Neuroanatomy of the Autonomic Nervous System

Sympathetic Division

The general function of the sympathetic nervous system (SNS) is to help the body cope with stressful situations. The response usually is the rapid release, and subsequent use, of energy. This is best exemplified by the reaction of the body to a dangerous situation. In this instance, sympathetic involuntary responses occur, including increased heart and respiratory rates, cold and clammy hands, wide-eyed stare, and dilated pupils. Blood is redistributed by means of vasoconstriction and vasodilation from such areas as the abdominal and pelvic organs and skin, to more important tissues such as the brain, heart, and skeletal muscles. The level of blood glucose increases, as does the blood pressure. Activity of the gastrointestinal (GI) and urinary systems is less important during this stressful situation; therefore the nonvascular smooth muscle of these organs is inhibited. The sympathetic division often is called the fight-or-flight division of the ANS because of this overall response.

Parasympathetic Division

The parasympathetic division generally is concerned with conserving and restoring energy. It is coordinated with the sympathetic division in the dual and antagonistic innervation of autonomic effectors (see Table 10-1). However, there is no parasympathetic innervation of autonomic effectors located in the extremities and body wall (i.e., sweat glands, arrector pili muscles, peripheral blood vessels). Because the sympathetic division has been nicknamed the fight-or-flight division, the parasympathetic division could appropriately be named the rest-and-digest division, because in general, parasympathetic activation results in decreased heart rate and increased GI glandular secretion and peristalsis. In contrast to the widespread control by the sympathetic system, the parasympathetic division controls effectors at a more local level. This relates to the overall pattern of organization of the parasympathetic division of the ANS. Compared with the sympathetic division, each parasympathetic preganglionic neuron synapses with fewer postganglionic neurons, and the location of the parasympathetic ganglia is near, or frequently within, the wall of the effector organ. The ganglia are the site of synapses between preganglionic and postganglionic neurons; however, afferent fibers, postganglionic sympathetic fibers, and even branchial arch efferent fibers can course through them.

The parasympathetic division also is called the craniosacral division. As with the thoracolumbar (sympathetic) division, this name refers to the location of the cell bodies of preganglionic neurons (see Fig. 10-2). These cell bodies are located in autonomic nuclei of the brain stem (cranio) and in the second, third, and fourth sacral cord segments (sacral). The parasympathetic efferents of the sacral cord course within the ventral roots and within pelvic splanchnic nerves. These nerves do not use the sympathetic trunk. Axons of the cell bodies located in the brain stem leave the brain stem traveling within the oculomotor, facial, glossopharyngeal, and vagus cranial nerves. Although numerous branches of various cranial nerves include these parasympathetic efferents, only the major branches are described. The somatic functions of the four cranial nerves are not discussed because this chapter is devoted to the innervation of autonomic effectors.

Enteric Nervous System

The third division of the ANS is the enteric nervous system (ENS). Experiments performed in the late nineteenth and early twentieth centuries led to the theory that motility of the GI system was under autonomous control by an intrinsic nervous system, when well-coordinated and purposeful motility still occurred independently after severing nerves to the GI system (Bayliss & Starling, 1899; Langley, 1903; Langley & Magnus, 1905). Since that time the concept that an intrinsic group of neurons exists in the wall of the gut, pancreas, and gallbladder has been fully accepted. This extensive integrated network of neurons is located in the esophagus, stomach, small and large intestines, gallbladder, and pancreas. Groups of these neurons acting as microcircuits process sensory information such as the current contractile state of muscle, mechanical stimulation of the mucosa, or changes in the chemical contents of the lumen. They respond by generating output to coordinate muscle contraction, to influence secretory activity, and to adjust blood flow to accommodate the metabolic needs of the gut. In addition, extrinsic vagal and spinal afferents signal information coming from the gut to the CNS, and sympathetic fibers from prevertebral ganglia (splanchnic nerves) and parasympathetic fibers via the vagus and pelvic splanchnic nerves synapse on the enteric neurons. This input can adjust, regulate, and (in some emergency situations) override this intrinsic system (Fig. 10-18).

The enteric nervous system (ENS) is found within the 4 layers of the wall of the GI tract and is considered to contain as many neurons as the spinal cord itself—approximately 100 million (Noback, Strominger, & Demarest, 1991; Camilleri, 1993; Kiernan, 2009) or, according to some studies on humans, as many as 200 to 600 million (Wood, 2009). The enteric system consists of two major interconnected plexuses of various functional classes of neuron cell bodies (ganglia) and their processes (Fig. 10-19) as well as glial cells that outnumber the neurons. One of these is the myenteric plexus of Auerbach, which is located between the inner circular and outer longitudinal smooth muscle layers of the muscularis externa and extends from the esophagus to the internal anal sphincter. The second plexus is the submucosal plexus of Meissner, which is found in the submucosa of the GI tract. The submucosal plexus is most prominent in the small and large intestine and is absent or sparse in the esophagus and stomach. In large mammals it consists of an inner plexus (Meissner’s plexus) located at the deep side of the muscularis mucosa and an outer plexus (Schabadasch’s plexus) located next to the luminal side of the circular layer of muscle. In humans, an additional intermediate plexus lies between the two within the intestines. Motor neurons of the submucosal plexus innervate the secretory glands of the intestines (e.g., Brunner’s glands and the crypts of Lieberkühn). Interconnections between the submucosal and myenteric plexuses allow for the integration and processing of information received from each plexus (Brookes & Costa, 2006; Wood, 2009). Nonganglionated nerve plexuses also are located in and supply various layers of the wall of the gut (Standring et al., 2008).

