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, urinary bladder), cardiac muscle, and glands (eg, sweat glands, salivary glands). Although survival is possible without an ANS, the ability to adapt to environmental stressors and other challenges is severely compromised (see Clinical Box 13–1). 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.
CLINICAL BOX 13–1
Multiple System Atrophy & Shy–Drager Syndrome
Multiple system atrophy (MSA) is a neurodegenerative disorder associated with autonomic failure due to loss of preganglionic autonomic neurons in the spinal cord and brain stem. In the absence of an autonomic nervous system, it is difficult to regulate body temperature, fluid and electrolyte balance, and blood pressure. In addition to these autonomic abnormalities, MSA presents with cerebellar, basal ganglia, locus coeruleus, inferior olivary nucleus, and pyramidal tract deficits. MSA is defined as “a sporadic, progressive, adult onset disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar ataxia in any combination.” Shy–Drager syndrome is a subtype of MSA in which autonomic failure dominates. The pathological hallmark of MSA is cytoplasmic and nuclear inclusions in oligodendrocytes and neurons in central motor and autonomic areas. There is also depletion of monoaminergic, cholinergic, and peptidergic markers in several brain regions and in the cerebrospinal fluid. The cause of MSA remains elusive, but there is some evidence that a neuroinflammatory mechanism causing activation of microglia and production of toxic cytokines may occur in brains of MSA patients. Basal levels of sympathetic activity and plasma norepinephrine levels are normal in MSA patients, but they fail to increase in response to standing or other stimuli and leads to severe orthostatic hypotension. In addition to the fall in blood pressure, orthostatic hypotension leads to dizziness, dimness of vision, and even fainting. MSA is also accompanied by parasympathetic dysfunction, including urinary and sexual dysfunction. MSA is most often diagnosed in individuals between 50 and 70 years of age; it affects more men than women. Erectile dysfunction is often the first symptom of the disease. There are also abnormalities in baroreceptor reflex and respiratory control mechanisms. Although autonomic abnormalities are often the first symptoms, 75% of patients with MSA also experience motor disturbances.
There is no cure for MSA but various therapies are used to treat specific signs and symptoms of the disease. Corticosteroids are often prescribed to retain salt and water to increase blood pressure. In some individuals, Parkinsonium-like signs can be alleviated by administration of levodopa and carbidopa. Various clinical trials are underway to test the effectiveness of using intravenous immunoglobulins to counteract the neuroinflammatory process that occurs in MSA; fluoxetine (a serotonin uptake inhibitor) to prevent orthostatic hypotension, improve mood, and alleviate sleep, pain, and fatigue in MSA patients; and rasagiline (a monoamine oxidase inhibitor) in MSA patients with parskinsonism.
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 brain stem 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.
ANATOMIC ORGANIZATION OF AUTONOMIC OUTFLOW
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.
FIGURE 13–1 Comparison of peripheral organization and transmitters released by somatomotor and autonomic nervous systems. In the case of the somatomotor nervous system, the neuron that leaves the spinal cord projects directly to the effector organ. In the case of the autonomic nervous system, there is a synapse between the neuron that leaves the spinal cord and the effector organ (except for neurons that innervate the adrenal medulla). Note that all neurons that leave the central nervous system release acetylcholine (ACh). DA, dopamine; Epi, epinephrine; NE, norepinephrine. (From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)
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.
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 chainbilaterally. This arrangement is seen in Figure 13–2 and Figure 13–3.
FIGURE 13–2 Projection of sympathetic preganglionic and postganglionic fibers. The drawing shows the thoracic spinal cord, paravertebral, and prevertebral ganglia. Preganglionic neurons are shown in red, and postganglionic neurons in dark blue. (Courtesy of P. Banyas, Michigan State University.)
FIGURE 13–3 Organization of sympathetic (left) and parasympathetic (right) nervous systems. Cholinergic nerves are shown in red and noradrenergic nerves are shown in blue. Preganglionic nerves are solid lines; postganglionic nerves are dashed lines. (Courtesy of P. Banyas, Michigan State University.)
