Autonomic nervous system and visceral afferents

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13 Autonomic nervous system and visceral afferents

Sympathetic Nervous System

The sympathetic system is so called because it acts in sympathy with the emotions. In association with rage or fear, the sympathetic system prepares the body for ‘fight or flight’: the heart rate is increased, the pupils dilate, and the skin sweats. Blood is diverted from the skin and intestinal tract to the skeletal muscles, and the sphincters of the alimentary and urinary tracts are closed.

The sympathetic outflow from the nervous system is thoracolumbar, the preganglionic neurons being located in the lateral gray horn of the spinal cord at thoracic and upper two (or three) lumbar segmental levels. From these neurons, preganglionic fibers emerge in the corresponding anterior nerve roots and enter the paravertebral sympathetic chain. The fibers do one of four things (Figure 13.1):

Clinical Panel 13.1 Sympathetic interruption

Stellate block

Injection of local anesthetic around the stellate ganglion – stellate block – is a procedure used in order to test the effects of sympathetic interruption on blood flow to the hand. Both pre- and postganglionic fibers are inactivated, producing sympathetic paralysis in the head and neck on that side, as well as in the upper limb. A successful stellate block is demonstrated by (a) a warm, dry hand, (b) Horner’s syndrome, which consists of a constricted pupil owing to unopposed action of the pupillary constrictor, and (c) ptosis (drooping) of the upper eyelid owing to paralysis of smooth muscle fibers contained in the levator muscle of the upper eyelid (Figure CP 13.1.1).

Dominance of the right stellate ganglion in control of the heart rate is shown by the marked slowing of the pulse following a right, but not a left, stellate block. (See also Box 13.1.)

Functional sympathectomy of the upper limb may be carried out by cutting the sympathetic chain below the stellate ganglion. This is not an anatomical sympathectomy because the ganglionic supply to the limb from the middle cervical and stellate ganglia remains intact. It is a functional one because the ganglionic neurons for the limb are deprived of tonic sympathetic drive. Horner’s syndrome is avoided by making the cut at the level of the second rib: the preganglionic fibers for the head and neck enter the stellate direct from the first thoracic spinal nerve.

Two indications for interruption of the sympathetic supply to one or both upper limbs are painful blanching of the fingers in cold weather (Raynaud phenomenon), and hyperhidrosis (excessive sweating) of the hands – usually an embarrassing affliction of teenage girls.

The sympathetic supply to the eye is considered further in Chapter 23.

The medulla of the adrenal gland is the homolog of a sympathetic ganglion, being derived from the neural crest. It receives a direct input from fibers of the thoracic splanchnic nerve of its own side (see later).

The sympathetic system exerts tonic (continuous) constrictor activity on blood vessels in the limbs. In order to improve the blood flow to the hands or feet, impulse traffic along the sympathetic system can be interrupted surgically (Clinical Panel 13.1).

Parasympathetic Nervous System

The parasympathetic system generally has the effect of counterbalancing the sympathetic system. It adapts the eyes for close-up viewing, slows the heart, promotes secretion of salivary and intestinal juices, and accelerates intestinal peristalsis. A notable instance of concerted sympathetic and parasympathetic activity occurs during sexual intercourse (Box 13.4).

The parasympathetic outflow from the CNS is craniosacral (Figure 13.2). Preganglionic fibers emerge from the brainstem in four cranial nerves – the oculomotor, facial, glossopharyngeal, and vagus – and from sacral segments of the spinal cord.

Neurotransmission in the Autonomic System

Junctional receptors

The physiological effects of autonomic stimulation depend upon the nature of the postjunctional receptors inserted by target cells into their own plasma membranes. In addition, transmitter release is influenced by prejunctional receptors in the axolemmal membrane of the nerve terminals.

Sympathetic junctional receptors (adrenoceptors) (Figure 13.5)

Two kinds of α adrenoceptor and two kinds of β adrenoceptor have been identified for norepinephrine:

3 Postjunctional β1 adrenoceptors increase pacemaker activity in the heart and increase the force of ventricular contraction (Box 13.1). In response to a severe fall of blood pressure, sympathetic activation of β1 receptors on the juxtaglomerular cells of the kidney causes secretion of renin. Renin initiates production of the powerful vasoconstrictor angiotensin II.

Box 13.1 Innervation of the heart

The preganglionic sympathetic supply to the heart arises from the lateral gray horn of cord segments T1–5. The fibers synapse in all three cervical and in the uppermost five thoracic ganglia of the sympathetic chain. Postganglionic adrenergic fibers are distributed to the specialized myocardial cells of nodal and conducting tissues, to the general myocardium (of the left ventricle in particular), and to the coronary arteries.