In the past it was thought that the ganglia of these plexuses functioned as parasympathetic relay-distribution centers similar to other autonomic ganglia in the body. In other words, preganglionic parasympathetic fibers synapsed on postganglionic neuron cell bodies within a ganglion and then the fibers of these synapsed on smooth muscle and glands. This concept has been discarded because a closer look at the plexuses reveals that they are an independent integrative neuronal network that also receives input from sympathetic postganglionic fibers as well as preganglionic parasympathetic fibers (Fig. 10-20). In fact, only 10% of vagal efferents supply the gut and other viscera (the other 90% are afferents), indicating that parasympathetic influence on gut function must be to activate large neuronal circuits instead of individual effectors (Schemann & Mazzuoli, 2010). The networks or microcircuits are positioned near effector organs (smooth muscle and glands and blood vessels) and are programmed to control individual effectors or to coordinate the actions of multiple groups of effectors. In addition, the plexuses consist of cell populations different from and more complex than those found in other autonomic ganglia. Each plexus contains clusters of neurons that are interconnected, and each cluster consists of a heterogeneous population of neurons (Loewy, 1990a; Camilleri, 1993; Kiernan, 2009). These neurons can be classified numerous ways including by the type of receptor expressed, morphologic characteristics, electrophysiologic properties, and chemical coding (Furness, 2000; Hansen, 2003a; Brookes & Costa, 2006; Standring et al., 2008; Wood, 2009). In fact, it has been suggested that peptidergic and monoaminergic neurons are the predominant neurons in the ENS (Standring et al., 2008). Based on the number of ENS neurons, the complexity of their interactions and formation of microcircuits, and the similarity in neurotransmission and signaling molecules to the brain, the ENS has been referred to as a ‘mini-brain’ (Wood, 2009; Mayer, 2011). In the late 1970s and early 1980s studies on this vast number of intermingled neurons showed there were different chemical markers associated with these neurons, which led to the chemical coding hypothesis. Simply stated, it suggested that functional classes of neurons could be distinguished from each other on the basis of chemical attributes that constituted a chemical code. This code included neuropeptides, which are useful because they are targets in immunohistochemical studies. Extensive investigations of the ENS of the guinea pig, primarily, but also humans, mice, rats, pigs, and sheep, led to the chemical codes of enteric neurons. It appears that codes related to essential functions of neurons are highly conserved between species—that is, all neurons regardless of species or gut region that have similar roles will contain the same primary neurotransmitter, although there is considerable variation in the other codes between species. There may also be subtle differences in the codes within a particular enteric population. Data from the investigations of chemical coding led to the conclusion that although the same neuron releases several transmitters, one neurotransmitter, called the primary transmitter, has a dominant role. For example, in the guinea pig there are eight transmitters in the chemical code for cholinergic nonvasodilator secretomotor neurons. This type of transmission where several neurotransmitters from one neuron are utilized is called plurichemical transmission (Furness, 2009). Evidence indicates that more than 30 neurotransmitters are involved in the synaptic neurotransmission. These are small molecules, peptides, or gases that modulate the release or action of the primary neurotransmitter or provide a trophic influence. Combining characteristic features from morphologic, chemical, electrophysiologic, and receptor classifications, three classes of neurons have been identified based broadly on functional properties. These are motor neurons, interneurons, and sensory (intrinsic primary afferent) neurons (see Fig. 10-20). These neurons ultimately control motility, secretory activity, and blood flow patterns of the gut by activating each effector system in a coordinated manner such that the organ functions as an integrated system.

Motor neurons are classified as those that innervate smooth muscle and those that innervate glands and blood vessels. Muscle motor neurons only innervate smooth muscle of the GI system and are excitatory or inhibitory. Most of the cell bodies are located in the myenteric plexus in small mammals but in humans there is a substantial population located in the outer submucosal plexus. The single axon of the motor neuron extends within the plexus before terminating as branches within the muscle. Motor neurons to intestinal circular muscle are excitatory or inhibitory. Excitatory neurons course in an oral direction or project locally and inhibitory neurons project aborally. Thus motor contraction will occur above the focal point of excitation with relaxation below this point (the law of the intestine suggested by Bayliss and Starling in 1899). Although less numerous than excitatory neurons, the firing of inhibitory neurons dominates when the two are activated simultaneously. Motor neurons that innervate longitudinal muscle are located within the myenteric plexus and their axons course within the muscle and parallel to the fibers. These neurons are primarily excitatory and project to local muscle fibers, allowing for graded motor control of the muscle in the immediate area. Long ascending or descending fibers of interneurons may activate these neurons if muscle contraction needs to be coordinated over long distances. The motor neurons to longitudinal muscle are a separate population from those that innervate circular muscle and although both can act independent of each other, they may also be activated simultaneously during muscle stretching (Brookes & Costa, 2006). In excitatory neurons the primary neurotransmitter is acetylcholine (ACh), which acts on muscarinic receptors (usually the subtypes M₂ and M₃), but there are also tachykinins, such as substance P, that function as cotransmitters. The inhibitory neurons use the co-transmitters nitric oxide (NO), vasoactive intestinal polypeptides (VIPs), and adenosine triphosphate (ATP), although the primary transmitter is generally NO (Furness, 2009).

The activity of inhibitory motor neurons, which is controlled by interneurons, determines if motor contraction occurs, and when it does occur it controls the length of the contracting segment and the direction of the ensuing propagation. Since some inhibitory neurons innervating circular muscle fire continuously, contraction of circular muscle in response to the interstitial cells of Cajal (see below) will only occur when interneurons inactivate the inhibitory neurons. (The control of sphincter musculature by inhibitory neurons is the opposite in that the neurons are normally quiet and are activated only at the appropriate time.) The control of inhibitory neurons is such that inactivation of inhibitory neurons results in specific gut segments contracting while inhibitory neurons firing to adjacent segments results in relaxation. Controlling the firing of inhibitory neurons such that they are progressively inactivated in an aboral direction allows contraction to occur, resulting in the normal propagation of luminal contents in the aboral direction. Reversal of this pattern would be required for the process of emesis to occur (Wood, 2007). Much of the effect of the motor neurons is thought to be mediated by the interstitial cells of Cajal (ICCs). These cells are specialized smooth muscle cells that act as pacemaker cells for the gastric musculature and intestinal circular musculature. They generate slow waves of depolarization and form an electrical syncytium such that action potentials and the pacemaker potentials propagate from muscle cell to muscle cell through gap junctions. Circular musculature is able to contract in response to these electrical slow waves when their inhibitory neurons are inactivated. Based on morphology and location within the gut wall, it has been shown that there are different types of ICCs (Komuro, 2006; Ward & Sanders, 2006; Mostafa, Moustafa, & Hamdy, 2010). They are in contact with each other and with smooth muscle cells, and are located in the vicinity of enteric motor neurons and vagal afferent fibers. Because of these interconnections, the ICCs may be involved with the mechanism of neurotransmission for intrinsic gut motility and for sensory signaling. It has been suggested that changes in the number, structure, or density of ICCs may be related to GI disorders such as achalasia, gastroparesis, chronic intestinal pseudoobstruction, and chronic constipation. Abnormal pacemaker activity may occur if there are few or no ICCs, resulting in decreased smooth muscle contractility and diminished intestinal transit (Mostafa, Moustafa, & Hamdy, 2010). Inhibitory motor neurons may be destroyed or inactive as a result of degenerative noninflammatory or inflammatory ENS neuropathies. This leads to no control of ICC activity and no organization of the muscle contractions. The smooth muscle will become hyperactive and contract continuously, behaving as an obstruction. This decrease in inhibitory neurons is the pathophysiologic beginning of disinhibitory motor disease, which includes several forms of chronic intestinal pseudoobstruction and sphincteric achalasia. Initially the symptoms appear similar to those presented in irritable bowel syndrome (IBS) cases but then as more neurons degenerate the symptoms worsen and finally manifest as chronic intestinal pseudoobstruction (Wood, 2007).