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, 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.
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 and submaxillary 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.
CHEMICAL TRANSMISSION AT AUTONOMIC JUNCTIONS
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 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 a logical site 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 channel or G protein-coupled receptors (GPCR). They bind to receptors on these cells, thus initiating their characteristic actions, and they are then removed from the area by reuptake or metabolism. Each of these steps can be stimulated or inhibited, with predictable consequences. Table 13–2lists how various drugs can affect neurotransmission in autonomic neurons and effector sites.
TABLE 13–1 Responses of some effector organs to autonomic nerve activity.
TABLE 13–2 Examples of drugs that affect processes involved in autonomic 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 NN receptors to distinguish them from the nicotinic cholinergic receptors (NM) that are located at the neuromuscular junction and are blocked by D-tubocurare. Nicotinic receptors are examples of ion gated channels; binding of an agonist to nicotinic receptors opens N+and K+ channels to cause depolarization.
FIGURE 13–4 Schematic of excitatory and inhibitory postsynaptic potentials (EPSP and IPSP) recorded via an electrode in an autonomic ganglion cell. In response acetylcholine release from the preganglionic neuron, two EPSPs were generated in the postganglionic neuron due to nicotinic (N) receptor activation. The first EPSP was below the threshold for eliciting an action potential, but the second EPSP was suprathreshold and evoked an action potential. This was followed by an IPSP, probably evoked by muscarinic (M2) receptor activation. The IPSP is then followed by a slower, M1-dependent EPSP, and this can be followed by an even slower peptide-induced EPSP. (From Katzung BG, Maters SB, Trevor AJ: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.)
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 NNreceptor. 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 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.
CLINICAL BOX 13–2
Organophosphates: Pesticides and Nerve Gases
The World Health Organization estimates that 1–3% of agricultural workers worldwide suffer from acute pesticide poisoning; it accounts for significant morbidity and mortality, especially in developing countries. Like organophosphate pesticides (eg, parathion, malathion), nerve gases (eg, soman, sarin) used in chemical warfare and terrorism inhibit acetylcholinesterase at peripheral and central cholinergic synapses, prolonging the actions of acetylcholine at these synapses. The organophosphate cholinesterase inhibitors are readily absorbed by the skin, lung, gut, and conjunctiva, making them very dangerous. They bind to the enzyme and undergo hydrolysis, resulting in a phosphorylated active site on the enzyme. The covalent phosphorous-enzyme bond is very stable and hydrolyzes at a very slow rate. The phosphorylated enzyme complex may undergo a process called aging in which one of the oxygen-phosphorous bonds breaks down, which strengthens the phosphorous-enzyme bond. This process takes only 10 min to occur after exposure to soman. The earliest signs of organophosphate toxicity are usually indicative of excessive activation of autonomic muscarinic receptors; these include miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. CNS signs of toxicity include cognitive disturbances, convulsions, seizures, and even coma; these signs are often accompanied by nicotinic effects such as depolarizing neuromuscular blockade.
The muscarinic cholinergic receptor antagonist atropine is often given parenterally in large doses to control signs of excessive activation of these receptors. When given soon after exposure to the organophosphate and before aging has occurred, nucleophiles such as pralidoxime are able to break the bond between the organophosphate and the acetylcholinesterase. Thus this drug is called a “cholinesterase regenerator.” If pyridostigmine is administered in advance of exposure to a cholinesterase inhibitor, it binds to the enzyme and prevents binding by the toxic organophosphate agent. The protective effects of pyridostigmine dissipate within 3–6 h, but this provides enough time for clearance of the organophosphate from the body. Since the drug cannot cross the blood brain barrier, protection is limited to peripheral cholinergic synapses. A mixture of pyridostigmine, carbamate, and atropine can be administered prophylactically to soldiers and civilians who are at risk for exposure to nerve gases. Benzodiazepines can be used to abort the seizures caused by exposure to organophosphates.
