Autonomic Nervous System

Question 1

What does the ANS do?

Answer 1

The ANS controls all vegetative (involuntary) functions e.g:

• heart rate
• blood pressure
• GI motility
• iris diameter

The ANS is separate from the voluntary (somatic) motor system.

It is entirely efferent (but is regulated by afferent inputs).

Question 2

What are the two divisions of the ANS?

Answer 2

1. The sympathetic division
2. The parasympathetic division

Question 3

Describe features of Parasympathetic nerves

Answer 3

• originate in the lateral horn of the medulla and sacral regions of the spinal cord
• have long myelinated pre-ganglionic fibres
• have short unmyelinated postganglionic fibres
• have ganglia that are located in the tissues innervated by the postsynaptic fibres
• have actions that (in general) oppose the sympathetic nervous system

Question 4

Describe features Sympathetic nerves

Answer 4

• originate in the lateral horn of the lumbar and thoracic spinal cord
• have short myelinated pre-ganglionic fibres
• have long unmyelinated post-ganglionic fibres
• have ganglia that are located in the paravertebral chain close to the spinal cord
• have actions that (in general) oppose the parasympathetic nervous system

Question 5

Describe neurotransmitters in the ANS

Answer 5

The principal (but by no means the only) neurotransmitters in the ANS are:

• All pre-ganglionic neurons are cholinergic i.e. they use ACh as their neurotransmitter
• Parasympathetic and sympathetic pre-ganglionic release of ACh results in the activation of post-ganglionic nicotinic ACh receptors
• Nicotinic ACh receptors are ligand-gated ion channels
• Parasympathetic post-ganglionic neurons are also cholinergic
• They release ACh which acts on muscarinic ACh receptors in the target (‘effector’) tissue
• Muscarinic ACh receptors are G-protein coupled receptors (GPCRs)
• Most sympathetic post-ganglionic neurons are noradrenergic i.e. they use noradrenaline (NA) as the principal neurotransmitter
• NA interacts with one of two major classes of adrenoceptors, a-adrenoceptors and b-adrenoceptors
• These can be further subdivided into a1 and a2 and b1, b2 and b3 subtypes

Question 6

What are some exceptions to the general rules of neurotransmission in the ANS?

Answer 6

-Some specialized sympathetic post-ganglionic neurons are cholinergic, not noradrenergic e.g. those innervating sweat glands, hair follicles (piloerection)

-Other transmitters are found in the ANS
• Non-Adrenergic, Non-Cholinergic (NANC) transmitters • These may be co-released with either NA or ACh

Examples include:

• ATP
• nitric oxide (NO)
• 5-hydroxytryptamine (5HT; serotonin)
• neuropeptides (e.g. VIP (vasoactive intestinal peptide), substance P)

Question 7

How do sympathetic postganglionic neurons in the adrenal medulla differ?

Answer 7

Sympathetic postganglionic neurons in the adrenal glands are different:

• They differentiate to form neurosecretory chromaffin cells
• Chromaffin cells can be considered as postganglionic sympathetic neurons that do not project to a target tissue
• Instead, on sympathetic stimulation these cells release adrenaline (US name: epinephrine) into the bloodstream

Question 8

What are chromaffin cells?

Answer 8

-Chromaffin cells are present in the adrenal medulla

• Chromaffin cells are innervated by pre-ganglionic sympathetic neurons

Question 9

Give a summary of neurotransmission in the ANS

Answer 9

Question 10

What are the physiological consequences of parasympathetic stimulation?

Answer 10

Question 11

What are the physiological consequences of sympathetic stimulation?

Answer 11

Question 12

Describe afferent/sensory inputs to the ANS

Answer 12

• Sensory neurons monitor levels of CO2, O2 and nutrients in the blood, arterial pressure, and GI tract content and chemical composition
• Blood O2 (and CO2 , pH) are also directly sensed by the carotid body, chemoreceptors at the bifurcation of the carotid artery, relaying information to the CNS via the glossopharyngeal nerve
• Primary sensory neurons project on to “second order” sensory neurons located in the medulla oblongata, forming the nucleus tractus solitarius (nTS), that integrates all visceral afferent information
• The nTS also receives input from the area postrema, that detects toxins in the blood and the cerebrospinal fluid and is essential for chemically-induced vomiting and conditional taste aversion
• Sensory information constantly modulates the activity of the efferent neurons of the ANS

Question 13

What are the basic steps of neurotransmission?

Answer 13

1. uptake of precursors
2. synthesis of transmitter
3. vesicular storage of transmitter
4. degradation of transmitter
5. depolarization by propagated action
6. potential
7. depolarization-dependent influx of Ca2+
8. exocytotic release of transmitter
9. diffusion to post-synaptic membrane
10. interaction with post-synaptic receptors
11. inactivation of transmitter
12. re-uptake of transmitter
13. interaction with pre-synaptic receptors

Question 14

How is acetylcholine synthesised?

Answer 14

Question 15

How is acetylcholine degraded?

