Viva M1(i)a

This chapter is relevant to Section M (i) of the 2017 CICM Primary Syllabus, which expects the exam candidates to "describe the autonomic nervous system, including anatomy, receptors, subtypes and transmitters (including their synthesis, release and fate)". To control size, this section is limited to a discussion of adrenergic and cholinergic neurotransmission, and the drugs that act on it.

What is the autonomic nervous system?

• The autonomic nervous system is a peripheral nervous system that regulates involuntary physiologic processes, and that has a distinct organisation from the somatic and sensory nervous systems.
• The autonomic nervous system is defined anatomically:
  • The sympathetic nervous system is defined as the efferent autonomic nerve fibres arising from the thoracolumbar spine (T1 to L2 or L3). 
  • The parasympathetic nervous system is defined as the efferent autonomic nerve fibres arising from the cranial nerve and sacrum (S2-S4).
  • The enteric nervous system consists of the myenteric and submucosal nervous plexuses and is largely self-contained, functioning via locally controlled paracrine and reflex activity

What are the similarities between the sympathetic nervous system and the parasympathetic nervous system?

• Same postganglionic secondary messenger systems. 
  • Both muscarinic and adrenergic receptors are G-protein coupled, i.e. metabotropic
• Same preganglionic neurotransmission. 
  • Both the sympathetic and parasympathetic preganglionic synapses release acetylcholine and use nicotinic receptors.
• Same nerve fibre types.  
  • Both sympathetic and parasympathetic preganglionic fibres are lightly and incompletely myelinated B-type fibres.  
• Same direction of change (excitatory). 
  • Both sympathetic and parasympathetic systems generally stimulate the organ they innervate, i.e. the result of increased activity is rarely the relaxation of a muscle or the decrease in the secretion of a gland.
• Same basic structural organisation
  • Both have preganglionic cell bodies in the CNS (eg. cranial nerve nuclei and the grey matter of the spinal cord) and both send preganglionic fibres to ganglia

In what ways are the two systems similar?

• Different CNS origins: 
  • The preganglionic cell bodies of the ANS lay in different locations, but are somewhat analogous. 
• Different peripheral organisation. 
  • The sympathetic nervous system radiates widely from its origin to innervate all blood vessels and skin
  • In contrast, the parasympathetic nervous system only does the head, neck, and abdominal organs.
  • As the result, the effects of ganglionic blockade (i.e. blocking nicotinic receptors) tends to have predominantly sympatholytic manifestations, as the parasympathetic effects are lost and overshadowed.
• Differently positioned ganglia. 
  • Parasympathetic ganglia are near, on, or in, the effector organs, whereas sympathetic ganglia are collected in neat paravertebral chains.
• Different postganglionic neurotransmission.
  •  Parasympathetic postganglionic neurons release acetylcholine, and use muscarinic receptors
  • Sympathetic neurons release noradrenaline (and adrenaline, in the case of the adrenal medulla). 
• Different (but not necessarily opposed) effects on the same organ: 
  • Under most circumstances each organ or tissue is innervated by one or the other system, predominantly. 

What are the central nervous system structures involved in the control of autonomic activity?

• Brainstem structures:
  • rostral ventrolateral medullary vasomotor centre
  • raphe nucleus
  • nucleus tractus solitarius
• Hypothalamic structures
  • paraventricular nucleus for example
• Cortical structures
  • Anterior insular cortex
  • Amygdala
  • Anterior cingulate cortex, 

Describe the structural organisation of the preganglionic sympathetic fibres

• Intermediolateral cell bodies send efferent fibres anteriorly into the ventral root
• From the ventral root, the fibres course into the spinal nerve, and then into the ventral (anterior) primary ramus of the spinal nerve
• From the ventral primary ramus of the spinal nerve,  preganglionic fibres exit via the white rami, so called because they are more full of myelin, and appear more pale. 
• The white rami join the sympathetic chain ganglia, where the fibres can either:
  • Synapse with a ganglionic neuron at the same level
  • Travel up or down the sympathetic trunk to synapse with a ganglionic neuron at some other level
  • Pass through the sympathetic trunk without synapsing, and carry on along a splanchnic nerve to synapse with a distant gangion somewhere peripherally
• The fibres that synapse with a ganglionic neuron send postganglionic fibres that return to spinal nerve via the grey rami, so called because they are darker and thinner, being composed of largely unmyelinated fibres.
• These postganglionic fibres then carry on with other somatic nerves to innervate their peripheral targets (vessels, skin, sweat glands, etc)

Describe the anatomy of sympathetic ganglia

• Paravertebral ganglia 
  • lined up along the spinal column
  • 24 paravertebral ganglia on each side, forming the sympathetic chains. 
  • There's generally one ganglion for each spinal level, except in the neck where there are only three:
    • Superior cervical ganglion is formed by sympathetic fibres fibres of the upper four spinal levels, running up the vertebral artery. Its a mass of postganglionic cell bodies about 3cm long, and it is positioned in front of the lateral mass of the atlas and axis.
    • Middle cervical ganglion sits in front of the vertebral artery at the level of around C6.
    • Inferior cervical ganglion lies behind the origin of the vertebral artery. It may not exist, instead being absorbed into the stellate ganglion.
    • The stellate ganglion is a fusion of the first thoracic ganglion and the inferior cervical ganglion, sitting in front of the neck of the first rib.
• Prevertebral ganglia are not necessarily bilaterally symmetrical, forming a network of nervous tissue structures ventral to the abdominal aorta
  • Coeliac ganglia are two semilunar masses of nervous tissue that wrap around the coeliac trunk artery,  medial to the adrenal glands and anterior to the crura of the diaphragm. 
    • Fibres from this ganglion innervate the lower oesophageal sphincter, stomach, liver, pancreas, spleen, and about half of the duodenum 
  • Superior mesenteric ganglion  sits in the retretroperitoneum at the origins of the SMA, and sends fibres to innervate basically all of the intestine, from the lower half of the duodenum down to the transverse colon (Patel et al, 2021)
  • Aorticorenal ganglia invest the renal arteries bilaterally and innervate the kidneys.
  • Inferior mesenteric ganglion innervates the rest of the colon and rectum. It wraps around the origin of the inferior mesenteric artery.

