Autonomic Nervous System

Neurons of the peripheral nervous system (PNS) that conduct impulses away from the central nervous system (CNS) are known as motor, or efferent, neurons (chapter 7, section 7.1). There are two major categories of motor neurons: somatic and autonomic. Somatic motor neurons have their cell bodies within the CNS and send axons to skeletal muscles, which are usually under voluntary control. This was briefly described in chapter 8 (see fig. 8.28), in the section on the reflex arc. The control of skeletal muscles by somatic motor neurons is discussed in depth in chapter 12, section 12.5. Unlike somatic motor neurons, which conduct impulses along a single axon from the spinal cord to the neuromuscular junction, autonomic motor control involves two neurons in the efferent pathway ( fig. 9.1 and table 9.1 ). The first of these neurons has its cell body in the gray matter of the brain or spinal cord. The axon of this neuron does not directly innervate the effector organ but instead synapses with a second neuron within an autonomic ganglion (a ganglion is a collection of cell bodies outside the CNS). The first neuron is thus called a preganglionic neuron. The second neuron in this pathway, called a postganglionic neuron, has an axon that extends from the autonomic ganglion to an effector organ, where it synapses with its target tissue ( fig. 9.1 ). Preganglionic autonomic fibers originate in the midbrain and hindbrain and in the upper thoracic to the fourth sacral levels of the spinal cord. Autonomic ganglia are located in the head, neck, and abdomen; chains of autonomic ganglia also parallel the right and left sides of the spinal cord. The origin of the preganglionic fibers and the location of the autonomic ganglia help to distinguish the sympathetic and parasympathetic divisions of the autonomic system. DIVISIONS OF THE AUTONOMIC NERVOUS SYSTEM Preganglionic neurons of the sympathetic division originate in the thoracic and lumbar levels of the spinal cord and send axons to sympathetic ganglia, which parallel the spinal cord. Preganglionic neurons of the parasympathetic division originate in the brain and in the sacral level of the spinal cord, and send axons to ganglia located in or near the effector organs.

Sympathetic Division The sympathetic division is also called the thoracolumbar division of the autonomic system because its preganglionic fibers exit the spinal cord, in the ventral roots of spinal nerves, from the first thoracic (T1) to the second lumbar (L2) levels. Most sympathetic nerve fibers, however, separate from the somatic motor fibers and synapse with postganglionic neurons within a double row of sympathetic ganglia, called paravertebral ganglia, located on either side of the spinal cord ( fig. 9.2 ). Ganglia within each row are interconnected, forming a sympathetic chain of ganglia that parallels the spinal cord on each lateral side. The myelinated preganglionic sympathetic axons exit the spinal cord in the ventral roots of spinal nerves, but they soon diverge from the spinal nerves within short pathways called white rami communicantes. The axons within each ramus enter the sympathetic chain of ganglia, where they can travel to ganglia at different levels and synapse with postganglionic sympathetic neurons. The axons of the postganglionic sympathetic neurons are unmyelinated and form the gray rami communicantes as they return to the spinal nerves and travel as part of the spinal nerves to their effector organs ( fig. 9.3 ). Because sympathetic axons form a component of spinal nerves, they are widely distributed to the skeletal muscles and skin of the body, where they innervate blood vessels and other involuntary effectors.

9.3 FUNCTIONS OF THE AUTONOMIC NERVOUS SYSTEM The sympathetic division of the autonomic system activates the body to fight or flight, largely through the release of norepinephrine from postganglionic fibers and the secretion of epinephrine from the adrenal medulla. The parasympathetic division often produces antagonistic effects through the release of acetylcholine from its postganglionic fibers. Cocaine blocks the reuptake of dopamine and norepinephrine into the presynaptic axon terminals. This causes an excessive amount of these neurotransmitters to remain in the synaptic cleft and stimulate their target cells. Because sympathetic nerve effects are produced mainly by the action of norepinephrine, cocaine is a sympathomimetic drug (a drug that promotes sympathetic nerve effects). This can result in vasoconstriction of coronary arteries, leading to heart damage (myocardial ischemia, myocardial infarction, and left ventricular hypertrophy). The combination of cocaine with alcohol is more deadly than either drug taken separately, and is a common cause of death from substance abuse.