CLINICAL BOX 13–3
Of the more than 5000 species of mushrooms found in the US, approximately 100 are poisonous and ingestion of about 12 of these can result in fatality. Estimates are an annual incidence of five cases per 100,000 individuals in the US; worldwide databases are not available. Mushroom poisoning or mycetism is divided into rapid- (15–30 min after ingestion) and delayed-on-set (6–12 h after ingestion) types. In rapid-onset cases caused by mushrooms of the Inocybe genus, the symptoms are due to excessive activation of muscarinic cholinergic synapses. The major signs of muscarinic poisoning include nausea, vomiting, diarrhea, urinary urgency, vasodilation, sweating, and salivation. Ingestion of mushrooms such as the Amanita muscaria exhibit signs of the antimuscarinic syndrome rather than muscarinic poisoning because they also contain alkaloids that block muscarinic cholinergic receptors. The classic symptoms of this syndrome are being “red as a beet” (flushed skin), “hot as a hare” (hyperthermia), “dry as a bone” (dry mucous membranes, no sweating), “blind as a bat” (blurred vision, cycloplegia), and “mad as a hatter” (confusion, delirium). The delayed-onset type of mushroom poisoning occurs after ingestion of Amanita phalloides, Amanita virosa, Galerina autumnalis, and Galerina marginata. These mushrooms cause abdominal cramping, nausea, vomiting, and profuse diarrhea; but the major toxic effects are due to hepatic injury (jaundice, bruising) and associated central effects (confusion, lethargy, coma). These mushrooms contain amatoxins that inhibit RNA polymerase. There is a 60% mortality rate associated with ingestion of these mushrooms.
The rapid-onset type muscarinic poisoning can be treated effectively with atropine. Individuals who exhibit the antimuscarinic syndrome can be treated with physostigmine, which is a cholinesterase inhibitor with a 2–4 h duration of action that acts centrally and peripherally. If agitated, these individuals may require sedation with a benzodiazepine or an antipsychotic agent. The delayed onset toxicity due to ingestion of mushrooms containing amatoxins does not respond to cholinergic drugs. Treatment of amatoxin ingestion includes intravenous administration of fluids and electrolytes to maintain adequate hydration. Administering a combination of a high dose of penicillin G and silibinin(a flavonolignan found in certain herbs with antioxidant and hepatoprotective properties) has been shown to improve survival. If necessary, vomiting can also be induced by using activated charcoal to reduce the absorption of the toxin.
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 Gq-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 G1 to inhibit adenylyl cyclase and decrease cyclic adenosine monophosphate (cAMP). Binding of an agonist to β-adrenoceptors activates the Gs-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 in which blood flow to the fingers and toes is transiently reduced, typically when a sensitive individual is exposed to stress or cold.
CLINICAL BOX 13–4
Horner syndrome is a rare disorder resulting from interruption of preganglionic or postganglionic sympathetic innervation to the face. The problem can result from injury to the nerves, injury to the carotid artery, a stroke or lesion in the brainstem, or a tumor in the lung. In most cases the problem is unilateral, with symptoms occurring only on the side of the damage. The hallmark of Horner syndrome is the triad of anhidrosis (reduced sweating), ptosis(drooping eyelid), and miosis (constricted pupil). Symptoms also include enophthalmos (sunken eyeball) and vasodilation.
There is no specific pharmacological treatment for Horner syndrome, but drugs affecting noradrenergic neurotransmission can be used to determine whether the source of the problem is interruption of the preganglionic or post-ganglionic innervation to the face. Since the iris of the eye responds to topical sympathomimetic drugs (ie, drugs that are direct agonists on adrenoceptors or drugs that increase the release or prevent reuptake of norepinephrine from the nerve terminal), the physician can easily test the viability of the noradrenergic nerves to the eye. If the postganglionic sympathetic fibers are damaged, their terminals would degenerate and there would be a loss of stored catecholamines. If the preganglionic fibers are damaged, the postganglionic noradrenergic nerve would remain intact (but be inactive) and would still have stored catecholamines in its terminal. If one administers a drug that causes release of catecholamine stores (eg, hydroxyamphetamine) and the constricted pupil does not dilate, one would conclude that the noradrenergic nerve is damaged. If the eye dilates in response to this drug, the catecholamine stores are still able to be released, so the damage must be preganglionic. Administration of phenylephrine (α-adrenoceptor agonist) would dilate the pupil regardless of the site of injury as the drug binds to the receptor on the radial muscle of the iris.