Answer 15

Question 16

Describe cholinergic transmission

Answer 16

Question 17

What are some therapeutic interventions affecting cholinergic transmission?

Answer 17

• Nicotinic acetylcholine receptors (nAChRs) at autonomic ganglia and the neuromuscular junction differ in structure. Therefore, some drugs have actions selectively at autonomic ganglia (e.g. the ganglion-blocking drug trimethaphan, which is used in hypertensive emergencies and to produce controlled hypotension during surgery).
• There are 5 muscarinic acetylcholine receptor (mAChR) subtypes (M1-M5), however, at present few subtype-selective mAChR agonists or antagonists are available clinically.
• Nevertheless, some newer agents do display limited tissue selectivity (e.g. the mAChR antagonist, tolterodine, which is used to treat “overactive bladder”).
• The actions of endogenously released ACh can also be enhanced by AChE inhibitors (e.g. pyridostigmine, used to treat myasthenia gravis; donepezil, used to treat Alzheimer’s disease).

Question 18

What does the lack of selectivity of most cholinergic drugs mean?

Answer 18

A relative lack of selectivity of cholinergic drugs means that unwanted ‘side-effects’ often limit their usage.

For example, a non-selective, muscarinic ACh receptor agonist is likely to cause autonomic side-effects

Question 19

What is sludge syndrome?

Answer 19

• massive discharge of the parasympathetic nervous system.
• the symptoms of “SLUDGE” are primarily due to chronic stimulation of muscarinic acetylcholine receptors, in organs and muscles innervated by the parasympathetic nervous system.

Salivation: stimulation of the salivary glands

Lacrimation: stimulation of the lacrimal glands

Urination: relaxation of the urethral internal sphincter muscle and detrusor muscle contraction

Defecation

Gastrointestinal upset: Smooth muscle tone changes causing GI problems, including diarrhoea

Emesis: Vomiting

An extension is SLUDGEM, where the additional M indicates:

• Miosis: stimulation of the pupillary constrictor muscles

Question 20

What causes sludge syndrome, and how is it treated?

Answer 20

• One common cause of SLUDGE is exposure to organophosphorus insecticides (e.g. parathion), or nerve gases (e.g. sarin). These agents covalently-modify (phosphorylate) acetylcholinesterase, thereby irreversibly deactivating the enzyme and raising acetylcholine levels to cause SLUDGE(M).
• SLUDGE may be treated with atropine, pralidoxime, or other anticholinergic agents.

Question 21

What are some clinical examples of drugs that affect cholinergic transmission?

Answer 21

Muscarinic ACh receptor agonists: pilocarpine and bethanechol are respectively used to treat glaucoma and acutely to stimulate bladder emptying.

Muscarinic ACh receptor antagonists: ipratropium and tiotropium are used to treat some forms of asthma and chronic obstructive pulmonary disease (COPD).

Tolterodine , darifenacin and oxybutynin are used to treat overactive bladder.

Question 22

What are varicosities (post-ganglionic sympathetic neurons)?

Answer 22

Post-ganglionic sympathetic neurons generally possess a highly branching axonal network with numerous varicosities, each of which is a specialized site for Ca2+-dependent noradrenaline release

Question 23

Describe the process of noradrenaline recycling

Answer 23

Question 24

Describe noradrenaline transmission

Answer 24

Following Ca2+-dependent exocytotic release of NA:

• NA diffuses across the synaptic cleft and interacts with adrenoceptors in the post-synaptic membrane to initiate signalling in the effector tissue
• NA interacts with pre-synaptic adrenoceptors to regulate processes within the nerve terminal – e.g. NA release
• NA has only a very limited time in which to influence pre- and post-synaptic adrenoceptors as it rapidly removed from the synaptic cleft by noradrenaline transporter proteins

Question 25

Describe the termination of noradrenaline transmission?

Answer 25

• NA actions are terminated by re-uptake into the pre- synaptic terminal by a Na+-dependent, high affinity transporter (UPTAKE 1)
• NA not re-captured by Uptake 1 is taken up by a lower affinity, non-neuronal mechanism (UPTAKE 2)

Question 26

Describe noradrenaline metabolism

Answer 26

Within the pre-synaptic terminal NA not taken up into vesicles is susceptible to metabolism by two enzymes:

• monoamine oxidase (MAO)
• catechol-O-methyltransferase (COMT)

Question 27

How can neurotransmitter release be modulated?

Answer 27

Presynaptic G protein-coupled receptors (e.g. the α2-adrenoceptor) can regulate neurotransmitter release by inhibiting Ca2+-dependent exocytosis

G protein βγ subunits inhibit specific types of voltage- operated Ca2+ channels (VOCCs) reducing Ca2+-influx and neurotransmitter release

Question 28

Why is b2 selectivity important when choosing a drug to administer?

Answer 28

The β2-adrenoceptor-selectivity of such agents is important as it limits possible cardiovascular side-effects (e.g. positive inotropic and chronotropic actions)

Question 29

How does b2 activation cause an effect on the heart?

Answer 29