Chapter 13: Autonomic Nervous System

After studying this chapter, you should be able to:

• Describe the location of the cell bodies and axonal trajectories of preganglionic and postganglionic sympathetic and parasympathetic neurons.

• Name the neurotransmitters that are released by preganglionic autonomic neurons, postganglionic sympathetic neurons, postganglionic parasympathetic neurons, and adrenal medullary cells.

• Name the types of receptors on autonomic ganglia and on various target organs and list the ways that drugs can act to alter the function of the processes involved in transmission within the autonomic nervous system.

• Describe functions of the sympathetic and parasympathetic nervous systems.

• Describe the location of some forebrain and brainstem neurons that are components of central autonomic pathways.

• Describe the composition and functions of the enteric nervous system.

The autonomic nervous system (ANS) is the part of the nervous system that is responsible for homeostasis. Except for skeletal muscle, which gets its innervation from the somatomotor nervous system, innervation to all other organs is supplied by the ANS. Nerve terminals are located in smooth muscle (eg, blood vessels, the wall of the gastrointestinal tract, and urinary bladder), cardiac muscle, and glands (eg, sweat glands and salivary glands). Although survival is possible without an ANS, the ability to adapt to environmental stressors and other challenges is severely compromised. The importance of understanding the functions of the ANS is underscored by the fact that so many drugs used to treat a vast array of diseases exert their actions on elements of the ANS. Also, many neurologic diseases or disorders result directly from a loss of preganglionic sympathetic neurons (eg, multiple system atrophy and Shy–Drager syndrome) and other common diseases (eg, Parkinson disease and diabetes) are associated with autonomic dysfunction (Clinical Box 13–1).

The ANS has two major and anatomically distinct divisions: the sympathetic and parasympathetic nervous systems. As will be described, some target organs are innervated by both divisions and others are controlled by only one. In addition, the ANS includes the enteric nervous system within the gastrointestinal tract. The classic definition of the ANS is the preganglionic and postganglionic neurons within the sympathetic and parasympathetic divisions. This would be equivalent to defining the somatomotor nervous system as the cranial and spinal motor neurons. A modern definition of the ANS takes into account the descending pathways from several forebrain and brainstem regions as well as visceral afferent pathways that set the level of activity in sympathetic and parasympathetic nerves. This is analogous to including the many descending and ascending pathways that influence the activity of somatic motor neurons as elements of the somatomotor nervous system.

GENERAL FEATURES

Figure 13–1 compares some fundamental characteristics of the innervation to skeletal muscles with innervation to smooth muscle, cardiac muscle, and glands. As discussed in earlier chapters, the final common pathway linking the central nervous system (CNS) to skeletal muscles is the α-motor neuron. Similarly, sympathetic and parasympathetic neurons serve as the final common pathway from the CNS to visceral targets. However, in marked contrast to the somatomotor nervous system, the peripheral motor portions of the ANS are made up of two neurons: preganglionic and postganglionic neurons. The cell bodies of the preganglionic neurons are located in the intermediolateral (IML) column of the spinal cord and in motor nuclei of some cranial nerves. In contrast to the large diameter and rapidly conducting α-motor neurons, preganglionic axons are small-diameter, myelinated, relatively slowly conducting B fibers. A preganglionic axon diverges to an average of eight or nine postganglionic neurons. In this way, autonomic output is diffuse. The axons of the postganglionic neurons are mostly unmyelinated C fibers and terminate on the visceral effectors.

One similar feature of autonomic preganglionic neurons and α-motor neurons is that acetylcholine is released at their nerve terminals (Figure 13–1). This is the neurotransmitter released by all neurons whose axons exit the CNS, including cranial motor neurons, α-motor neurons, γ-motor neurons, preganglionic sympathetic neurons, and preganglionic parasympathetic neurons. Postganglionic parasympathetic neurons also release acetylcholine, whereas postganglionic sympathetic neurons release either norepinephrine or acetylcholine.