CLINICAL BOX 13–5
Approximately 5% of men and 8% of women experience an episodic reduction in blood flow primarily to the fingers, often during exposure to cold or during a stressful situation. Vasospasms in the toes, tip of nose, ears, and penis can also occur. Smoking is associated with an increase in the incidence and severity of the symptoms of Raynaud phenomenon. The symptoms begin to occur between the age of 15 and 25; it is most common in cold climates. The symptoms often include a triphasic change in color to the skin of the digits. Initially, the skin becomes pale or white (pallor), cold, and numb. This can be followed by a cyanotic period in which the skin turns blue or even purple, during which time the reduced blood flow can cause intense pain. Once the blood flow recovers, the digits often turn deep red (rubor) and there can be swelling and tingling. Primary Raynaud phenomenon or Raynaud diseaserefers to the idiopathic appearance of the symptoms in individuals who do not have another underlying disease to account for the symptoms. In such cases, the vasospastic attacks may merely be an exaggeration of a normal response to cold temperature or stress. Secondary Raynaud phenomenon or Raynaud syndrome refers to the presence of these symptoms due to another disorder such as scleroderma, lupus, rheumatoid arthritis, Sjogren syndrome, carpel tunnel syndrome, and anorexia. Although initially thought to reflect an increase in sympathetic activity to the vasculature of the digits, this is no longer regarded as the mechanism underlying the episodic vasospasms.
The first treatment strategy for Raynaud phenomenon is to avoid exposure to the cold, reduce stress, quit smoking, and avoid the use of medications that are vasoconstrictors (eg, β-adrenoceptor antagonists, cold medications, caffeine, and narcotics). If the symptoms are severe, drugs may be needed to prevent tissue damage. These include calcium channel blockers (eg, nifedipine) and α-adrenoceptor antagonists (eg, prazosin). In individuals who do not respond to pharmacological treatments, surgical sympathectomy has been done.
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).
RESPONSES OF EFFECTOR ORGANS TO AUTONOMIC NERVE IMPULSES
The ANS is responsible for regulating and coordinating many physiological 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, one can shift from contraction 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 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 blood flow and leads to erection while activation of sympathetic nerves to the penis 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 sublingual salivary 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.
The sympathetic (noradrenergic) division discharges as a unit in emergency situations and can be called the catabolic nervous system. 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. 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.
DESCENDING INPUTS TO AUTONOMIC PREGANGLIONIC NEURONS
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, neuroanatomical 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 brain stem inputs to sympathetic preganglionic neurons. There are parallel pathways from the hypothalamic paraventricular nucleus, pontine catecholaminergic A5 cell group, rostral ventrolateral medulla, and medullary raphé 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.
FIGURE 13–5 Pathways that control autonomic responses. Direct projections (solid lines) to autonomic preganglionic neurons include the hypothalamic paraventricular nucleus, pontine A5 cell group, rostral ventrolateral medulla, and medullary raphé.
Drugs, neurodegenerative diseases, trauma, inflammatory processes, and neoplasia are a few examples of factors that can lead to dysfunction of the ANS (see Clinical Boxes 13–1 through 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), impotence, neurogenic bladder, gastrointestinal dysmotility, sudomotor failure, and Horner’s syndrome. Autonomic hyperactivity can be the basic for neurogenic hypertension, cardiac arrhythmias, neurogenic pulmonary edema, myocardial injury, hyperhidrosis, hyperthermia, and hypothermia.