Adrenergic and Cholinergic Synaptic Transmission Acetylcholine (ACh) is the neurotransmitter of all preganglionic fibers (both sympathetic and parasympathetic).Acetylcholine is also the transmitter released by most parasympathetic postganglionic fibers at their synapses with effector cells ( fig. 9.7 ). Transmission at these synapses is thus said to be cholinergic. The neurotransmitter released by most postganglionic sympathetic nerve fibers is norepinephrine ( noradrenaline ). Transmission at these synapses is thus said to be adrenergic. There are a few exceptions, however. Some sympathetic fibers that innervate blood vessels in skeletal muscles, as well as sympathetic fibers to sweat glands, release Ach (are cholinergic). Since the cells of the adrenal medulla are Embryologically related to postganglionic sympathetic neurons, it is not surprising that their hormones are epinephrine (about 85%) and norepinephrine (about 15%). Epinephrine differs from norepinephrine only in that the former has an additional methyl (CH 3 ) group, as shown in figure 9.8 . Epinephrine, norepinephrine, and dopamine (a transmitter within the CNS) are all derived from the amino acid tyrosine and are collectively termed catecholamines ( fig. 9.8 ). Where the axons of postganglionic autonomic neurons enter into their target organs, they have numerous swellings, called varicosities, that contain the neurotransmitter molecules.

Neurotransmitters can thereby be released along a length of axon, rather than just at the axon terminal. Thus, autonomic neurons are said to form synapses en passant (synapses in passing) with their target cells ( fig. 9.9 ). Sympathetic and parasympathetic axons often innervate the same target cells, where they release different neurotransmitters that promote different (and usually antagonistic) effects.

Many people with hypertension were once treated with a betablocking drug known as propranolol. This drug blocks 1 receptors, which are located in the heart, and thus produces the desired effect of lowering the cardiac rate and blood pressure. Propranolol, however, also blocks 2 receptors, which are located in the bronchioles of the lungs. This reduces the bronchodilation effect of epinephrine, producing bronchoconstriction and asthma in susceptible people. A more selective 1 antagonist, atenolol, is now used instead to slow the cardiac rate and lower blood pressure. At one time, asthmatics inhaled an epinephrine spray, which stimulates 1 receptors in the heart as well as 2 receptors in the airways. Now, drugs such as terbutaline that more selectively function as 2 agonists are commonly used. Drugs such as phenylephrine, which function as 1 agonists, are often included in cold medicines because they

promote vasoconstriction in the nasal mucosa. Clonidine is a drug that selectively stimulates 2 receptors located on neurons in the brain. As a consequence of its action, clonidine suppresses the activation of the sympathoadrenal system and thereby helps to lower blood pressure. This drug is also helpful in treating patients with an addiction to opiates who are experiencing withdrawal symptoms.

ACh receptors are ligand-gated ion channels. That is, binding to ACh causes the ion channel to open within the receptor protein. This allows Na + to diffuse inward and K + to diffuse outward. However, the Na + gradient is steeper than the K + gradient, and so the net effect is a depolarization. As a result, nicotinic ACh receptors are always excitatory. In contrast, muscarinic ACh receptors are coupled to G-proteins, which can then close or open different membrane channels and activate different membrane enzymes. As a result, their effects can be either excitatory or inhibitory ( fig. 9.11 ). Scientists have identified five different subtypes of muscarinic receptors (M 1 through M 5 ; table 9.6 ). CLINICAL The muscarinic effects of ACh are specifically inhibited by the drug atropine, derived from the deadly nightshade plant (Atropa belladonna). Indeed, extracts of this plant were used by women during the Middle Ages to dilate their pupils ( atropine inhibits parasympathetic stimulation of the iris). This was thought to enhance their beauty (in Italian, bella = beautiful, donna = woman). Atropine is used clinically today to dilate pupils during eye examinations, to reduce secretions of the respiratory tract prior to general anesthesia, to inhibit spasmodic contractions of the lower digestive tract, and to inhibit stomach acid secretion in a person with gastritis. Atropine is also given intramuscularly to treat exposure to nerve gas, which inhibits acetylcholinesterase and thereby increases synaptic transmission at both nicotinic and muscarinic ACh