The movement of luminal contents through the intestines is the result of various patterns of propulsive contractions created by the polysynaptic peristaltic reflex circuitry. Wood (2009) referred to this as the intestinal analog of spinal motor reflexes. Like the spinal reflex, the peristaltic reflex is hardwired to appropriately synchronize the activation of excitatory and inhibitory motor neurons. Distension of the intestinal wall and mechanical stimulation of the mucosa result in a stereotypic motor response—relaxation of the circumferential muscle group and contraction of the longitudinal muscle group below the site of stimulation and contraction of the circumferential group above the point of stimulation. The reflex circuit must activate the excitatory and inhibitory motor neurons controlling longitudinal muscle groups and circular muscle groups appropriately in the receiving segment for the forward-moving intraluminal contents and coordinate the firing of the excitatory and inhibitory motor neurons to the two muscle groups in the propulsive segment. It is thought that the reflex circuits are arranged in units that are interconnected in series within the intestinal wall. When one of the circuits is activated, it is able to recruit other circuits, providing the mechanism for propulsion to occur over various distances of the intestine. The hardwired circuitry involved in somatic spinal reflexes may be modified according to the motor program that is to be used (i.e., reflexes, automatic movements, and purposeful movements). ENS circuits are also modified by sensory feedback and other input to compensate for local changes or for changes that affect the entire intestine in order to adjust the strength of contraction and the rate of repeating a particular motor pattern. The reflex circuitry is also under control by other ENS circuits during various digestive states and during emesis, when the distance over which propulsion occurs and the direction in which it occurs vary. Similar to spinal networks involved in the programming of somatic motor neurons for repetitive, rhythmic types of movement such as walking, it is thought that central pattern generators also exist within the ENS circuitry in the intestine. Wood (2009) suggests that each circuit is multifunctional, consisting of a ‘library’ of programs that can be reconfigured by modulatory input, resulting in various motor patterns. Some of the programs are designed to control motility and secretion occurring during various digestive states such as the postprandial state and the interdigestive state, and also during the emetic state. In addition, there is a protective program resulting in power propulsion that is activated in response to potentially dangerous agents within the lumen such as food allergens or toxins. The neuromodulatory signals altering the neurotransmission within the programmed neuronal circuits may be chemical mediators released from enteroendocrine cells and immune or inflammatory cells within the gut wall, such as the histamine released from enteric mast cells, or they may be signals from neurons (Wood, 2009) (see section Enteric Nervous System and the Immune System).

Secretomotor and vasomotor (dilator) neurons of the enteric nervous system regulate secretions and blood flow in response to chemical and mechanical stimuli. Vasomotor fibers control the diameter of submucosal and mucosal arterioles to adjust blood flow relative to the level of gut secretory activity. These cholinergic fibers cause nitric oxide (NO) to be released from the vascular endothelium, resulting in dilation and increased blood flow. Secretomotor fibers are the major pathways that regulate secretion from the intestinal crypts of Lieberkühn, Brunner’s glands, and goblet cells in the intestine and activate ion fluxes and water movement across the epithelium. Many of these submucosal neurons project to both targets, thus coordinating blood flow with secretory demand. When activation occurs, water, NaCl, bicarbonate, and mucus from glands are secreted into the lumen and blood flow is increased (Wood, 2007). Prominent among the submucosal neurons are neurons (noncholinergic) that use the VIP family peptides as the primary transmitter. These neurons receive both excitatory and inhibitory synaptic input from a variety of sources including intrinsic primary afferent neurons (IPANs), interneurons, and sympathetic postganglionic neurons These VIP family neurons appear to play the major role in physiologic responses by adjusting and regulating most of the local reflex responses. Other secretomotor/vasodilator neurons use ACh as their primary transmitter. One population of vasodilator neurons uses ACh as its primary transmitter along with seven different neuropeptides. Nonneural cells located in the mucosa and submucosa, such as enterochromaffin cells, mast cells, and other immune/inflammatory cells, release chemicals that activate the VIP family neurons (Brookes & Costa, 2006; Wood, 2007; Furness, 2009).

Secretomotor neurons may be inhibited by intrinsic enteric neurons and by postganglionic sympathetic neurons. Norepinephrine (NE) released from the sympathetic fibers binds to α₂ receptors, inhibiting the firing of the secretomotor neurons with subsequent reduced secretory activity and a decrease in the concentrations of water and electrolytes. This mechanism of sympathetic activation can occur for normal homeostatic maintenance where blood needs to be shunted from the viscera to the systemic circulation and also in pathologic conditions resulting in a constipated state. Secretomotor neurons also express receptors that promote excitation and therefore an increase in secretory activity by the intestinal epithelium. In a pathologic state this may lead to secretory diarrhea. VIP, ACh, and substance P are able to activate these receptors on the neurons. An excessive amount of serotonin released from enterochromaffin cells stimulates secretomotor neurons and may be the mechanism by which the diarrhea state exists in the irritable bowel syndrome (IBS) diarrhea-predominant condition in patients. Inflammation of the intestinal mucosa or submucosa causes histamine and other mediators to be released, which can result in secretory diarrhea. These chemicals excite secretomotor neurons and also act presynaptically on postganglionic sympathetic fibers to inhibit their release of NE. The latter results in the removal of sympathetic inhibition on the secretomotor neurons and allows for an increase in their activity and more secretion to occur (Wood, 2007).

Interneurons aid in forming the circuitry necessary for processing sensory input and for determining the proper motility pattern. The interneuronal circuits are established for organizing reflex responses and also for housing the integrative programs for the diverse motor functions of the gut such as migrating myoelectric complexes (cyclical waves of intestinal contractions occurring between meals), mixing patterns during digestion, and powerful propulsive contractions during peristalsis. Interneurons receive input from intrinsic primary afferent neurons (IPANs), from other interneurons, and from extrinsic neurons and they project to all classes of enteric neurons. The interneurons are arranged into functional chains, which allows for reflex circuits to extend farther superiorly and inferiorly within the gut wall. It has been suggested that this organization can allow a segment of the chain that controls a specific set of enteric neurons to act as a switch, controlled by sympathetic or vagal fibers, between motility patterns utilized during feeding and fasting periods (Brookes & Costa, 2006). Two classes of interneurons are found in the ENS. One class consists of three populations of interneurons that have axons that are descending (aborally directed). Two populations are cholinergic and project to both plexuses. However, one of these two populations is also somatostatin immunoreactive and synapses on interneurons and inhibitory motor neurons whereas the other is also serotonin (5-hydroxytryptamine, 5-HT) immunoreactive and does not likely synapse on inhibitory motor neurons. The third population of descending interneurons is comprised of a heterogeneous neuronal group of which many are cholinergic and all are similar morphologically. The other class of interneurons comprises about 5% of myenteric neurons. This interneuron is predominantly cholinergic and has a short ascending (orally) directed axon. It synapses with other ascending interneurons and with excitatory motor neurons, propagating excitation up the gut wall and coordinating motor contractility over long distances (Brookes & Costa, 2006).

