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  The autonomic nervous system plays a central role in maintaining homeostasis and regulates almost every organ system in the body.

  
  
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  The major functional divisions are the sympathetic and parasympathetic nervous systems. A third division, the enteric nervous system, is an intrinsic neural network that regulates gastrointestinal function.

  
  
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  In most organs, the sympathetic and parasympathetic nervous systems produce functionally opposite effects and can be viewed in simple terms as physiologic antagonists.

  
  
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  The sympathetic nervous system is activated in response to changes in the environment and produces a coordinated “fight-or-flight” response to a threat.

  
  
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  The parasympathetic nervous system is continuously active, and coordinates the function of multiple organs in accord with the physiologic state of the organism, thereby facilitating such functions as digestion and excretion.

  
  
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  Because of its importance to the physiology of the organism, the autonomic nervous system is a target for many pharmacologic interventions and is also responsible for the untoward effects of many medications and toxins.

  
  
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  The peripheral autonomic nervous system (both sympathetic and parasympathetic divisions) consists of a preganglionic neuron in the brainstem or spinal cord that innervates postganglionic neurons in peripheral autonomic ganglia. Synaptic transmission in the autonomic ganglia is mediated by acetylcholine interacting with a nicotinic receptor that is pharmacologically distinct from receptors in the brain or at the neuromuscular junction. The postganglionic neurons innervate target organs throughout the body.

  
  
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  Acetylcholine is the main neurotransmitter used by parasympathetic postganglionic neurons; its target receptors are muscarinic acetylcholine receptors.

  
  
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  With a few exceptions, postganglionic sympathetic neurons release norepinephrine, which acts on α- and β-adrenergic receptors located on end organs.

The autonomic nervous system (ANS) is a semiautonomous division of the nervous system that innervates virtually every organ in the body. Central control of autonomic function involves integration of afferent information and cortical input by brainstem centers and the hypothalamus. These structures control the overall activity of the ANS (autonomic tone). The peripheral ANS (or visceral system) serves to distribute autonomic efferents throughout the body and can also mediate simple autonomic reflexes independent of central control.

The overall function of the ANS is to maintain homeostasis in the body (ie, optimize conditions for survival) in the face of constantly changing environmental and activity demands. For example, the ANS adjusts blood pressure and heart rate to meet the circulatory needs of the body that can vary tremendously from supine sleep to vigorous exercise. The ANS also maintains a constant body temperature despite changing environmental conditions and metabolic activity. Under ordinary circumstances, the ANS functions independently of consciousness yet can be influenced to some degree by volition and emotion. Without autonomic innervation, most organ systems continue to function but cannot adapt to changing environmental and emotional conditions.

Because of its anatomic accessibility and its robust regulation of peripheral organ functions, the ANS was among the first components of the mammalian nervous system to be studied. Consequently, many of the principles of neuropharmacology were derived from classic studies of autonomic systems. Such studies enabled investigators to establish the chemical basis of neurotransmission, identify acetylcholine (ACh) and norepinephrine as neurotransmitters, explore the pharmacology of cholinergic and adrenergic receptors, and discover the role of inhibitory presynaptic autoreceptors in neurotransmission. Indeed, many of the pharmacologic agents studied during the past century originally were characterized according to their actions on the ANS.

Central autonomic centers are distributed throughout the brain and include limbic cortical areas, amygdala, hypothalamus, and numerous brainstem nuclei 9–1. Cortical autonomic centers and amygdala are involved with initiating autonomic responses to emotion and pain. Brainstem centers receive visceral information and generate patterns of output through the peripheral autonomic nerves. The hypothalamus has multiple roles in autonomic regulation and has direct connections to the pituitary, peripheral autonomic neurons, and central autonomic nuclei. The hypothalamus can be considered the main coordinating center of the ANS. It is involved with control of circadian rhythm, temperature regulation, hunger, and thirst and also serves as a relay center for all sympathetic autonomic information descending to the body 9–2.

