visceral organs and the vasculature.’’

(Furness, 2006)

Tonic and phasic activity in autonomic pathways

Tonic activity Phasic activity

Sympathetic

Skin vasoconstriction

Muscle vasoconstriction

Gut vasoconstriction

Inhibition of gut motility

Inhibition of gut secretions

Detrusor relaxation

Internal urethral sphincter contraction

Sweating (thermal and stress)

Piloerection

Increased cardiac output

Mucous saliva production

Pupil dilation

Sexual activity (ejaculation)

Parasympathetic

Reduced cardiac output at rest

Pupil constriction

Basal tear secretion

Basal saliva secretion

Accommodation

Tear production in crying

Salivation (during speech, eating)

Receptive relaxation and emptying of stomach

Pancreatic secretion

Urination

Sexual activity (erection)

Common Misconceptions Regarding the ANS (2)

Table adapted from Gibbins (2013)

Now test yourself by trying from the information provided in

this and the following lecture and recommended reading to

identify the subtypes of receptor that mediate the above

tonic and phasic activities of the ANS

Consolidation of the Fundamentals of the ANS

Has central and peripheral components. The motor (efferent) component

conducts signals to the entire body, apart from skeletal muscle

The ANS:

Regulates essential physiological functions, helping to maintain homeostasis

via complementary actions of its sympathetic and parasympathetic divisions

The motor component comprises cholinergic preganglionic neurones with a

sympathetic thoracolumbar origin, or a parasympathetic craniosacral origin

In the sympathetic division, preganglionic fibres synapse upon usually

adrenergic postganglionic neurones in either paravertebral, or prevertebral,

ganglia

In the parasympathetic division, preganglionic fibres synapse upon

cholinergic postganglionic neurones in effector organs, or close to them

Cholinergic fibres release ACh as transmitter that activates cholinoceptors

that are either (i) ligand-gated ion channels (nicotinic), or (ii) G-protein-

coupled receptors (GPCRs, muscarinic)

Adrenergic fibres release NA as transmitter that activates adrenoceptors, all

of which (α and β) are G-protein-coupled receptors

In addition to the classical transmitters (ACh and NA), co-transmitters (e.g.

ATP, NPY, NO and VIP) also regulate the activity of target organs

facts