The sensory neurons of the enteric nervous system are called intrinsic primary afferent neurons (IPANs) (see later discussion and Fig. 10-21). They are found in both the submucosal and myenteric plexuses of the small and large intestines but are absent from the esophagus and rare in the stomach (Furness, 2008). Their processes, which greatly outnumber those of vagal or spinal afferent fibers, terminate in the lamina propria of the mucosa. They are located throughout the wall of the gut and are subjected to gut wall distortion, toxins, nutrients, hormones, inflammatory mediators, and gut metabolic changes and therefore influence reflex circuitry for multiple reasons. They are able to act as mechanoreceptors and chemoreceptors and may be activated by mechanical stimuli of the mucosa, by distension of the gut wall or distortion of their processes, or by luminal chemical stimuli such as fatty acids, acids, alkaline solutions, and glucose. Evidence shows that the activation of neurons by distortion and chemical stimuli is caused by the release of serotonin from enteroendocrine cells in response to these stimuli (Gershon, 2005) (see later discussion). Based on responses to stimuli, it appears that there are three classes of IPANs: submucosal IPANs that respond to mechanical stimuli of the mucosa; myenteric IPANs, the majority of which respond to chemical stimulation of the mucosa; and other myenteric IPANs that respond to stretching of the gut wall (Brookes & Costa, 2006). IPANs have processes with extensive connections onto most other enteric neurons including other IPANs, interneurons, and motor neurons, and so they also play a major role in activating the enteric neuronal circuitry for the physiologic reflex control of motility, secretion, and blood flow. The peristalsis reflex is an example of the interaction of these neurons. Distension or the presence of chemical stimuli activates the IPANs that project to interneurons. The interneurons in turn synapse with orally directed excitatory motor neurons and anally directed inhibitory motor neurons (Standring et al., 2008), thus initiating peristalsis. Also, IPANs that are activated in response to luminal nutrients produce a reflex response by stimulating secretomotor fibers that results in secretion. This response not only is local but also can be widespread throughout the GI tract by means of the integrated circuitry of the plexuses that activates secretomotor neurons at different levels. IPANs may also initiate reflex responses to potentially harmful conditions. They are able to detect mucosal irritants such as bacterial by-products or parasitic infestations and initiate a protective response of heightened secretion and motility manifested as diarrhea (Furness, 2006). In the small intestine of the guinea pig, all types of neurons have been identified. The IPANs in these animals and likely in humans have been shown to use ACh and tachykinins as the primary neurotransmitters although secondary neurotransmitters also are involved in the secretory process (Furness, 2009).

The enteric neurons and effectors of the gut wall are modulated and innervated, respectively, by fibers from extrinsic sources. These are vagal, pelvic, and spinal afferent fibers and parasympathetic and sympathetic efferent fibers. All of these fibers terminate as varicose fibers within the enteric ganglia. The extrinsic afferent neurons are other sensory neurons located in the GI system. These neurons send input to the CNS about the GI environment with regard to normal physiologic processes and the feelings of discomfort and pain. They provide the input for spinal and brain stem reflex mechanisms and the input to the central autonomic network that regulates behaviors associated with the GI system. These afferents course in the vagus nerve, pelvic splanchnic nerves (referred to as pelvic afferents), and thoracolumbar splanchnic nerves (referred to as spinal afferents) along with efferent fibers and encode activity within physiologic levels. However, the spinal afferents are also activated by pathophysiologic stimuli and mediate the sensation of pain (see Spinal Afferent Fibers under section Visceral Afferents). The cell bodies of both spinal afferents and pelvic afferents are located in dorsal root ganglia. The cell bodies of the spinal afferents exhibit a generalized overlapping viscerotopic distribution in that a dorsal root ganglion will have a preponderance of fibers associated with one particular area although it innervates many areas. Spinal afferent fibers constitute about 10% to 20% of the splanchnic fibers; pelvic afferents constitute about 30% to 50 % of the pelvic splanchnic fibers (Beyak et al., 2006). Spinal afferents terminate in muscle layers near ganglionic cell bodies and smooth muscle cells, in the mucosa, serosa, and mesentery. They are predominantly high-threshold mechanonociceptors. A small minority of spinal afferents that terminate in the muscle layers are muscle afferents that are sensitive to mechanical stimuli. Another small population of endings are mucosal mechanoreceptors that respond to light mechanical stimuli (not stretch) (Zagorodnyuk, Brookes, & Spencer, 2010). There is little direct evidence that suggests they are involved with sensing luminal contents (Beyak et al., 2006). Other spinal afferents are mechanosensitive and terminate on intramural blood vessels in the submucosa. These have been shown to be activated by large-amplitude circumferential stretch of the submucosa. Nonmechanosensitive collaterals of the afferent fibers branch in the myenteric and submucosal ganglia and terminate on blood vessels. Blood vessels in the mesentery are also innervated by mechanosensitive afferents. These afferents fire in response to blood vessel compression, perfusion changes, and large-amplitude stretch. Vascular afferents comprise a distinct and significant type of afferent fiber and may be a contributing component in the neural transmission of nociception. In general, spinal afferent fibers respond to mechanical stimuli and to potentially noxious chemical or mechanical stimuli resulting from ischemia, tissue damage, or inflammation. These afferent fibers express numerous receptors such as the 5-HT3 receptor and receptors for bradykinin, ATP, prostaglandins, histamine, and mast cell proteases (Wood, 2007). When these afferent fibers are activated, they send input regarding noxious stimuli into the dorsal horn where they initiate reflex responses or synapse on tract neurons. These tract neurons convey information to higher centers for further processing. In some instances these afferent fibers and dorsal horn neurons can undergo the process of sensitization, resulting in functional gastrointestinal disorders such as IBS (see Neurotransmission of Visceral Pain under section Visceral Afferents).

Pelvic afferents supply the distal colon and rectum, terminating as intraganglionic laminar endings (IGLEs), which are similar to vagal intraganglionic laminar endings. These fibers transmit information from low-threshold stretch-sensitive mechanoreceptors of predominantly the rectum where the density of the IGLEs is greater than that in the distal colon (Zagorodnyuk, Brookes, & Spencer, 2010). Pelvic afferents also terminate in the mucosa on mechanoreceptors. Some of these receptors respond to light stroking whereas others respond to light stroking and distension. Like vagal afferents (see below) the pelvic afferents signal information to the CNS concerning normal physiologic functioning of the gut and they initiate centrally mediated reflexes (Brookes & Costa, 2006). Spinal afferent neurons are immunoreactive for calcitonin gene–related peptide (CGRP) and tachykinins (e.g., substance P). These neurotransmitters are known to be chemical mediators involved in the neurogenic inflammatory process and GI inflammation. Pelvic afferents are nonpeptidergic and are immunoreactive for vesicular glutamate transporters (VGluT1 and VGluT2) (Zagorodnyuk, Brookes, & Spencer, 2010).

Vagal afferent fibers signal the physiologic states of the gut to the CNS and are part of the inflammatory reflex (see section ANS and the Immune System). Afferent fibers coursing in the vagus nerve outnumber efferents by a 9:1 ratio (Beyak et al., 2006). Three types of afferent endings have been described. One type is associated with branching varicose fibers that are interspersed among the circular and longitudinal muscle cell layers. These are called intramuscular arrays and they are sparse in the intestine but fairly dense in the lower esophagus, upper stomach, and pylorus. It has been speculated that they may be a type of mechanoreceptor sensitive to length (Beyak et al., 2006; Brookes & Costa, 2006; Zagorodnyuk, Brookes, & Spencer, 2010). The second type, called intraganglionic laminar endings (IGLEs), consists of endings that surround the myenteric ganglia. These vagal IGLEs are present in the esophagus and stomach, decrease in number throughout the intestines, and are absent in the rectum (Beyak et al., 2006; Brookes & Costa, 2006). These monitor the stress and strains produced by muscle stretch or contraction. A third type of afferent fiber terminates as mucosal endings. These have been described in the gut wall from the esophagus to the distal colon and extend throughout the lamina propria of villi near the basal lamina of epithelial cells and are often close to enteroendocrine cells. They are sensitive to light mechanical stimuli such as gentle stroking or compression but not to stretch or distension and thus may be able to detect luminal contents moving across the mucosal surface (Zagorodnyuk, Brookes, & Spencer, 2010). They also are activated indirectly by a variety of chemicals including nutrients involved with the digestion process and by changes in osmolarity and acidity in the contents of the lumen. An extensive discussion of GI physiology relevant to the functions of all chemical mediators is beyond the scope of this chapter. However it is important to mention some of the mediators and their relationships with extrinsic afferent fibers and IPANs.

