Notes on the Autonomic Nervous System (for FANZCA part I)

Adrenergic ANS
Cholinergic ANS
Enteric ANS

The word 'autonomic' comes from two Greek words that mean 'self' and 'law'. In contrast to the somatic nervous system over which we have voluntary control, the autonomic nervous system is largely a law unto itself. It is traditional to break the autonomic nervous system (ANS) into a central and peripheral component, and then to further subdivide the peripheral ANS into:

  1. sympathetic nervous system (SNS)
  2. parasympathetic nervous system (PNS)
  3. enteric nervous system (grudgingly added some time after the first two components were identified; we will abbreviate this to ENS).

In fact, there is intricate interplay between all of the above 'components', and indeed between the ANS and the somatic nervous system, so such subdivision makes about as much sense as arbitrarily sub-dividing, say, a charging elephant into a left side and a right side! Nevertheless, it is convenient to talk about such 'subdivisions', and who are we to break with hallowed tradition? It is also traditional to regard the SNS and the PNS as antagonists - the SNS is said to mediate 'flight, fight or fright' responses, and the PNS more relaxed visceral and 'vegetative' functions. This too is crude over-simplification, as many viscera are controlled by both sympathetic and parasympathetic innervation, and there is always some sympathetic tone, even in the most relaxed individual parked off on a beach!

This talk assumes a basic understanding of anatomical and physiological terminology. Familiarity is assumed with terms such as 'afferent' and 'efferent'. We have elsewhere discussed receptor basics, also discussed in some detail here. In the following we refer to norepinephrine as 'noradrenaline', and epinephrine as adrenaline, mainly because we find the words more euphonious!

What does the ANS control?

Resisting the temptation to say 'everything', we note the important functions of the ANS:

The relevance of the ANS

The autonomic nervous system is so important in regulation of a vast number of body processes that one could say "it's relevant in almost every disease state"! However, autonomic dysfunction plays a particularly prominent role in certain diseases, including:

Basic ANS anatomy

If we look at the gross anatomy of the ANS, we can identify several components:

  1. The 'cranial parasympathetic outflow', fibres that run with cranial nerves III, VII, IX, and the most important of all, the vagus (X). Important structures innervated include the eye, the lacrimal gland, the salivary gland, and of course all of the viscera influenced by the vagus.

  2. The 'thoracolumbar sympathetic outflow', filaments that emerge with with spinal nerves T1, T2, and so on down to L3 or L4. Filaments then diverge as white rami communicantes , passing to the sympathetic ganglia that lie alongside the vertebral bodies. Most of the ganglia form two chains to the left and right of the vertebrae, but some form large, unpaired, midline ganglia within the abdomen. Sympathetic fibres pass from ganglia to destination organs, either on their own, or more commonly, back from the ganglia to the spinal nerves via grey rami communicantes , and thence to their target. The thoracolumbar sympathetic outflow covers a lot of territory - the eyes and salivary glands, the heart, the adrenal, and many intra-abdominal viscera to boot. Sympathetic nerve fibres also provide vital control of blood vessels and sweat glands, running with the relevant spinal (segmental) nerve. Note that there is no cervical sympathetic outflow!

  3. The 'sacral parasympathetic outflow' (nervi erigentes - most anatomists are men), running to the bladder, rectum and indeed, the genitalia.

Understanding the ANS is predicated on a knowledge of its basic anatomy. The anatomy of the peripheral ANS is fairly straightforward, and based on one vital word - ganglia .

Looking at the cells that make up the ANS, we find a simple two-neurone plan. Cell bodies within the central nervous system send filaments that synapse on a second set of cells located within peripheral nervous system ganglia. These nerve cells within the ganglia have fibres that then innervate the target organs. As a general rule, parasympathetic ganglia are close to the organ innervated, while the sympathetic ganglia lie much closer to the spinal cord and vertebrae. It's important to realise that there is no 1:1 relationship between preganglionic fibres going into a ganglion, and postganglionic fibres coming out.

There is only one exception to the pattern of having preganglionic fibres originating in the central nervous system, these synapsing on the misleadingly-named postganglionic neurone within a ganglion. This exception is the adrenal gland - here there certainly are preganglionic fibres, but what has happened to the postganglionic neurone? Easy, it's lost its axons and dendrites, and turned into a cell that sits in the adrenal medulla, and releases the catecholamines noradrenaline and adrenaline on commands from the sympathetic nervous system! This similarity between adrenal medullary cells and postganglionic sympathetic neurones is highlighted when we look at tumours of the adrenal medulla - phaeochromocytomas. About 10% of phaeochromocytomas arise not in the adrenal, but in the midline sympathetic ganglia that lie near the abdominal aorta!