Experimental evidence indicates that the preganglionic parasympathic supply originates in neurons occupying the caudal ventrolateral medulla oblongata. The fibers descend within the trunk of the vagus and synapse within mural ganglia on the posterior walls of the atria and in the posterior atrioventricular groove (Figure Box 13.1.1). Postganglionic cholinergic fibers supply the same tissues as those of the sympathetic, although the direct supply to ventricles and coronary arteries is slight.

There is a high level of autonomic interaction where innervation is dense, notably within nodal tissue, in the modes shown in Figures 13.5 and 13.7. Many sympathetic nerve endings also release neuropeptide Y, which binds to a specific receptor on cholinergic terminals with adjuvant inhibitory effect on ACh release.

Many parasympathetic endings co-release VIP, which attenuates release of ACh by binding with VIP-specific inhibitory autoreceptors on the endings that release it.

An abundance of NANC neurons modulate the activity of parasympathetic ganglion cells. Also found are scattered adrenergic neurons whose preganglionic supply traverses the sympathetic chain, and bipolar local circuit neurons.

Autoregulation of myocardial performance by the intramural ganglionic networks of the normal heart is sufficient to withstand the total extrinsic denervation involved in a cardiac transplant.

A fourth set of neurons is afferent in nature. Unipolar somas in the inferior ganglion of the vagus provide stretch-sensitive nerve endings close to the endocardium – notably in the right atrium where distension produces reflex slowing of the heart rate by way of a central pathway to the dorsal vagal nucleus via the solitary nucleus (Ch. 24).

Some unipolar somas in spinal dorsal root ganglia send peripheral processes to form chemosensitive endings in the myocardium. Metabolites released by ischemic myocardial cells in response to coronary artery occlusion generate impulse trains which travel along the central processes of these cells to reach the posterior gray horn via anterior nerve roots. The central processes synapse upon projection cells of the lateral spinothalamic tract, with consequent perception of referred pain (see main text). A prominent transmitter in the nociceptive neurons is substance P, which is released at both ends simultaneously: in the gray matter, this peptide is excitatory to spinothalamic projection cells, and in the ischemic tissue it activates specific excitatory receptors on cholinergic endings, thus slowing the heart.

The cardiac pacemaker (sinuatrial node) is on the right side of the body and mainly innervated by the two right-sided sets of autonomic neurons. The atrioventricular node is on the left side and receives a corresponding preponderance.

The sinuatrial node is highly responsive to emotional states having their seat of origin in the right, ‘emotional’ hemisphere (Ch. 34). The descending pathways concerned are largely ipsilateral and polysynaptic, prior to reaching the lower autonomic nervous system centers of medulla and cord. Sympathetic overactivity, in response to ‘approach’ emotions of sexual or combative nature, may cause the heart to ‘miss a beat’ (extrasystole) or the ‘pulse to race’ (tachycardia). Parasympathetic overactivity, in response to ‘withdraw’ (aversive) emotions, usually of olfactory or visual origin, may cause bradycardia – or even cardiac arrest.

The atrioventricular node and Purkinje fibers concordantly increase or reduce the speed of transference of action potentials to the ventricles.

Ventricular contractility, and synchrony throughout the ventricular myocardium, are increased by raised sympathetic activity. Both are diminished by the parasympathetic, in this case mainly by autonomic interaction: the scarce cholinergic fibers terminate mainly ‘on top’ of adrenergic ones without any direct influence on the myocardium.

The coronary arterial tree possesses a considerable degree of autoregulation based on release of myocardial cellular metabolites. However, adrenoceptors are also important. The arterioles (< 120 µm in diameter) are rich in β2 receptors responsive to neural norepinephrine at the commencement of exercise, and to circulating epinephrine when exercise gets under way. The arteries (>120 µm) contain α1 receptors exerting a restraining effect, directing blood to the subendocardial ventricular myocardium, which is vulnerable on two counts: it is the most distal coronary territory; and it is the most compressed myocardial component during systole, receiving blood only during diastole.

Cholinergic coronary nerve endings are scarce, but they have a significant dilator effect on the main arteries – precisely those most at risk of atherosclerosis! It transpires that released ACh acts indirectly, by causing release of the potent dilator nitric oxide from the vascular endothelium. Progressive devitalization of the endothelium by underlying atherosclerotic plaques leads to more or less complete failure of beneficial nitric oxide production.