The mucosa of the GI tract is lined predominantly by simple columnar epithelial cells and in the intestine these absorptive cells are called enterocytes. Located among the enterocytes is a population of enteroendocrine (EE) cells and within this group is a small subpopulation (1% to 3% of all human epithelial cells [Bertrand & Bertrand, 2010]) of cells called enterochromaffin (EC) cells. These EE and EC cells are likely the predominant sensory cell population functioning as mechanical and nutrient sensors (a process referred to as “nutrient tasting” [Raybould, 1999; Grundy, 2002]). In other words, it appears that most stimuli of the gut wall do not directly interact with sensory nerve terminals but instead activate these sensory cells (Xue et al., 2007; Bertrand & Bertrand, 2010). These cells thus provide the site for sensory transduction to occur, resulting in the release of mediators such as ATP and the hormones secretin, cholecystokinin (CCK), and serotonin (5-HT). Intestinal glucose is one nutrient that is detected in the lumen by the enteroendocrine and enterochromaffin cells. Studies indicate that the membrane transport protein at least on EC cells may be a glucose-specific sensor that when activated results in depolarization and release of 5-HT (Raybould, 2007; Raybould, 2010) instead of a glucose transporter. Several G protein–coupled receptors are also expressed on EE cells that are activated by luminal chemicals such as glucose, calcium, umami, protein hydrolysates (strong stimulants resulting in EE cell secretion), and both long- and short-chain fatty acids. Evidence indicates that fatty acids and protein hydrolysates induce the release of CCK and of GLP-1 (glucagon-like peptide 1) and CCK, respectively (Raybould, 2010). Interestingly, some gut epithelial cells and EE cells also express the same G protein–coupled receptors (T2R) and G proteins that are part of the components that mediate bitter taste in the oral cavity. When activated, the cells release CCK. Research also shows that EE cells express toll-like receptors, which recognize bacterial breakdown products such as lipopolysaccharide. Depending on the bacterial ligand, studies show that CCK, defensin, and chemokines may be released, which activate pro-inflammatory pathways. Because it appears that EE cells respond to bacterial breakdown products, it may be that this response is a method to defend the integrity of the mucosa (Raybould, 2010). As one can see, enteroendocrine cells play a very important role in the sensory transduction caused by chemical and mechanical stimuli within the lumen of the gut by releasing chemical mediators. Enterochromaffin (EC) cells in the gut are also very important. These cells synthesize, store, and release serotonin (5-HT). Serotonin is a very important mediator that has a pivotal role with the mediation of a variety of GI reflexes through its interactions with enteric neurons. The GI tract has the largest accumulation (approximately 90%) of 5-HT in the body. In addition to the EC cells, 5-HT is also found in enteric neurons (it is expressed in 2% to 20% of all enteric neurons) (McLean, Borman, & Lee, 2007). Other molecules stored in the EC cell include gamma-aminobutyric acid (GABA), ATP, uroguanylin, and melatonin (Bertrand & Bertrand, 2010). Along with mediators from EE cells such as CCK and ATP, serotonin initiates and regulates motor and secretory behaviors of the gut in response to various stimuli of the lumen at any given time and in any region. 5-HT acts in a paracrine manner and activates the 5-HT receptors on intrinsic and extrinsic sensory nerve terminals. Based on in vitro studies, it appears that these receptors are important for the initiation and propagation of peristalsis and other gut reflexes including secretory activity (Bertrand & Bertrand, 2010). Studies indicate that 5-HT is released in response to the presence of luminal nutrients and chemicals and as a result of mechanical stimuli such as compression of the mucosal epithelium and circular and longitudinal muscle contractions (Bertrand & Bertrand, 2010). Because there are no serotonergic neurons in the mucosa, enterocytes function to terminate 5-HT signaling, thus preventing excessive stimulation of the receptors and possibly desensitization. These cells express a membrane serotonin reuptake transporter (SERT), which mediates the transmembrane transport of 5-HT into the cell where it is degraded. The effects of 5-HT on the enteric neurons are through its activation of several different receptor types such as the 5-HT₃ and 5-HT₄ receptors and the putative 5-HT_1P receptors (Gershon, 2005) (Fig. 10-21). 5-HT_1P receptors are expressed on submucosal IPANs. These neurons initiate peristaltic and secretory reflexes in response to mucosal stimuli. 5-HT₄ receptors are presynaptic and are found on the terminal endings of submucosal IPANs, at synapses with myenteric neurons, and at the neuromuscular junction. It is postulated that by binding to the 5-HT₄ receptors on submucosal IPANs, 5-HT increases the release of neurotransmitters (ACh and CGRP), thus strengthening neurotransmission and enhancing the peristaltic and secretory responses. 5-HT₃ receptors are postsynaptic and are expressed on the terminals of extrinsic afferent neurons where they may respond to noxious stimuli. In addition, they are found on myenteric IPANs and on neurons in the myenteric plexus.

These receptors have been targeted by modulating drugs (agonists and antagonists) in the treatment of functional GI disorders such as IBS (Gershon, 2005; McLean, Borman, & Lee, 2007). Because the subtypes of 5-HT receptors are on distinct populations of neurons (i.e., the submucosal IPANs, which initiate peristaltic and secretory reflexes, versus the extrinsic afferent neurons, which are activated by noxious stimuli), drugs can be used to treat symptoms resulting from the activation of one group without affecting the other (Gershon, 2005). 5-HT has a very important role in mediating physiologic responses such as modulation of smooth muscle activity and of neuronal function and intestinal secretion within normal GI function parameters. Although it appears that decreased levels of 5-HT do not disrupt normal GI function, there is evidence to suggest that very high levels of 5-HT release can contribute to the diarrhea associated with cholera, the nausea associated with chemotherapy or radiation therapy, and similar symptoms manifested in chronic intestinal diseases such as chronic constipation, enterocolitis, inflammatory bowel disease, and irritable bowel syndrome. Also, studies show that a mechanism may exist during inflammation that can alter the number of EC cells and amount of 5-HT (Bertrand & Bertrand, 2010). In general, understanding the cellular and molecular mechanisms of 5-HT release, the activation of its numerous receptors, and the serotonin reuptake transporter may allow for a better understanding of the pathologic processes occurring in chronic GI disorders and treatment protocols.