Although all parts work together in a coordinated fashion, the ANS can be divided into multiple discrete components. These include the following:

1. 
   

   Neurohumoral component of the ANS (which is usually considered as part of the endocrine system). This consists of hormones that regulate energy metabolism, blood volume, and other functions (Chapter 10).

   
   
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   Intrinsic enteric nervous system. The gut has its own independent nervous system that consists of interconnected neurons in the wall of the bowel from the esophagus to the anus. There are as many neurons in the gut as in the spinal cord. These regulate bowel motility and other functions such that the bowel can operate independent of extrinsic input.

   
   
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   Sympathetic nervous system.

   
   
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   Parasympathetic nervous system.

The latter two components form the traditional peripheral ANS. The sympathetic and parasympathetic systems usually produce opposite functional effects and thus are viewed as physiologic antagonists. Most organs are innervated by both. Because they also are regulated independently, their combined actions result in an especially fine degree of control 9–3; 9–1. The sympathetic nervous system, which is characterized by episodic activity, assists an organism in adjusting to changes in the environment, such as those occurring during periods of danger or stress. It usually discharges as a whole, orchestrating a coordinated, multiorgan response to a threat. Activation of this system is associated with increases in the force and rate of heart contractions, an increase in blood pressure, a shift in blood flow from the skin and viscera to skeletal muscle, an increase in blood glucose, and dilation of the bronchial tree. These responses prepare an organism for fight or flight in response to threatening stimuli. The sympathetic system is also activated in response to emotional stress and anxiety (Chapter 15), exercise, dehydration, and in disease states such as congestive heart failure.

In contrast, the parasympathetic nervous system is characterized by graded activity in anatomically discrete segments that serves to coordinate the functioning of individual organs with the physiologic state of an organism. This system assists in maintaining the organism by facilitating functions such as digestion and excretion. There are many specific functions, including slowing the heart, constricting the pupils, stimulating the gut and salivary glands, stimulating bladder emptying, and sexual function.

It is important to remember that the two branches of the ANS have different neuroanatomy (see 9–3). Both branches of the peripheral ANS have several anatomic similarities with the somatic motor system 9–4. The central (preganglionic) autonomic motor neurons are cholinergic and leave the CNS via cranial nerves and ventral spinal roots 9–5. The preganglionic autonomic fibers synapse with neurons in autonomic ganglia that are spread throughout the body. The ganglionic neurons then send postganglionic axons to innervate multiple targets throughout the body. Autonomic ganglia not only are relay stations but also mediate simple autonomic reflexes and coordinate autonomic function between different organ systems.

Sympathetic Nervous System

Preganglionic sympathetic neurons reside in the intermediolateral cell column of the thoracolumbar (T1 to L2–3) spinal cord 9–3, 9–5. Myelinated preganglionic fibers leave the spinal cord and, in most cases, innervate paravertebral sympathetic ganglia connected in a chain by nerve fibers that extend along either side of the vertebral columns from the base of the skull to the coccyx. The postganglionic axons are nonmyelinated and provide sympathetic innervation to most organ systems.

Among cervical sympathetic ganglia, the superior cervical ganglion is notable because it gives rise to the carotid plexus, a network of postganglionic fibers that follow the ramifications of the carotid arteries and furnish the sympathetic innervation of the entire head. Some fibers end in blood vessels and sweat glands of the head and face; others supply the lacrimal and salivary glands. The eye receives sympathetic fibers that innervate the dilator muscles of the pupil and the smooth muscle fibers that help raise the eyelid. The lower cervical ganglia supply the viscera of the neck.

The heart and lungs receive sympathetic innervation from thoracic sympathetic ganglia. The abdominal and pelvic viscera are supplied by thoracic splanchnic nerves, which synapse with postganglionic autonomic neurons in the celiac, superior mesenteric, and aorticorenal ganglia. Lumbar splanchnic nerves carry preganglionic fibers to inferior mesenteric and hypogastric ganglia, from which postganglionic fibers reach end organs in the lower abdomen and pelvis.