SYMPATHETIC DIVISION

In contrast to α-motor neurons, which are located at all spinal segments, sympathetic preganglionic neurons are located in the IML of only the first thoracic to the third or fourth lumbar segments. This is why the sympathetic nervous system is sometimes called the thoracolumbar division of the ANS. The axons of the sympathetic preganglionic neurons leave the spinal cord at the level at which their cell bodies are located and exit via the ventral root along with axons of α- and γ-motor neurons (Figure 13–2). They then separate from the ventral root via the white rami communicans and project to the adjacent sympathetic paravertebral ganglion, where some of them end on the cell bodies of the postganglionic neurons. Paravertebral ganglia are located adjacent to each thoracic and upper lumbar spinal segment; in addition, there are a few ganglia adjacent to the cervical and sacral spinal segments. The ganglia are connected to each other via the axons of preganglionic neurons that travel rostrally or caudally to terminate on postganglionic neurons located at some distance. Together these ganglia and axons form the sympathetic chain bilaterally. This arrangement is seen in Figure 13–2 and Figure 13–3.

Some preganglionic neurons pass through the paravertebral ganglion chain and end on postganglionic neurons located in prevertebral (or collateral) ganglia close to the viscera, including the celiac, superior mesenteric, and inferior mesenteric ganglia (Figure 13–3). There are also preganglionic neurons whose axons terminate directly on the effector organ, the adrenal gland.

The axons of some of the postganglionic neurons leave the chain ganglia and reenter the spinal nerves via the gray rami communicans and are distributed to autonomic effectors in the areas supplied by these spinal nerves (Figure 13–2). These postganglionic sympathetic nerves terminate mainly on smooth muscle (eg, blood vessels and hair follicles) and on sweat glands in the limbs. Other postganglionic fibers leave the chain ganglia to enter the thoracic cavity to terminate in visceral organs. Postganglionic fibers from prevertebral ganglia also terminate in visceral targets.

PARASYMPATHETIC DIVISION

The parasympathetic nervous system is sometimes called the craniosacral division of the ANS because of the location of its preganglionic neurons; preganglionic neurons are located in several cranial nerve nuclei (III, VII, IX, and X) and in the IML of the sacral spinal cord (Figure 13–3). The cell bodies in the Edinger–Westphal nucleus of the oculomotor nerve project to the ciliary ganglia to innervate the sphincter (constrictor) muscle of the iris and the ciliary muscle. Neurons in the superior salivatory nucleus of the facial nerve project to the sphenopalatine ganglia to innervate the lacrimal glands and nasal and palatine mucous membranes and to the submandibular ganglia to innervate the submandibular (also called submaxillary) and sublingual glands. The cell bodies in the inferior salivatory nucleus of the glossopharyngeal nerve project to the otic ganglion to innervate the parotid salivary gland. Vagal preganglionic fibers synapse on ganglia cells clustered within the walls of visceral organs; thus these parasympathetic postganglionic fibers are very short. Neurons in the nucleus ambiguus innervate the sinoatrial (SA) and atrioventricular (AV) nodes in the heart; and neurons in the dorsal motor vagal nucleus innervate the esophagus, trachea, lungs, and gastrointestinal tract. The parasympathetic sacral outflow (pelvic nerve) supplies the pelvic viscera via branches of the second to fourth sacral spinal nerves.

ACETYLCHOLINE & NOREPINEPHRINE

The first evidence for chemical neurotransmission was provided by a simple yet dramatic study by Otto Loewi in 1920 in which he showed that the slowing of the heart rate produced by stimulation of the vagal parasympathetic nerves was due to the release of acetylcholine (see Chapter 7). Transmission at the synaptic junctions between preganglionic and postganglionic neurons and between the postganglionic neurons and the autonomic effectors are chemically mediated. The principal transmitter agents involved are acetylcholine and norepinephrine. The autonomic neurons that are cholinergic (ie, release acetylcholine) are (1) all preganglionic neurons, (2) all parasympathetic postganglionic neurons, (3) sympathetic postganglionic neurons that innervate sweat glands, and (4) sympathetic postganglionic neurons that end on blood vessels in some skeletal muscles and produce vasodilation when stimulated (sympathetic vasodilator nerves). The remaining sympathetic postganglionic neurons are noradrenergic (ie, release norepinephrine). The adrenal medulla is essentially a sympathetic ganglion in which the postganglionic cells have lost their axons and secrete both norepinephrine and epinephrine directly into the bloodstream.