Receptors for these mediators are expressed on enteric neurons and on extrinsic (primarily vagal) sensory afferents. Vagal afferents express receptors for many regulatory molecules such as CCK, glucagon-like peptides, peptide YY, leptin, orexin, ghrelin, and serotonin. Activation of these afferents by mediators attributable to nutrient or chemical stimuli can influence food intake and initiate a vago-vagal reflex regulating GI functions such as intestinal fluid secretion, gastric emptying, and pancreatic exocrine secretion. At times, the reflex may be of a protective nature (propulsion and elimination) in response to the sensing by EE cells of bacterial breakdown products or to bitter substances (Raybould, 2007; Raybould, 2010).

As mentioned earlier, IPANs are the intrinsic sensory neurons that respond to luminal contents and distension and initiate reflexes adjusting motility, blood flow, and secretion. There are other afferent enteric neurons that appear to have a broader function that involves the sympathetic system. These intestinofugal or viscerofugal (i.e., impulses traveling away from the intestine/viscera) neurons are in-parallel stretch receptors that monitor the degree of stretch of the circular muscle. They function as slowly adapting mechanoreceptors that detect changes in volume (Szurszewski & Miller, 2006). They are likely to be active most of the time, providing peripheral input to prevertebral ganglia and initiating ongoing reflexes mediated by postganglionic sympathetic fibers that control normal functions. The fibers synapse only with postganglionic sympathetic neurons that regulate secretion and motility. Intestinofugal neuron cell bodies are located primarily in the myenteric ganglia. Animal studies indicate that there is a proximodistal gradient in the number of cell bodies, that the greatest number is at the end of the ascending colon, and that 90% of cell bodies of intestinofugal fibers terminating in the celiac, superior, and inferior mesenteric ganglia are found in the colon (Szurszewski & Miller, 2006). The axons of the intestinofugal neuron cell bodies project to sympathetic prevertebral ganglia (see Fig. 10-20). The axons that use ACh as the primary neurotransmitter do not appear to form collateral branches to the gut wall (Brookes & Costa, 2006). Because of the preponderance of cell bodies in the distal areas of the gut, they are likely involved with coordinating the activity of proximal regions of the gut by activating sympathetic neurons in prevertebral ganglia that are evenly distributed within the gut wall. Prevertebral ganglia (PVGs) neurons do not form circuits that control stereotypic patterns of motor activity. It appears that the axons of these neurons modify the programs established in enteric circuitry by inhibiting the firing of excitatory myenteric motor neurons and preventing the release of inhibitory neurotransmitters from secretomotor neurons. Based on the termination of their projection fibers, PVGs are arranged organotropically such that the cranial PVGs innervate the more proximal region of the gut and distal regions of the gut are innervated by the more caudal PVGs. The celiac ganglion innervates mainly the stomach and small intestine; the superior mesenteric ganglion, the small intestine; the inferior mesenteric ganglion, the colon; and the pelvic ganglion, the distal colon and rectum (Szurszewski & Miller, 2006). Animal studies of the prevertebral celiac ganglion show that three populations of noradrenergic neurons innervate the gut. One population, which is also immunoreactive for neuropeptide Y, functions as a vasoconstrictor and projects to the spleen, mesenteric blood vessels, and arterioles in the gut wall. A second population, which is immunoreactive for somatostatin, inhibits secretomotor neurons. This population terminates in the submucosal ganglia of the small intestine, cecum, and proximal colon. The third population inhibits motility and projects to the myenteric ganglia. Intestinofugal sensory neurons project to the two populations of postganglionic neurons that inhibit secretion and inhibit motility but not to the vasomotor neurons (Furness, 2003). Activation of postganglionic sympathetic fibers that course back to the myenteric plexus results in reflex sympathetic inhibition on regions of the GI wall. Studies of the colon indicate that this enteroenteric reflex is initiated by the activation of intestinofugal neurons by distension of the intestine. It appears that these neurons can be stimulated directly by the distension and by local neurons that synapse with them. Acidic chyme in the small intestine also activates an enteroenteric reflex, resulting in inhibition of gastric motility. Based on numerous experimental data, the reflex response produced by the sympathetic efferent fibers is thought to inhibit the motility of a more proximal (orally directed) region of the GI tract relative to the location of the initial stimulus. Therefore it appears that the enteroenteric reflex, via prevertebral ganglia, regulates the movement of luminal contents from a proximal to a distal direction (Furness, 2003).

The functional relationship between the intestinofugal fibers and the sympathetic system becomes somewhat more complex when it is noted that all prevertebral ganglia neurons receive additional input. This input is from the CNS via preganglionic sympathetic fibers within splanchnic nerves, from collateral branches of spinal afferent fibers that are conveying information to the spinal cord (see Fig. 10-20), and, as seen from studies in rat celiac ganglia, from the dorsal motor nucleus of the vagus (Szurszewski & Miller, 2006). Therefore the prevertebral ganglia may serve a variety of functions related to GI activity. Unlike the paravertebral (sympathetic chain) ganglia, which receive input only from intermediolateral cell column preganglionic fibers, the prevertebral sympathetic ganglia receive input from the IML cell column as well as convergent input from enteric neurons and collateral branches of spinal afferent fibers and, in the case of some neurons, fibers from the dorsal motor nucleus of the vagus. The input from preganglionic fibers to the postganglionic neurons in the prevertebral ganglia is divergent, which allows for spatial and synaptic amplification of the incoming signals. Although there is variation among different ganglia and among species, in general the ratio is 1:200. Sympathetic fibers controlling the vasculature may use these ganglia simply as a relay station in which preganglionic fibers cause the firing of postganglionic vasomotor fibers. However, and more importantly, the ganglia also may serve as an integrative center for collecting CNS input from preganglionic fibers, as well as peripheral input from sensory neurons in the GI wall. Neither of these inputs alone is capable of causing the postganglionic neurons to reach their firing threshold; therefore the continual activity of sensory neurons from the gut, in essence, determines the firing threshold of the postganglionic neurons. As long as this activity is at a high enough level, the spatial summation of these afferent fibers, together with the input from preganglionic sympathetic fibers, allows CNS information to reach the effectors. The necessity of summation to allow for proper GI function demonstrates the importance of sensory input to the prevertebral sympathetic ganglia. This input provides a means by which the prevertebral ganglia can regulate and adjust (modulate) incoming information from the CNS that is destined for the GI tract (Jänig, 1988).