The following table lists various viscera and their innervation, including the receptors involved in organ/tissue effects, and levels of origin of the sympathetic fibres. It looks formidable, until one realises that:

In fact, knowing the above, you may even wish to skip the table!

ANS organ innervation
Organ Sympathetic innervation Parasympathetic innervation
action segments receptor action/nerves receptor
Eye: iris dilates (by constricting radial muscle)T1 via carotid alpha constricts M3
Eye: ciliary muscle relaxation ± T1 via carotid beta-1 contraction (III: ciliary ganglion: short ciliary nerves)M3
Lacrimal gland - secretion (VII: greater petrosal nerve: pterygopalatine ganglion: zygomaticotemporal and lacrimal nerves M3
Submandibular salivary glands secretion T1 via facial artery alpha; beta-1 (!) - 'viscous' secretions <-- metoprolol inhibits saliva production! [Eur J Oral Sci 1996 Jun;104(3):262-8] --> secretion (VII: chorda tympani: submandibular ganglion: lingual nerve: - 'watery secretions' full of amylase M3
Parotid gland similar to submandibular T1 via middle meningeal artery alpha, beta-1 secretion (IX: otic ganglion: auriculotemporal nerve) M3
Cranial vessels constriction T1?(alpha) -
Skin: Sweat glands sweating various (cholinergic) -
Skin: Sweat glands on palms of hands sweating T2 alpha [?] -
Skin: hair follicles piloerection various alpha -
Blood vessels (segmental) constriction various alpha -
Lung: bronchi: glands - secretion M3
Lung: bronchi: muscle constriction M3
Heart: atrial muscle inotropy cardiac sympathetics originate T1 to T4 ß1 {and ß2} negative inotropy M2
Heart: SA node tachycardia ß1 {and ß2} bradycardia M2
Heart: AV node increased automaticity ß1 negative dromotropy M2
Heart: coronary arteries constriction alpha -
Large veins constriction various alpha -
oesophagus (distal part) ? T5-T6 ? (vagus) variable response - relaxation [NO+VIP] / LES contraction [M3]
Adrenal medulla ('suprarenal') (T8-L1: effectively a 'sympathetic ganglion' that produces adrenaline + noradrenaline) -
Liver increased glucose production [glycogenolysis, gluconeogenesis], lipolysis T7-9 alpha
Innervation is rich and complex [Liver 1998 Oct;18(5):352-9] The denervated liver may show an impaired response to hypoglycaemia! [J Clin Invest 1997 Aug 15;100(4):931-41]
Gallbladder relaxation T7-T9 beta contraction M3?
Kidney more renin secretion -ß -
Kidney: vessels low blood flow T10-L1 alpha-2 (!) > alpha-1 -
Ureter increased motility T12 alpha? decreased motility {?}
Stomach: secretion - acid secretion M1
Stomach: motility less T6-T10 alpha more (various)
Pancreas effects on insulin secretion T6-10 "inhibition of insulin secretion = alpha, stimulation of glucagon release = beta" rich cholinergic innervation! [Can J Physiol Pharmacol 1992 Feb;70(2):167-206]
'GI sphincters' constriction various: small bowel T9-10; colon to splenic flexure T11-L1; distal L1-2 alpha1, alpha2 {ß2} dilatation M3
'GI smooth muscle' less motility alpha 2 {ß2} more motility M3
Splanchnic vessels constriction alpha -
Bladder: detrusor relaxation ?ß2 ? contraction M3?
Bladder: sphincter contraction T11-L2 alpha relaxation M3?
Uterus contraction T12-L1 alpha; {relaxation ß2} (minor) -
Male genitalia ejaculation T10-11 alpha erection NO
clitoris -?- erection NO
Note that the anatomy of the sympathetics is rather complex - the greater splanchnic nerve is made up of fibres from T5-9, the lesser splanchnic nerve from T9-T10, and the least splanchnic nerve from T12 (all are approximate). There are also lumbar splanchnic nerves. Various intra-abdominal plexuses are defined in most anatomy books, including the large coeliac plexus (around the origins of the coeliac trunk and superior mesenteric artery), and the "phrenic, splenic, left gastric, intermesenteric, suprarenal, renal, gonadal, superior mesenteric and inferior mesenteric plexuses". The upper two splanchnic nerves contribute extensively to the formation of the coeliac plexus which in turn gives off fibres to most of the other plexuses, so who knows what goes where?