Table 13–1 shows the types of cholinergic and adrenergic receptors at various junctions within the ANS. The junctions in the peripheral autonomic motor pathways are logical sites for pharmacologic manipulation of visceral function. The transmitter agents are synthesized, stored in the nerve endings, and released near the neurons, muscle cells, or gland cells where they bind to various ion channels or G-protein-coupled receptors (GPCR) to initiate their characteristic actions. The neurotransmitters are then removed from the area by reuptake or metabolism. Each of these steps can be stimulated or inhibited, with predictable consequences. Table 13–2 lists how various drugs can affect neurotransmission in autonomic neurons and effector sites.

CHOLINERGIC NEUROTRANSMISSION

The processes involved in the synthesis and breakdown of acetylcholine were described in Chapter 7. Acetylcholine does not usually circulate in the blood, and the effects of localized cholinergic discharge are generally discrete and of short duration because of the high concentration of acetylcholinesterase at cholinergic nerve endings. This enzyme rapidly breaks down the acetylcholine, terminating its actions.

Transmission in autonomic ganglia is mediated primarily by the actions of acetylcholine on nicotinic cholinergic receptors that are blocked by hexamethonium (Figure 13–4). These are called N_N receptors to distinguish them from the nicotinic cholinergic receptors (N_M) that are located at the neuromuscular junction and are blocked by D-tubocurare. Nicotinic receptors are examples of ligand-gated ion channels; binding of an agonist to nicotinic receptors opens N⁺ and K⁺ channels to cause depolarization.

The responses produced in postganglionic neurons by stimulation of their preganglionic innervation include both a rapid depolarization called a fast excitatory postsynaptic potential (EPSP) that generates action potentials and a prolonged excitatory postsynaptic potential (slow EPSP). The slow response may modulate and regulate transmission through the sympathetic ganglia. The initial depolarization is produced by acetylcholine acting on the N_N receptor. The slow EPSP is produced by acetylcholine acting on a muscarinic receptor on the membrane of the postganglionic neuron.

The release of acetylcholine from postganglionic fibers acts on muscarinic cholinergic receptors, which are blocked by atropine. Muscarinic receptors are GPCR and are divided into subtypes M₁–M₅, but M₂ and M₃ are the main subtypes found in autonomic target organs. M₂ receptors are located in the heart; binding of an agonist to these receptors opens K⁺ channels and inhibits adenylyl cyclase. M₃ receptors are located on smooth muscle and glands; binding of an agonist to these receptors leads to the formation of inositol 1,4,5-triphosphate (IP₃) and diacylglycerol (DAG) and an increase in intracellular Ca²⁺.

Compounds with muscarinic actions include congeners of acetylcholine and drugs that inhibit acetylcholinesterase. Clinical Box 13–2 describes some of the signs and therapeutic strategies for the treatment of acute intoxication from organophosphate cholinesterase inhibitors. Clinical Box 13–3 describes an example of cholinergic poisoning resulting from digestion of toxic mushrooms.

NORADRENERGIC NEUROTRANSMISSION

The processes involved in the synthesis, reuptake, and breakdown of norepinephrine were described in Chapter 7. Norepinephrine spreads farther and has a more prolonged action than acetylcholine. Norepinephrine, epinephrine, and dopamine are all found in plasma. The epinephrine and some of the dopamine come from the adrenal medulla, but most of the norepinephrine diffuses into the bloodstream from sympathetic nerve endings. Metabolites of norepinephrine and dopamine also enter the circulation.