Perhaps of equal importance is that the prevertebral ganglia are thought to be involved in the circuitry that protects the GI tract from potential or real injury. Spinal afferents, the cell bodies of which are located in dorsal root ganglia, have been shown to transmit information from mechanoreceptors and receptors sensitive to molecules such as bradykinin and hydrogen chloride. As they course to the spinal cord, these afferent fibers send collateral branches into the prevertebral ganglia. This input to the prevertebral ganglia, which is only approximately 10% of all of the synapses at this location (Furness, 2003), and to the spinal cord provides the sensory limb for viscerovisceral, viscerosympathetic, and viscerosomatic reflexes (discussed later in this chapter), as well as for visceral sensation. The collateral branches synapsing in the ganglia are thought to cause a lowering of the firing threshold of the postganglionic fibers. This would allow spatial summation of the sensory afferent fibers and preganglionic fibers to occur more readily, thereby facilitating, for example, the motor limb of the intestino-intestinal reflex (Jänig, 1988). PVGs consist of populations of neurons that are different from each other based on characteristics such as their morphology, chemical coding, and type of neurotransmission. They function as coordinating and distributing centers. Because PVG visceromotor neurons exhibit the properties of plurichemical transmission, convergence, modulation, weak synaptic input, and possession of a variety of receptors and numerous ionic channels, they are able to function as integrating centers (Szurszewski & Miller, 2006). PVGs act as an interface for the ENS and CNS and help regulate and control GI functions.

In the somatic motor system, the final neuronal pathway to skeletal muscle is provided by alpha and gamma motor neurons. In the ANS, the final neuronal pathway that modulates the activity of ENS neurons is provided by parasympathetic and sympathetic fibers. Parasympathetic fibers are preganglionic fibers and are predominantly cholinergic. They arise from the dorsal motor nucleus of the vagus and the sacral spinal cord segments S2-4. A few have been shown to innervate EE cells but the majority terminate primarily in the myenteric ganglia. The terminal endings have varicosities and course throughout the ganglia, giving off collateral branches that contact many enteric neurons. The proximal and distal parts of the GI tract receive the vast majority of the parasympathetic fibers. Parasympathetic fibers coursing in the vagus are excitatory to enteric neurons, and activation of those to the stomach results in both excitatory (increased secretion and motility in the distal stomach) and inhibitory effects (relaxation of the upper stomach), the latter via inhibitory neurons. The rectum and distal colon are strongly activated by parasympathetic fibers coursing in pelvic nerves and their branches. In general, parasympathetic efferent fibers are excitatory and modulate the ongoing activity of neuronal circuits involved with local reflex responses and increase their effectiveness. Because they comprise a small number of vagal fibers, they do not affect individual motor neurons but instead they allow the CNS to control the activation of blocks of integrated microcircuits in the gut wall. In addition, they provide a powerful input to the motility patterns resulting in defecation and emesis (Brookes & Costa, 2006). Sympathetic postganglionic fibers provide the major extrinsic input into the gut wall. In general, they have an inhibitory influence on enteric networks controlling motility, they play a minor role in the relaxation of non–sphincter musculature, and they cause contraction of the sphincters through direct innervation. Sympathetic activity is involved in maintaining homeostasis by its control of the cardiovascular system and the body’s water and electrolyte balance. Fibers directly innervate blood vessels and activation of the fibers causes vasoconstriction of vessels, thereby shunting blood from the viscera to deprived vascular beds in tissues. Sympathetic fibers also reduce the secretion of water and electrolytes by inhibiting secretomotor neurons (Brookes & Costa, 2006; Furness, 2008). They arise from prevertebral ganglia and terminate as varicose endings densely covering all neuron cell bodies in both the myenteric and submucosal ganglia. Based on their chemical coding characteristics, it appears that different effectors (i.e., myenteric and submucosal plexus neurons and blood vessels) are innervated by different populations of sympathetic fibers, implying that these effectors and thus the functions of motility, blood flow, and secretion can be regulated separately. The primary neurotransmitter released in the enteric ganglia is norepinephrine (NE, noradrenaline). Binding of NE to α₂ receptors expressed on enteric neurons causes presynaptic inhibition of neurotransmitter release. This may be a mechanism for suppressing reflex pathways and for quieting spontaneous activity created within enteric neuronal networks and from parasympathetic input. NE binding to the α₂ receptor expressed on submucosal secretomotor neurons containing VIP results in direct, postsynaptic inhibition. NE may have an excitatory effect on enteric neurons by binding to α₁ receptors (Brookes & Costa, 2006).

In summary, the enteric nervous system consists of neurons that form integrative circuits within the gut wall that are organized to function independently of the CNS—somewhat like a “local minibrain” or “brain-in-the-gut.” These circuits are arranged into microcircuits that appear to be programs that can control specific functions for the muscular wall, the glands, and the blood vessels to act independently of one another for local homeostatic adjustments. These microcircuits can also coordinate and control these effectors so that the entire organ functions as an integrated unit (Wood, 2004; Wood, 2009). The output of the enteric circuits is based upon the sensory information it receives. In general, the input concerns the current status of the effector such as the tone of the muscular wall, the contents of the lumen, or the presence of changes in the environment of the lumen (such as osmolarity or pH). The sensory fibers include the IPANs (initiate tone-dependent peristaltic contractions), interneurons (initiate tone-independent stretch-activated reflex contractions), vagal afferents (allow the gut to respond to tension), viscerofugal/intestinofugal neurons (allow the gut to fill), and spinal afferents (signal nociceptive information) (Szurszewski & Miller, 2006). Although the ENS functions autonomously, the CNS is not totally “blind” to the activity of the gut and receives sensory information through vagal afferents (primarily) and spinal afferents. It provides input to the ENS for integrative functions via the sympathetic preganglionic/postganglionic fibers and parasympathetic efferent fibers. These fibers modify programmed circuits and coordinate ENS activity in different regions of the gut, resulting in the activation of effectors controlling motility patterns, secretion, and blood flow. In general, parasympathetic input to the ENS results in the stimulation of gut motility and secretion and also the relaxation of the GI sphincters. Sympathetic input in general results in the inhibition of GI motility and secretion and also the constriction of the sphincters. To maintain gut homeostasis, local neural circuits and CNS structures establish a hierarchy of gut reflexes and loops (Mayer, 2011) (Fig. 10-22). Many local responses to stretch or chemical stimuli that cause peristalsis and secretomotor activity may utilize enteric circuits confined to the gut wall. Vago-vagal reflexes (e.g., gastric reflexes) use the nucleus tractus solitarius (NTS) and dorsal motor nucleus and reflexes involving coordinating distinct regions of the gut (intestino-intestinal) use prevertebral ganglia. Responses to nociceptive input involve spinal and supraspinal reflex loops, which may elicit strong autonomic and emotional behaviors such as motivation and affect. Integration of visceral and somatic input occurs in the brain stem and is further integrated with external environmental stimuli and behavioral control regions in cortical areas. In cortical regions such as the insula and cingulate cortex, the input is processed, leading to complex gut-related homeostatic states with affective and motivational aspects such as nausea, pain, hunger, and the feeling of ‘well-being’. Through top-down modulation the supraspinal areas allow for optimal homeostatic regulation of GI function by activating autonomic efferent fibers, the neuroendocrine system, and pain modulatory pathways (see section Control of Autonomic Afferents: Central Autonomic Network). Research has already produced much data that describe the enteric neuronal population and its interactions with other neuronal populations. However, future studies will further elucidate details on this extensive population of neurons and its complex interactions with prevertebral ganglia and CNS neurons (i.e., spinal cord, medulla of the brain stem, and higher centers) in normal physiologic states and in the realm of GI pathologies.