What are the splanchnic nerves, and what do they supply?

• Splanchnic nerves:
  • Greater splanchnic nerve from T5-9, to coeliac ganglion
  • Lesser splancnic nerve from T10 and T11, to coeliac ganglion
  • Least splanchnic nerve from T12, to renal ganglion
  • Lumbar splanchnic nerve from L1 and L2, to aortic plexus
  • Sacral splanchnic nerves, from T12-L2, to the inferior hypogastric plexus, the superior hypogastric plexus and the aortic plexus

Describe the process of ganglionic neurotransmission

• At the ganglia, the synaptic junctions are cholinergic, i.e. release acetylcholine
• The signal to release the acetylcholine is calcium-mediated, and triggered by the depolarisation of the presynaptic membrane
• The acetylcholine receptors mediating transmission are N2 nicotinic receptors.
• These are cation channels
• Their transmission is rapid - the postsynaptic membrane depolarises and the action potential is conducted to the next neuron
• Acetylcholine is then degraded by acetylcholinesterase

What are the characteristics of postganglionic sympathetic fibres and nerve endings?

• Sympathetic postganglionic fibres are unmyelinated
  • The fibres that synapse with a ganglionic neuron send postganglionic fibres that return to spinal nerve via the grey rami, so called because they are darker and thinner, being composed of largely unmyelinated fibres.
  • These postganglionic fibres then carry on with other somatic nerves to innervate their peripheral targets (vessels, skin, sweat glands, etc)
• Sympathetic nerve endings
  • Ultrastructure: "beaded strands", varicosities along the axon release the neurotransmitters in proximity (within 1-2 μm) of target organ/tissue
  • Mostly release noradrenaline
  • A minority (4%) are cholinergic - innervate the eccrine sweat glands

Which organs and tissues are innervated EXCLUSIVELY by the sympathetic nervous system?

• The adrenal glands
• The majority of the blood vessels (where the parasympathetic nervous system only innervates the helical arteries and sinusoids of the erectile tissues in your reproductive organs and some of the blood vessels to various glands)
• The pilomotor muscles in the skin (hair follicles),
• Sweat glands

Which organs and tissues are NOT innervated by the sympathetic nervous system?
In other words, what is EXCLUSIVELY innervated by the parasympathetic nervous system?

• Salivary glands (which are minimally responsive to sympathetic stimulation)
• Gastric G-cells (which produce gastric acid)
• Mucus glands of the reproductive tract
• Lacrimal glands
• Nasopharyngeal mucus glands

Which tissues rely on nonsynaptic adrenergic transmission, i.e. adrenaline rather than noradrenaline?

• The entire β-2 receptor system is not directly innervated by noradrenergic sympathetic fibres, as β-2 receptors could not care less for noradrenaline, and respond only to adrenaline. 
• The bronchial smooth muscle
• the vast majority of the arteriolar smooth muscle cells (as the blood vessels are sparsely innervated by the SNS, which means many cells will rely mostly on humoral signals),
• the adipose tissue (which receives some direct innervation from the sympathetic nervous system, but which mostly relies on humoral control and expresses α₁ and β3 receptors)
• Bone, which receives sympathetic innervation only via perivascular vasomotor fibres, but which expresses β2 receptors on the surface of osteoblasts and osteocytes

How are the preganglionic neurons of the parasympathetic nervous system arranged? i.e. where are they anatomically?

• Edinger-Westphal nucleus of the midbrain, which controls the pupil via the third nerve, and which is responsible for the efferent arc of the pupillary light reflex. 
• Superior salivary nucleus in the pontine tegmentum, which innervates the lacrimal glands and some of the salivary glands, as well as the nasal mucosa
• Inferior salivary nucleus in the lowermost dorsal pons, at the junction with the medulla, which innervatres the parotid glands  
• Dorsal vagal nucleus in the medulla, which innervates seemingly everything in the chest and abdomen via the vagus nerve
• Nucleus ambiguus, also in the medulla, which needs a special mention because it sends parasympathetic fibres to the heart.
• Intermediolateral laminae (V-VII) of the second third and fourth sacral spinal cord segments.  

Describe the anatomy of the parasympathetic ganglia

• These are generally close to the organ they are innervating
• The ciliary ganglion  is a tiny structure approximately the size of a pinhead, in the posterior orbital fat
• The pterygopalatine ganglion is the largest of the four parasympathetic ganglia in the neck, and is located deep in the nose, posterior to the insertion of the middle nasal concha- relatively exposed, under a layer of thin mucosa. Its depth confers to it an invulnerability to rhinotillexomania, which means one should not be able to accidentally stimulate it. 
• The submandibular ganglion sits on the hypoglossus muscle, which is one of the muscles that tether the tongue to the hyoid bone. 
• The otic ganglion is a small structure under the foramen ovale, in the infratemporal fossa (where it is protected from pyring eyes by the zygomatic arch)
• The ganglia of the vagus are widespread, small, nameless, and forgettable. To give the reader an example, the tracheal ganglia sit on the adventital surface of the trachea, forming a disorganised mesh, and comprise of groups of no more than about 25 cells. In the heart, the ganglia are present mainly in the atria, nearest to the origins of the greater vessels and (obviously) close to the SA and AV nodes, according to Singh et al (1996).