Parasympathetic Nervous System

Preganglionic fibers of the parasympathetic nervous system originate in the brainstem and in the sacral region of the spinal cord. The brainstem fibers travel in cranial nerves, including the vagus nerve (cranial nerve X), which provides parasympathetic input to most of the viscera of the body (from the neck down to the distal one third of the colon). Sacral preganglionic neurons provide innervation to the rectum, bladder, and reproductive organs via pelvic splanchnic nerves. Parasympathetic preganglionic neurons have relatively long myelinated axons that synapse with postganglionic neurons in the many small ganglia located close to or within target organs (see 9–3).

Principal Neurotransmitters

The ANS functions predominantly through the actions of ACh and norepinephrine 9–4. As discussed in Chapter 6, ACh is the neurotransmitter released at the neuromuscular junction. In the ANS, all preganglionic neurons in both the sympathetic and parasympathetic nervous systems are cholinergic. These autonomic neurons are analogous to the anterior horn cells of the somatic motor system. Thus, all of the efferent fibers that leave the CNS are cholinergic. In both sympathetic and parasympathetic ganglia, the synaptic connection between the cholinergic preganglionic neuron and the postganglionic neuron is mediated by nicotinic ACh receptors. These neuronal ACh receptors are structurally similar but pharmacologically different from those at the neuromuscular junction, based on differences in their constituent subunits (Chapter 6). ACh is also the main neurotransmitter used by postganglionic neurons in the parasympathetic nervous system 9–4. The cholinergic signal from postganglionic parasympathetic fibers is transmitted to target organs primarily through muscarinic ACh receptors.

In contrast, norepinephrine is used by most of the postganglionic neurons of the sympathetic nervous system. The norepinephrine signal acts on several α- and β-adrenergic receptors located on target organs. Not all postganglionic sympathetic neurons are adrenergic. Sympathetic neurons that innervate sweat glands and certain blood vessels are cholinergic and act by means of muscarinic ACh receptors. Moreover, chromaffin cells of the adrenal medulla receive innervation from preganglionic sympathetic cholinergic fibers that act through neuronal nicotinic ACh receptors. In response to stimulation, chromaffin cells release epinephrine, which, like norepinephrine, acts on α- and β-adrenergic receptors located on end organs. In this way, adrenal chromaffin cells are functionally analogous to sympathetic postganglionic neurons.

Neuropeptides

Most sympathetic and parasympathetic neurons express, in addition to their principal neurotransmitters, a variety of neuropeptides. Neuropeptide Y (NPY) is most often coexpressed with norepinephrine in postganglionic sympathetic neurons, and vasoactive intestinal peptide (VIP) is typically coexpressed with ACh in postganglionic parasympathetic neurons. Other peptides expressed more sparingly in the ANS include galanin, enkephalin, somatostatin, and substance P. Most evidence suggests that, at least in the ANS, peptide transmitters act synergistically with small-molecule transmitters; for example, VIP promotes salivary gland secretion by itself, and the effect is intensified when VIP is coupled with ACh. Similarly, NPY increases vascular smooth muscle contraction by itself and produces synergistic increases in vascular tone when coupled with norepinephrine. These synergistic actions are significant because, outside of the ANS, peptide cotransmitters sometimes antagonize the actions of small-molecule transmitters (Chapter 7).

As previously mentioned, pharmacologic studies of the ANS in many ways defined the field of neuropharmacology during the past 100 years. Indeed, the number and variety of pharmacologic agents that influence autonomic function are vast and well beyond the scope of this book. The sections that follow provide a concise summary of the classes of drugs that affect the ANS and an overview of their physiologic actions. Examples of drugs that act on the ANS and their clinical uses are summarized in 9–2.