The norepinephrine released from sympathetic postganglionic fibers binds to adrenoceptors. These are also GPCR and are divided into several subtypes: α₁, α₂, β₁, β₂, and β₃. Table 13–1 shows some of the locations of these receptor subtypes on smooth muscles, cardiac muscle, and glands on autonomic effector targets. Binding of an agonist to α₁-adrenoceptors activates the G_q-coupling protein, which leads to formation of IP₃ and DAG and an increase in intracellular Ca²⁺. Binding of an agonist to α₂-adrenoceptors causes dissociation of the inhibitory G-protein G_i to inhibit adenylyl cyclase and decrease cyclic adenosine monophosphate (cAMP). Binding of an agonist to β-adrenoceptors activates the G_s-coupling protein to activate adenylyl cyclase and increase cAMP.

There are several diseases or syndromes that result from dysfunction of sympathetic innervation of specific body regions. Clinical Box 13–4 describes Horner syndrome, which is due to interruption of sympathetic nerves to the face. Clinical Box 13–5 describes a vasospastic condition (Raynaud phenomenon) in which blood flow to the fingers and toes is transiently reduced, typically when a sensitive individual is exposed to stress or cold.

NONADRENERGIC & NONCHOLINERGIC TRANSMITTERS

In addition to the “classical neurotransmitters,” some autonomic fibers also release neuropeptides, although their exact functions in autonomic control have not been determined. The small granulated vesicles in postganglionic noradrenergic neurons contain adenosine triphosphate (ATP) and norepinephrine, and the large granulated vesicles contain neuropeptide Y (NPY). There is some evidence that low-frequency stimulation promotes release of ATP, whereas high-frequency stimulation causes release of NPY. Some visceral organs contain purinergic receptors, and evidence is accumulating that ATP is a mediator in the ANS along with norepinephrine.

Many sympathetic fibers innervating the vasculature of viscera, skin, and skeletal muscles release NPY and galanin in addition to norepinephrine. Vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), or substance P are co-released with acetylcholine from the sympathetic innervation to sweat glands (sudomotor fibers). VIP is co-localized with acetylcholine in many cranial parasympathetic postganglionic neurons supplying glands. Vagal parasympathetic postganglionic neurons in the gastrointestinal tract contain VIP and the enzymatic machinery to synthesize nitric oxide (NO).

GENERAL PRINCIPLES

The ANS is responsible for regulating and coordinating many physiologic functions that include blood flow, blood pressure, heart rate, airflow through the bronchial tree, gastrointestinal motility, urinary bladder contraction, glandular secretions, pupillary diameter, body temperature, and sexual physiology.

The effects of stimulation of the noradrenergic and cholinergic postganglionic nerve fibers are indicated in Figure 13–3 and Table 13–1. These findings point out another difference between the ANS and the somatomotor nervous system. The release of acetylcholine by α-motor neurons only leads to contraction of skeletal muscles. In contrast, release of acetylcholine onto smooth muscle of some organs leads to contraction (eg, walls of the gastrointestinal tract) while release onto other organs promotes relaxation (eg, sphincters in the gastrointestinal tract). The only way to relax a skeletal muscle is to inhibit the discharges of the α-motor neurons; but for some targets innervated by the ANS, contraction can be shifted to relaxation by switching from activation of the parasympathetic nervous system to activation of the sympathetic nervous system. This is the case for the many organs that receive dual innervation with antagonistic effects, including the digestive tract, airways, and urinary bladder. The heart is another example of an organ with dual antagonistic control. Stimulation of sympathetic nerves increases heart rate; stimulation of parasympathetic nerves decreases heart rate.

In other cases, the effects of sympathetic and parasympathetic activation can be considered complementary. An example is the innervation of salivary glands. Parasympathetic activation causes release of watery saliva, while sympathetic activation causes the production of thick, viscous saliva.