Postjunctional β2 receptors relax smooth muscle, notably in the tracheobronchial tree and in the accommodatory muscles of the eye. Some postjunctional β2 receptors are on the surface of hepatocytes in the liver, where they initiate glycogen breakdown to provide glucose for immediate energy needs.

Prejunctional β2 receptors on adrenergic terminals promote release of norepinephrine.

Most of the norepinephrine liberated at sympathetic terminals is retrieved by an amine uptake pump. Some is degraded after uptake, by a mitochondrial enzyme, monoamine oxidase.

The effects of drugs on the sympathetic system are considered in Clinical Panel 13.2.

Clinical Panel 13.2 Drugs and the sympathetic system

Considerable scope is offered for pharmacological interference at sympathetic nerve endings. Drugs which cross the blood–brain barrier (Ch. 5) may exert their effects upon central rather than peripheral adrenoceptors. Potential sites of drug action are numbered in Figure CP 13.2.1.

3 α or β receptors can be selectively either stimulated or blocked. As was mentioned in Chapter 7, a receptor can be likened to a lock, and a drug which operates the lock is an agonist. A drug which ‘jams’ the lock without operating it is a blocker. ‘Beta agonists’ are used to relax the bronchial musculature in asthmatic patients. Cardioselective ‘beta blockers’ are used to limit access of norepinephrine to α1 receptors.

Parasympathetic junctional receptors

Parasympathetic junctional receptors are called muscarinic because they can be mimicked by application of the drug muscarine (Figure 13.7). Parasympathetic stimulation produces the following muscarinic effects:

In addition to the above postjunctional effects, prejunctional muscarinic receptors located on sympathetic varicosities inhibit release of norepinephrine (Figure 13.6).

The effects of drugs on the parasympathetic system are considered in Clinical Panel 13.3. Drugs having muscarinic effects are described as cholinergic. Drugs that prevent access of ACh to junctional receptors are anticholinergic.

Clinical Panel 13.3 Drugs and the parasympathetic system

Possible peripheral effects of cholinergic and anticholinergic drugs are listed in Figure CP 13.3.1. Some success has been achieved in the search for organ- or tissue-specific drugs. For example, the contribution of the vagus nerve to acid secretion in the stomach involves activation of a muscarinic receptor (M1) which is distinct from the receptor type (M2) found in the heart or on smooth muscle. An M1-receptor blocker is available for patients suffering from peptic ulcer, for the specific purpose of reducing gastric acidity.

A major consideration in the use of drugs either to imitate or to suppress sympathetic or parasympathetic activity is the existence of α, β, and muscarinic receptors in the central nervous system. In psychiatric practice, in particular, drugs are often chosen for their action at their central rather than peripheral receptors.

Regional Autonomic Innervation

Box 13.1 describes the autonomic innervation of the heart, Box 13.2 the enteric nervous system, Box 13.3 lower-level bladder controls, and Box 13.4 the functional innervation of the genital tract.

Box 13.2 Enteric nervous system

The enteric nervous system (ENS) shown in Figure Box 13.2.1 extends from the midregion of the esophagus all the way to the anal canal. Throughout the length of this tube, it controls peristaltic activity, glandular secretion, and water and ion transfer. In addition, the ENS supplies the pancreas, liver, and gall bladder. The number of intrinsic neurons in the wall of the gastrointestinal tract has been reckoned about the same as in the entire spinal cord. The ENS is sometimes referred to as the ‘gut brain’ on account of its size and relative functional independence.

The intrinsic neurons of the gut are mainly deployed in two intramural plexuses, namely the myenteric plexus (of Auerbach) between the longitudinal and circular layers of smooth muscle, and the smaller submucous plexus (of Meissner). The principal ‘drivers’ of the muscle and glands belong to the parasympathetic division of the autonomic system.

The dorsal (motor) nucleus of the vagus provides the preganglionic parasympathetic supply (1) to all parts with the exception of the distal colon and rectum, which receive their preganglionic supply from the pelvic splanchnic nerves (having parent neurons in the intermediolateral cell column of cord segments S2–S4). The drivers throughout are intramural ganglion cells located in both intramural plexuses. The beaded postganglionic fibers of the myenteric plexus (2) initiate peristaltic waves by simultaneously causing the gut to contract in their own location (3) and to relax distally by activating inhibitory neurons (4). Parasympathetic ganglion cells in the wall of the gall bladder cause expulsion of bile. Those in the submucous plexus (5), and in the pancreas, cause glandular secretion.

Peristaltic activity persists even after total extrinsic denervation because of the intrinsic circuitry and the spontaneous excitability of ‘pacemaker’ patches of smooth muscle (notably in stomach and duodenum).