Afferent autonomic fibres

Far more research has been done on efferent fibres than afferent ones. After all, it's far more exciting to stimulate a nerve and see a visceral response, than stimulate an afferent (which 'merely' causes pain in the subject being stimulated)! In general, afferent fibres for a viscus follow a similar course to the efferent ones - the catch is that pain perception may be referred to strange somatic sites. We all know about anginal pain being referred to the neck and left arm, ureteric pain that is felt in the groin, and so on.

Neurotransmitters in the ANS

The adrenal gland provides a convenient mnemonic for the whole SNS. If we recall our traditional view of the SNS as a 'flight or fight' system (producing catecholamines), and that the adrenal medulla is really just a modified sympathetic ganglion, it's easy to remember that almost all postganglionic SNS neurones run on noradrenaline . Organs that are innervated by sympathetic nerve fibres have receptors that will respond to noradrenaline.

In contrast, postganglionic para sympathetic neurones use acetylcholine (ACh) as their neurotransmitter of choice. Target organs respond to this ACh when it stimulates muscarinic ACh receptors on their cell surfaces.

Although the postganglionic cells of the ANS are so conspicuously divergent in their use of neurotransmitters to influence their target organs, preganglionic fibres are much more boring. Both those of the PNS and those of the SNS rely on acetylcholine, and the main receptor on the postganglionic cell is (in both cases) simply the nicotinic receptor. (This paragraph is only a half-truth, as there are in fact a few muscarinic receptors in ganglia as well, which is of substantial significance when we look at the pharmacology of agents that affect the ANS).

Careful readers will have noted how we said that almost all sympathetic postganglionic neurones are noradrenergic. The exception is sympathetic fibres to sweat glands - these use acetylcholine as their neurotransmitter. (In some animals, there are also sympathetic cholinergic fibres that go to blood vessels supplying muscle - of minimal importance in man).

Okay, we lied just a little! There is in fact a host of different transmitters involved in communication within the ANS. Fortunately, our above gross oversimplification is useful when we manipulate the SNS and PNS with drugs. (We don't really have much of a clue when it comes to pharmacological tweaking of the enteric nervous system). Here's a list of some of the other transmitters involved in passing messages within the ANS:

More ANS neurotransmitters
Transmitter Functions
nitric oxide (NO) parasympathetic - important in erection and in gastric emptying. Activates guanylate cyclase.
vasoactive intestinal polypeptide (VIP) parasympathetic - co-release with ACh affects salivation; also in sympathetic cholinergic fibres. May be important throughout the gastrointestinal tract.
adenosine triphosphate (ATP) sympathetic - blood vessels and vas deferens. Co-released with catecholamines.
neuropeptide Y (NPY) sympathetic - facilitates effect of noradrenaline (co-released). Causes prolonged vasoconstriction.
serotonin (5HT) important in enteric neurones (peristalsis)
gamma-amino butyric acid (GABA) enteric.
dopamine May mediate vasodilatation in the kidney
gonadotropin releasing hormone (GnRH) co-transmitter with ACh in sympathetic ganglia.
Substance P sympathetic ganglia, enteric neurones
calcitonin gene related peptide (CGRP) contributes to neurogenic inflammation

Principles of ANS function

As is often done when dealing with any fairly complex system, people have tried to extract simplifying principles. Here are a few (after Rang, Dale & Ritter):

  1. Dale's principle is a gross oversimplification. This principle is that a mature neurone releases the same transmitter(s) at all of its synapses. Although generally true, we now know that not only is release of a 'cocktail' of neurotransmitters the rule rather than the exception, but also that the 'mix' may vary depending on stimulation frequency, and so on. (As an aside, neurones may during their lifetime also change the transmitters they release).

  2. Cannon's law of denervation tells us that if a post-ganglionic neurone has it's pre-ganglionic input removed, then it will become super-sensitive to the normal neurotransmitters that mediate that pre-ganglionic input. There is a variety of reasons for this, including up-regulation of receptors for the neurotransmitter(s), post-receptor effects, and impaired removal of neurotransmitters from the synapse.