The two divisions of the ANS can also act in a synergistic or cooperative manner in the control of some functions. One example is the control of pupil diameter in the eye. Both sympathetic and parasympathetic innervations are excitatory, but the former contracts the radial (or dilator) muscle to cause mydriasis (widening of the pupil) and the latter contracts the sphincter (or constrictor) muscle to cause miosis (narrowing of the pupil). Another example is the synergistic actions of these nerves on sexual function. Activation of parasympathetic nerves to the penis increases penile blood flow and leads to erection while activation of sympathetic nerves to the male reproductive tract causes ejaculation.

There are also several organs that are innervated by only one division of the ANS. In addition to the adrenal gland, most blood vessels, the pilomotor muscles in the skin (hair follicles), and sweat glands are innervated exclusively by sympathetic nerves (sudomotor fibers). The lacrimal muscle (tear gland), ciliary muscle (for accommodation for near vision), and the nasopharyngeal gland are innervated exclusively by parasympathetic nerves.

PARASYMPATHETIC, CHOLINERGIC, & SYMPATHETIC NORADRENERGIC DISCHARGE

In a general way, the functions promoted by activity in the cholinergic division of the ANS are those concerned with the vegetative aspects of day-to-day living. For example, parasympathetic action favors digestion and absorption of food by increasing the activity of the intestinal musculature, increasing gastric secretion, and relaxing the pyloric sphincter. For this reason, the cholinergic division is sometimes called the anabolic nervous system or the “rest and digest” division of the ANS.

The sympathetic (noradrenergic) division discharges as a unit in emergency situations and can be called the catabolic nervous system or the “flight or fight” division of the ANS. The effect of this discharge prepares the individual to cope with an emergency. Sympathetic activity dilates the pupils (letting more light into the eyes), accelerates the heartbeat and raises the blood pressure (providing better perfusion of the vital organs and muscles), and constricts the blood vessels of the skin (which limits bleeding from wounds). Noradrenergic discharge also leads to elevated plasma glucose and free fatty acid levels (supplying more energy). On the basis of effects like these, Walter Cannon called the emergency-induced discharge of the sympathetic nervous system the “preparation for flight or fight.”

The emphasis on mass discharge in stressful situations should not obscure the fact that the sympathetic fibers also subserve other functions and, in fact, there is activity in sympathetic nerves even under resting conditions. For example, tonic sympathetic discharge to the arterioles maintains arterial pressure, and variations in this tonic discharge are the mechanism by which carotid sinus feedback regulation of blood pressure occurs (see Chapter 32). In addition, sympathetic discharge is decreased in fasting animals and increased when fasted animals are again fed. These changes may explain the decrease in blood pressure and metabolic rate produced by fasting and the opposite changes produced by feeding.

As is the case for α-motor neurons, the activity of autonomic nerves is dependent on both reflexes (eg, baroreceptor and chemoreceptor reflexes) and a balance between descending excitatory and inhibitory inputs from several brain regions. To identify brain regions that provide input to preganglionic sympathetic neurons, neuroanatomic tract tracing chemicals can be injected into the thoracic IML. These chemicals are picked up by axon terminals and transported retrogradely to the cell bodies of origin. Figure 13–5 shows the source of some forebrain and brainstem inputs to sympathetic preganglionic neurons. There are parallel pathways from the hypothalamic paraventricular nucleus, pontine catecholaminergic A5 cell group, rostral ventrolateral medulla, and medullary raphe nuclei. This is analogous to projections from the brainstem and cortex converging on somatomotor neurons in the spinal cord. The rostral ventrolateral medulla is generally considered to major source of excitatory input to sympathetic neurons. In addition to these direct pathways to preganglionic neurons, there are many brain regions that feed into these pathways, including the amygdala, mesencephalic periaqueductal gray, caudal ventrolateral medulla, nucleus of the tractus solitarius, and medullary lateral tegmental field. This is analogous to the control of somatomotor function by areas such as the basal ganglia and cerebellum. Chapter 32 describes the role of some of these brain regions as well as the role of various reflexes in setting the level of activity in autonomic nerves supplying cardiovascular effector organs.