The preganglionic sympathetic nerve supply originates in lateral horn cells of cord segments T5–T11. The fibers traverse the paravertebral sympathetic chain (6) without synapsing here and terminate in the prevertebral, splanchnic ganglia (7) within the abdomen (celiac, superior and inferior mesenteric). Their beaded postganglionic fibers supply the smooth muscle of the intestine and of blood vessels, which they relax via β2 receptors.

Visceral afferents reaching the CNS have their unipolar somas in a nodose ganglion of the vagus (8) and in posterior root ganglia at spinal levels T5–T11(9). The spinal afferents reach the posterior gray horn via anterior nerve roots. These ventral root afferents are of special clinical importance because they include first-order nociceptive afferents which synapse centrally upon lateral spinothalamic projection cells providing the principal ‘pain pathway’ to the brain.

Intrinsic visceral afferent neurons are in the form of bipolar neurons (12). Some participate in local reflex arcs within the myenteric or submucous plexus. Others (not shown) project as far as the splanchnic ganglia with the potential of exerting more widespread reflex effects.

Transmitters and modulators are numerous among the enteric ganglion cells. The principal excitatory transmitter is ACh, with substance P cotransmitted as a modulator. The principal inhibitory transmitters are nitric oxide, GABA, and VIP. Large numbers of different peptides have been revealed by means of histochemistry. More often than not, two or more are present within individual cells.

Box 13.3 Lower-level bladder controls

The female bladder is selected for this description, and also for higher-level bladder controls in Chapter 24.

The micturition cycle (Figure Box 13.3.1)

Box 13.4 Functional innervation of male genital tract (Figure Box 13.4.1)

Visceral Afferents

Afferents from thoracic and abdominal viscera utilize autonomic pathways to reach the CNS. They participate in important reflexes involved in the control of circulation, respiration, digestion, micturition, and coition.

Visceral activities are not normally perceived, but they do reach conscious levels in a variety of disease states. Visceral pain is of immense importance in the context of clinical diagnosis.

Visceral pain

There are three fundamental types of visceral pain:

Pain and the mind

Although visceral pain has well-established causative mechanisms (inflammation, spasm of smooth muscle, ischemia, distension), thoracic or abdominal pain may be experienced in the complete absence of visceral disease. Pain that recurs or persists over a long period (months), and is not accounted for by standard investigational procedures, is more likely to have a psychological rather than a physical explanation. This is not to deny that the pain is real, but to imply that it originates within the brain itself. An example is the abused child whose abdominal pains represent a cry for help. In adults, recurrent and rather ill-defined pains are a common manifestation of major depression (see Ch. 26).

Irritable bowel syndrome is a very common disorder usually arising in the third or fourth decade. In this syndrome there is evidence of abnormality at intestinal cellular level, but alterations of bowel behavior appear to be heightened by a disorder of the brain–gut axis (Clinical Panel 13.4).

Clinical Panel 13.4 Irritable bowel syndrome

IBS (irritable bowel syndrome) is considered to be the the most prevalent of all GI tract disorders, affecting as much as 20% of the population in most countries. The exact incidence is uncertain because of the absence of a specific test; diagnosis is based upon a constellation of symptoms associated with a suggestive psychosocial history. The disorder is three times more common in women and onset is most frequent during the third and fourth decades.

The typical clinical picture is one of recurrent abdominal pain relieved by defecation. Some patients may have less than three bowel movements per week, others more than three per day. Both groups experience bloating (feeling of abdominal distension). Sensitivity to visceral sensations may have been triggered by a previous infectious or food-allergy gastroenteritis. The typical pysychological profile is one of introspection and hypochondriasis accompanied by feelings of mental stress and anxiety. Sometimes a history of childhood physical or sexual abuse may be elicited.

The overall situation is generally accepted as one of dysfunction of the brain–gut axis.

Figure 34.10 shows the position of the emotional nociceptive area within the cingulate gyrus. This area is activated by aversive (unpleasant) painful stimulation of any body part, as revealed by PET (positron emission tomography). In IBS patient volunteers it is activated by baloon distension of the distal colon at a lower balloon volume than in healthy controls. Heightened sensitivity to intestinal events seems to some extent centrally rather than peripherally generated. It is now believed that the preganglionic neurons of the parasympathetic system synapse mainly on internuncial neurons in the intestinal wall, rather than on the ‘traditional’ postganglionic motor neurons shown in Figure Box 13.2.1. The central drive of the parasympathetic may be an expression of stress, and because internuncial neurons may activate nociceptive afferents as well as motor neurons, heightened sensitivity may be maintained or even increased through this feedback loop.