  3. The modulation of transmission ('neuromodulation') at a synapse may be either at a presynaptic or postsynaptic level. Presynaptic modulation is discussed within the next section, and post-synaptic effects a bit later.

Normal nerve transmission

We all know the basics of synaptic transmission - in response to a stimulus, the presynaptic nerve terminal releases the contents of tiny intracellular vesicles by the process of exocytosis . The neurotransmitters contained within these vesicles then diffuse across the synapse and bind to post-synaptic receptors, so the stimulus is propagated across the synaptic cleft.

We have recently begun to fill in the details of this process, and now know that there is a synaptic vesicle cycle , where vesicles are made, stocked with neurotransmitter, dock just under the synaptic membrane, exocytose their burden into the cleft, are recaptured by endocytosis, and return to the endosome which then buds of new vesicles, and so on..

Control of movement of synaptic vesicles is very precise, being regulated by 'trafficking proteins' located both in the synaptic vesicle itself (SNARES) and the plasma membrane (SNAPs). There are several important questions about the above process, which we will soon ask. But first note that vesicles are not the whole story!

There are also pre-synaptic carrier proteins that release a small amount of neurotransmitter into the cleft, separate from the release of synaptic vesicles. In addition, certain neurotransmitters are not stored in vesicles, for example nitric oxide, and prostaglandins - both of these are synthesized on demand and then diffuse into the synapse. Finally, some transmitters are not synthesised in the presynaptic terminal, but are made in the nerve cell body and then transported to the terminal (some peptide transmitters).

How do synaptic vesicles release their contents?

Synaptic vesicles docked beneath the synaptic membrane are closely associated with voltage-gated calcium channels. When the synaptic membrane depolarises, the voltage-gated calcium channels open, calcium ions enter the cell, and then vesicle exocytosis follows.

SNARES and SNAPs - The synaptic vesicle cycle
This is insanely complex - there may be fifty to one hundred different proteins required to regulate the cycle. There are two distinct functional pools of synaptic vesicles - a large reserve pool kept in check by the neuronal (actin) cytoskeleton, and a smaller 'releasable' pool beneath the synaptic membrane. [Philos Trans R Soc Lond B Biol Sci 1999 Feb 28;354(1381):243-57] There is fine control of the various steps:
  1. release from the reserve pool;
  2. targeting to the active zone;
  3. docking;
  4. priming;
  5. fusion;
  6. endocytosis;

The most abundant proteins on synaptic vesicles are phosphoproteins called synapsins . They are probably responsible for tethering synaptic vesicles to the actin cytoskeleton, amongst several other functions.

A fairly recent article by Augustine et al (available in full online) details research into synaptic vesicle trafficking. They show the vital role of synapsins in regulating the reserve pool, including mobilisation of vesicles from this pool - docking to the plasma membrane appears to be mediated by a GTP-binding protein (such as "rab3a").

Before exocytosis occurs in docked vesicles, they must be primed , a process that involves ATP, phosphorylation of vesicle lipids, and dissociation of complexed 'SNARE' proteins, mediated by an ATPase called NSF.

The key protein involved in release of neurotransmitter after calcium ions enter in response to presynaptic voltage changes may be synaptotagmin within the membrane of vesicles, perhaps with a little help from its friends the SNARE proteins.

Recovery of vesicles by endocytosis seems to be preceded by "coating" of the pits left by the exocytosed vesicles, probably by clathrin .

Fusion to the endosome may be mediated by SNAP and NSF proteins.

What modulates transmitter release?

A variety of things influence release of neurotransmitters. There is a long list of neurotransmitters that influence the release of other transmitters, and the list grows daily. There are however two main mechanisms:

  1. Often, a presynaptic terminal is itself the target of branches from nearby neurones. These branches synapse on the presynaptic terminal and modulate its activity, for example, nearby sympathetic neurones may inhibit the activity of a parasympathetic neurone, and vice versa. The fancy name for such inhibition is heterotropic interaction .