ENTERIC NERVOUS SYSTEM
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 comprised 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, urinary bladder), cardiac muscle, and glands (eg, sweat gland, salivary glands).
Acetylcholine is released at nerve terminals of all preganglionic neurons, postganglionic parasympathetic neurons, and a few postganglionic sympathetic neurons (sweat glands, 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, β1, 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 raphé 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).
For all questions, select the single best answer unless otherwise directed.
1. A 26-year-old male developed hypertension after he began taking amphetamine to boost his energy and to suppress his appetite. Which of the following drugs would be expected to mimic the effects of increased sympathetic discharge on blood vessels?
2. A 35-year-old female was diagnosed with multiple system atrophy and had symptoms indicative of failure of sympathetic nerve activity. Which of the following statements about the sympathetic nervous system is correct?
A. All postganglionic sympathetic nerves release norepinephrine from their terminals.
B. Cell bodies of preganglionic sympathetic neurons are located in the intermediolateral column of the thoracic and sacral spinal cord.
C. The sympathetic nervous system is required for survival.
D. Acetylcholine is released from all sympathetic preganglionic nerve terminals.
E. The sympathetic nervous system adjusts pupillary diameter by relaxing the pupillary constrictor muscle.
3. A 45-year-old male had a meal containing wild mushrooms that he picked in a field earlier in the day. Within a few hours after eating, he developed nausea, vomiting, diarrhea, urinary urgency, vasodilation, sweating, and salivation. Which of the following statements about the parasympathetic nervous system is correct?
A. Postganglionic parasympathetic nerves release acetylcholine to activate muscarinic receptors on sweat glands.
B. Parasympathetic nerve activity affects only smooth muscles and glands.
C. Parasympathetic nerve activity causes contraction of smooth muscles of the gastrointestinal wall and relaxation of the gastrointestinal sphincter.
D. Parasympathetic nerve activity causes contraction of the radial muscle of the eye to allow accommodation for near vision.
E. An increase in parasympathetic activity causes an increase in heart rate.
4. Which of the following is correctly paired?
A. Sinoatrial node: Nicotinic cholinergic receptors
B. Autonomic ganglia: Muscarinic cholinergic receptors
C. Pilomotor smooth muscle: β2-adrenergic receptors
D. Vasculature of some skeletal muscles: Muscarinic cholinergic receptors
E. Sweat glands: α2-adrenergic receptors
5. A 57-year-old male had severe hypertension that was found to result from a tumor compressing on the surface of the medulla. Which one of the following statements about pathways involved in the control of sympathetic nerve activity is correct?
A. Preganglionic sympathetic nerves receive inhibitory input from the rostral ventrolateral medulla.
B. The major source of excitatory input to preganglionic sympathetic nerves is the paraventricular nucleus of the hypothalamus.
C. The activity of sympathetic preganglionic neurons can be affected by the activity of neurons in the amygdala.
D. Unlike the activity in δ-motor neurons, sympathetic preganglionic neurons are not under any significant reflex control.
E. Under resting conditions, the sympathetic nervous system is not active; it is active only during stress giving rise to the term “flight or fight” response.
6. A 53-year-old female with diabetes was diagnosed with diabetic autonomic neuropathy a few years ago. She recently noted abdominal distension and a feeling of being full after eating only a small portion of food, suggesting the neuropathy had extended to her enteric nervous system to cause gastroparesis. Which of the following statements about the enteric nervous system is correct?
A. The enteric nervous system is a subdivision of the parasympathetic nervous system for control of gastrointestinal function.
B. The myenteric plexus is a group of motor neurons located within circular layer of muscle in a portion of the gastrointestinal tract.
C. The submucosal plexus is a group of sensory neurons located between the circular muscle and the luminal mucosa of the gastrointestinal tract.
D. Neurons comprising the enteric nervous system are located only in the stomach and intestine.
E. The enteric nervous system can function independent of the autonomic innervation to the gastrointestinal tract.
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