receptors. Atropine blocks the muscarinic effects of nerve gas, which include increased mucous secretions of the respiratory tract and muscular spasms in the pulmonary airways.

Organs Without Dual Innervation Although most organs receive dual innervation, some receive only sympathetic innervation. These include: 1. the adrenal medulla; 2. the arrector pili muscles in the skin; 3. the sweat glands in the skin; and 4. most blood vessels. of the sympathetic fibers. Constriction of cutaneous blood vessels, for example, is produced by increased sympathetic activity that stimulates alpha-adrenergic receptors, and vasodilation results from decreased sympathetic nerve stimulation. The sympathoadrenal system is required for nonshivering thermogenesis: animals deprived of their sympathetic system and adrenals cannot tolerate cold stress. The sympathetic system itself is required for proper thermoregulatory responses to heat. The effects of sympathetic and parasympathetic stimulation on the reproductive and urinary systems are cooperative. Erection of the penis, for example, is due to vasodilation resulting from parasympathetic nerve stimulation; ejaculation is due to stimulation through sympathetic nerves. The two divisions of the autonomic system thus cooperate to enable sexual function in the male. They also cooperate in the female; clitoral erection and vaginal secretions are stimulated by parasympathetic nerves, whereas orgasm is a sympathetic nerve response, as it is in the male. There is also cooperation between the two divisions in the micturition (urination) reflex. Although the contraction of the urinary bladder is largely independent of nerve stimulation, it is promoted in part by the action of parasympathetic nerves. This is exploited clinically in helping people with incontinence (involuntary urination) caused by overactive bladder. In this condition, contractions of the detrusor muscle (of the urinary bladder; chapter 17, section 17.1) are stimulated by ACh released by parasympathetic axons. Newer drugs ( darifenacin and solifenacin ) are available

to block the specific muscarinic receptor subtypes (primarily M 3 ) that mediate the parasympathetic stimulation of bladder contractions. The micturition reflex is also enhanced by sympathetic nerve activity, which increases the tone of the detrusor (bladder) muscle; in this way, the sympathetic division acts in cooperation with the parasympathetic division in the control of micturition. Emotional states that are accompanied by high sympathetic nerve activity (such as extreme fear) may thus result in reflex urination at bladder volumes that are normally too low to trigger this reflex.

Endothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are overexpressed, they contribute to high blood pressure (hypertension) and heart disease. Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Among the strongest vasoconstrictors known, endothelins are implicated in vascular diseases of several organ systems, including the heart, general circulation and brain. Overproduction of endothelin in the lungs may cause pulmonary hypertension, which can sometimes be treated by the use of an endothelin receptor antagonist, such as bosentan, sitaxentan or ambrisentan. The latter drug selectively blocks endothelin A receptors, decreasing the vasoconstrictive actions and allowing for increased beneficial effects of endothelin B stimulation, such as nitric oxide production. The precise effects of endothelin B receptor activation depends on the type of cells involved. Adenosine is a purine nucleoside comprising a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a -N9-glycosidic bond. Adenosine plays an important role in biochemical processes, such as energy transferas adenosine triphosphate (ATP) and adenosine diphosphate (ADP) as well as in signal transduction as cyclic adenosine monophosphate, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal, with levels increasing with each hour an organism is awake. Believed to be anti-inflammatory and a vasodilator.