  2. In addition, the presynaptic membrane may have receptors for its own neurotransmitter(s). Commonly, large amounts of the relevant neurotransmitter floating around in the synapse will stimulate these presynaptic receptors, and inhibit further transmitter release. We can use this "homotropic interaction " to good effect, for example the elderly anti-hypertensive drug alpha methyldopa is converted to alpha methylnoradrenaline which may act by potently stimulating presynaptic alpha-2 adrenergic receptors in the central nervous system, decreasing sympathetic outflow and lowering blood pressure. (Things are never simple - imidazoline receptors may also play an important role, although these receptors are more important in the action of drugs such as rilmenidine and moxonidine - see for example a recent overview by Head [Ann N Y Acad Sci 1999 Jun 21;881:279-86]. Not content with the term 'homotropic interaction', physiologists have also coined the name "autoinhibitory feedback" for the same phenomenon)!

It won't surprise you to learn that most of the above transmitters modulate synaptic vesicle release by affecting calcium entry into the nerve terminal. (Vesicle release is after all calcium-dependent). A common mechanism of control is to alter the phosphorylation of voltage-gated calcium channels, and thus affect their activity. (Changes in transmembrane potential may also play a role - wherever we go in excitable tissue, potassium channels seem to be tweaking the transmembrane potential).

How are transmitters removed from the cleft?

This is fun stuff. There are two main mechanisms - the first, most important, and certainly the most sensible mechanism is simply to take the transmitter back into the presynaptic terminal. The second is to destroy the transmitter.

  1. Re-uptake : Just as there is a synaptic vesicle cycle, so there is a neurotransmitter cycle ! Specific transporter proteins exist in the presynaptic membrane, driven by the higher extracellular concentration of sodium ions (which they co-transport into the cell, together with chloride ions). There has been a lot of recent interest in these transporters - a super-family of over 20 proteins. They are thought to have twelve transmembrane domains. Specific transporters exist for noradrenaline (NET), dopamine (DAT), serotonin and even GABA ('GAT1'). A wide variety of influences alter transporter activity, including membrane potential changes, exposure to ethanol, NO, and presynaptic receptor effects, perhaps mediated by alterations in activity of protein kinase C and also phosphatases. [Pharmacol Ther 2001 Oct;92(1):21-55]. The neuronal catecholamine transporters are often contrasted with the extraneuronal "organic cation transporters" (OCT1 and OCT2) which clear catecholamines from the bloodstream (found mainly in liver, kidney and intestine). Drugs such as cocaine act in part by inhibiting re-uptake of dopamine, noradrenaline and serotonin; amphetamines may increase synaptic levels of transmitters by causing reversal of direction of transport! [Eur J Pharmacol 2000 Oct 6;406(1):1-13]. SSRI anti-depressants act at least in part by inhibiting re-uptake of serotonin. The anti-epileptic tiagabine inhibits GABA re-uptake.

  2. Transmitter inactivation : The prototype of such removal is the destruction of acetylcholine by acetylcholinesterase, but similar mechanisms exist for a variety of neurotransmitters. We will later consider such inactivation in detail for the various neurotransmitters.

Why are multiple transmitters released at one cleft?

This is unclear. There are several possible reasons:

What are the general principles of post-receptor effects?

Conventionally, we see neurotransmitters as evanescent entities that diffuse across the synaptic membrane, pass the message on, and then vanish. Often the stimulus is brief, and soon after the neurotransmitter disappears from the cleft, things settle back to baseline. We now know that this simple model is often far from the truth. Some transmitters have profound and prolonged effects, not only on the cells they are stimulating, but also on the subsequent response of the cell to themselves and/or other neurotransmitters. An example is neuropeptide Y, which enhances the effects of noradrenaline at a post-synaptic level; transmitters such as substance P also have a prolonged excitatory post-synaptic effect.

We still have a lot to learn about the complex response to receptor stimulation, but there is a fair understanding of the mechanisms of response to receptor stimulation. Before we consider details of responses to receptor stimulation, it's important to revise the basics - you may wish to do this now!


  1. A strongly recommended textbook is: Pharmacology - HP.Rang, MM Dale, JM Ritter. 4ed.

  2. For details of the synaptic vesicle cycle see: Augustine GJ et al. J Physiol 1999 Oct 1;520 Pt 1:33-41. The free full text is available online!

  3. Frank Vincenzi's (U. Washington) virtual laboratory for studying autonomic drugs

  4. A good overview (with lots of diagrams) from the Neurology Department at Washington University in St Louis.

  5. Eric Chudler has a basic introduction to the ANS
Adrenergic ANS
Cholinergic ANS
Enteric ANS