AUTONOMIC DYSFUNCTION

Drugs, neurodegenerative diseases, trauma, inflammatory processes, and neoplasia are a few examples of factors that can lead to dysfunction of the ANS (Clinical Boxes 13–1, 13–2, 13–3, 13–4). The types of dysfunction can range from complete autonomic failure to autonomic hyperactivity. Among disorders associated with autonomic failure are orthostatic hypotension, neurogenic syncope (vasovagal response), erectile dysfunction, neurogenic bladder, gastrointestinal dysmotility, sudomotor failure, and Horner syndrome. Autonomic hyperactivity can be the basis for neurogenic hypertension, cardiac arrhythmias, neurogenic pulmonary edema, myocardial injury, hyperhidrosis, hyperthermia, and hypothermia.

The enteric nervous system, which can be considered as the third division of the ANS, is located within the wall of the digestive tract, all the way from the esophagus to the anus. It is composed of two well-organized neural plexuses. The myenteric plexus is located between longitudinal and circular layers of muscle; it is involved in control of digestive tract motility. The submucosal plexus is located between the circular muscle and the luminal mucosa; it senses the environment of the lumen and regulates gastrointestinal blood flow and epithelial cell function.

The enteric nervous system contains as many neurons as the entire spinal cord. It is sometimes referred to as a “mini-brain” as it contains all the elements of a nervous system including sensory neurons, interneurons, and motor neurons. It contains sensory neurons innervating receptors in the mucosa that respond to mechanical, thermal, osmotic, and chemical stimuli. Motor neurons control motility, secretion, and absorption by acting on smooth muscle and secretory cells. Interneurons integrate information from sensory neurons and feedback to the enteric motor neurons.

Parasympathetic and sympathetic nerves connect the CNS to the enteric nervous system or directly to the digestive tract. Although the enteric nervous system can function autonomously, normal digestive function often requires communication between the CNS and the enteric nervous system (see Chapter 25).

• Preganglionic sympathetic neurons are located in the IML of the thoracolumbar spinal cord and project to postganglionic neurons in the paravertebral or prevertebral ganglia or the adrenal medulla. Preganglionic parasympathetic neurons are located in motor nuclei of cranial nerves III, VII, IX, and X and the sacral IML. Postganglionic nerve terminals are located in smooth muscle (eg, blood vessels, gut wall, and urinary bladder), cardiac muscle, and glands (eg, sweat gland and salivary glands).

• Acetylcholine is released at nerve terminals of all preganglionic neurons, postganglionic parasympathetic neurons, and a few postganglionic sympathetic neurons (sweat glands and sympathetic vasodilator fibers). The remaining sympathetic postganglionic neurons release norepinephrine.

• Ganglionic transmission results from activation of nicotinic receptors. Postganglionic cholinergic transmission is mediated by activation of muscarinic receptors. Postganglionic adrenergic transmission is mediated by activation of α₁-, β-, or β₂-adrenoceptors, depending on the target organ. Many common drugs exert their therapeutic actions by serving as agonists or antagonists at autonomic synapses.

• Sympathetic activity prepares the individual to cope with an emergency by accelerating the heartbeat, raising blood pressure (perfusion of the vital organs), and constricting the blood vessels of the skin (limits bleeding from wounds). Parasympathetic activity is concerned with the vegetative aspects of day-to-day living and favors digestion and absorption of food by increasing the activity of the intestinal musculature, increasing gastric secretion, and relaxing the pyloric sphincter.

• Direct projections to sympathetic preganglionic neurons in the IML originate in the hypothalamic paraventricular nucleus, pontine catecholaminergic A5 cell group, rostral ventrolateral medulla, and medullary raphe nuclei.

• The enteric nervous system is located within the wall of the digestive tract and is composed of the myenteric plexus (control of digestive tract motility) and the submucosal plexus (regulates gastrointestinal blood flow and epithelial cell function).