At peripheral level, biopsies taken from ileum and colon indicate that heightened sensitivity may be the outcome of an immune response generated by earlier gastrointestinal infection or food allergy, as evidenced by proliferation of enterochromaffin cells in the wall of intestinal crypts, and/or mast cells in the lamina propria (Figure CP 13.4.1). The peptide granules of enterochromaffin (chromate-staining) cells collectively contain more serotonin (5-HT) than does the entire brain. Serotonin liberated in response to intestinal distension has a double effect: it activates 5-HT3 receptors on smooth muscle cells, thereby promoting peristaltic contractions; and it activates nociceptors on nearby visceral afferents, thereby causing mast cells to liberate histamine, which in turn may potentiate the local effect of serotonin.

Following investigations to rule out organic disease, reassurance alone may be sufficient to restore equilibrium, although many patients benefit from psychotherapy. Drug treatments are essentially symptomatic, e.g. 5-HT3-receptor antagonists or M3-receptor anticholinergics for diarrhea, 5-HT3-receptor agonists or cholinergics for constipation.

Note on vascular afferents

Two vascular sets of unipolar neurons are customarily included in descriptions of the visceral afferent system. One supplies the carotid sinus and aortic arch with stretch receptors involved in the maintenance of the systemic blood pressure (Ch. 24); the other supplies the carotid body with chemoreceptors and is involved in respiratory control (Ch. 24). There is a progressive tendency to acknowledge all vascular afferents as being visceral, because those on peripheral blood vessels are morphologically and functionally the same as those serving the heart. They all contain substance P, are ‘silent’ in health, and subserve pain in the presence of disease or injury – as witness, the ‘dragging’ leg pains accompanying varicose veins, or the stab of pain when a clumsily inserted antecubital venipuncture needle strikes the brachial artery. The pathway to the posterior nerve roots is still uncertain, but it appears that (to an approximation) perivascular fibers above elbow and knee send impulses by the sympathetic route (but in the reverse direction), and that more peripheral perivascular fibers send messages in company with cutaneous nerves (and in the same direction). The notion of visceral afferents running in cutaneous nerves is reminiscent of their same service with respect to nerve fibers terminating in Golgi tendon organs at wrist and ankle.

Core Information

The autonomic nervous system contains three neuron chains of effector neurons: central neurons project from hypothalamus/brainstem to brainstem/spinal cord preganglionic neurons. These send preganglionic fibers to autonomic ganglion cells, which in turn send postganglionic fibers to target tissues.

Sympathetic preganglionic outflow to the sympathetic chain of ganglia is thoracolumbar. Some fibers synapse in nearest ganglia. Some ascend to the superior cervical, middle cervical, or stellate ganglion, whence postganglionic fibers innervate head, neck, upper limbs, and heart. Some descend to synapse in lumbar or sacral ganglia, whence postganglionic fibers enter the lumbosacral plexus to supply lower limb vessels. Some pass through the chain and synapse instead in central abdominal ganglia (for the supply of gastrointestinal and genitourinary tracts) or in the adrenal medulla.

Parasympathetic preganglionic outflow is craniosacral. Cranial nerve distributions are oculomotor nerve via ciliary ganglion to sphincter pupillae and ciliaris; facial nerve via pterygopalatine ganglion to lacrimal and nasal glands; facial nerve via submandibular ganglion to submandibular and sublingual glands; glossopharyngeal nerve via otic ganglion to parotid gland; vagus nerve via ganglia on or in walls of heart, bronchi, and alimentary tract to muscle tissue and glands. Sacral nerves 2–4 deliver preganglionic fibers to intramural ganglia of distal colon and rectum, and to pelvic ganglia for supply of bladder and internal pudendal artery.

All preganglionic neurons are cholinergic. They activate nicotinic receptors in the ganglia. All postganglionic fibers end at neuroeffector junctions. In the sympathetic system, these are generally adrenergic, liberating norepinephrine, which may activate postjunctional α1 adrenoceptors on smooth muscle, prejunctional α2 adrenoceptors on local nerve endings, postjunctional β1 on cardiac muscle, or postjunctional β2, which are more responsive to epinephrine. Epinephrine is liberated by adrenomedullary chromaffin cells and resultant activation of β2 receptors on smooth muscle causes relaxation.

Parasympathetic postganglionic fibers are cholinergic. The cholinoceptive receptors on cardiac and smooth muscle and glands are muscarinic.