Innervation of Peripheral Effectors

Innervation of the Heart and Lungs

Innervation to the Head

In general, preganglionic sympathetic cell bodies for the head (and neck) are located in the T1 (primarily) to T3 (and some in T4 and T5) spinal cord segments. These fibers enter the sympathetic chain and ascend to the superior cervical ganglion, where they synapse. Postganglionic fibers leave the ganglion and travel with branches of the carotid arteries to gain access to autonomic effectors in the head (see Fig. 10-9, A). One large branch (the internal carotid nerve) leaves the ganglion and branches to form the internal carotid plexus, which travels on the internal carotid artery into the cranial cavity. Some fibers (vasoconstrictors) of the plexus continue to the cerebral arteries, where they meet additional sympathetic fibers of the vertebral plexus. Other fibers leave the artery and travel to their destination by “hitching a ride” on cranial nerves in the region.

The perivascular plexus surrounding the external carotid artery and its branches contains fibers that are vasomotor, pilomotor, and secretomotor to all sweat glands of the face except the sweat glands in the medial part of the forehead. These are supplied by branches of the internal carotid plexus (Watson & Vijayan, 1995; Salvesen, 2001).

Although sympathetic efferents employ arterial transportation, parasympathetic fibers to the head emerge from the brain stem as a part of the oculomotor, facial, and glossopharyngeal nerves. These nerves innervate glandular tissue and smooth muscle.

There is dual innervation to the lacrimal, mucosal, and salivary glands. In general, parasympathetic fibers are secretomotor and sympathetic fibers are vasoconstrictive although they modulate lacrimal glandular secretion (Standring et al., 2008) and salivary gland function (see below). Parasympathetic fibers that innervate the lacrimal gland, nasal and palate mucosal glands, and major salivary glands (sublingual and submandibular) travel with the facial nerve. Preganglionic neurons originate in the superior salivatory nucleus located in the brain stem. Those en route to the lacrimal and mucosal glands synapse in the pterygopalatine ganglion, and those destined for the salivary glands synapse in the submandibular ganglion. Parasympathetic efferents innervating the parotid salivary gland course in the glossopharyngeal cranial nerve. These preganglionic fibers originate in the inferior salivatory nucleus of the brain stem and course to the otic ganglion. After synapsing, the postganglionic secretomotor fibers travel to the parotid gland (see Figs. 10-15 and 10-16, A). Secretion by salivary glands (parotid, submandibular, and sublingual) is a reflex mediated by autonomic fibers. There is always a resting flow of saliva that serves to protect the oral mucosal surface. During short periods of intense reflex stimulation of taste receptors, olfactory receptors, mechanoreceptors, and nociceptors attributable typically to tasting food and chewing, increased amounts of saliva are produced. Not only will the volume of saliva increase but also the composition of saliva can vary as a result of the mixing of secretions from the three different glands. In addition, the composition of saliva from one gland can change based upon different afferent stimuli. Afferent input to the brain stem leads to activation of salivary nuclei, which appear to have connections with other nuclei. There is evidence of projections to the lateral hypothalamus where feeding, drinking, and body temperature are integrated. Although the exact circuitry is unclear, it appears that there is central modulation of salivary secretion because excitatory and inhibitory modulation of the salivary nuclei may occur (Proctor & Carpenter, 2007). Because there is no peripheral inhibition, interconnections with higher centers and the ability to centrally inhibit salivary nuclei may be the mechanism by which anxiousness produces dry mouth. The parasympathetic and sympathetic innervation of the salivary glands is typical in the sense that parasympathetic fibers are cholinergic and utilize muscarinic receptors and sympathetic fibers are adrenergic and employ the α₁ and β₁ adrenoceptors. However, they do not function in the typical antagonistic fashion but instead interact synergistically. Sympathetic preganglionic neurons originate in the upper thoracic segments, and postganglionic neurons are located in the superior cervical ganglion. Although sympathetic fibers do control glandular blood flow (i.e., vasoconstriction), it does not occur as part of the salivary reflex response. The increase in blood flow during the reflex response occurs in response to parasympathetic stimulation mediated by the release of endothelial factors such as nitric oxide, resulting in vasodilation. Parasympathetic secretomotor activity is predominant and stimulates most of the salivary fluid secretion, most of the mucin secretion, and a variable amount of cellular exocytosis (protein secretion). Sympathetic activity does not result in the inhibition of salivary secretion, but instead it has a synergistic effect on the same cells innervated by parasympathetic fibers. It modifies the molecular composition of saliva by increasing cellular exocytosis, and like the parasympathetic fibers it also induces the contraction of myoepithelial cells (Proctor & Carpenter, 2007).

The ANS is also intimately involved with the innervation of effectors located in the region of the orbit. These include the smooth muscle (Müller’s muscle or superior tarsal muscle) of the eyelids, blood vessels of the eye, and the smooth muscle of the iris and ciliary body. This innervation is responsible for some of the functions that can be assessed during a neurologic examination. Regulation of blood flow to the eye is extremely important in maintaining an adequate nutrient supply to the retina. Retinal arterioles are autoregulated, but choroidal arterioles are autonomically innervated. Sympathetic activation causes vasoconstriction, whereas parasympathetic stimulation, via the facial nerve, is vasodilatory (Loewy, 1990b).

The upper eyelid contains skeletal muscle (levator palpebrae superioris), which is innervated by somatic efferents of the oculomotor nerve. It (and the lower eyelid to a lesser extent) also contains smooth muscle fibers (Müller’s muscle or superior tarsal muscle). The smooth muscle is innervated by sympathetic fibers. Because ptosis (drooping) of the upper eyelid is an important indicator of damage to the sympathetic nervous system, knowledge of the two innervations is necessary for differentiating a lesion involving the oculomotor nerve from a lesion of the sympathetic system.

Other smooth muscle fibers in this region are the intrinsic muscles of the eye (i.e., the sphincter and dilator pupillae muscles of the iris and the ciliary muscle of the ciliary body). The iris acts as a diaphragm and regulates the amount of light entering the eye. The dilator muscle is innervated by sympathetic postganglionic efferents that have left the internal carotid plexus to travel with the ophthalmic fibers of the trigeminal nerve. The parasympathetic innervation supplies the sphincter muscle fibers and is the motor arc of the pupillary light reflex. The origin of the parasympathetic preganglionic fibers is the Edinger-Westphal nucleus of the midbrain. The fibers emerge from the brain stem, lie superficially in the dorsomedial aspect of the oculomotor nerve, and travel to the ciliary ganglion located in the orbit (see Fig. 10-15). After synapsing, postganglionic fibers innervate the sphincter muscle fibers of the iris. When these fibers are activated to cause pupillary constriction, there is an accompanying inhibition of the innervation to the dilator muscle (Loewy, 1990b). During alert but resting periods, a constant sympathetic tone is sustained through hypothalamic input; parasympathetic drive to the sphincter pupillae muscle is decreased at the same time (Cross, 1993b; Standring et al., 2008).

An additional smooth muscle, the ciliary muscle, also is involved in the normal function of the eye. This muscle controls the tension of the suspensory ligaments attached to the lens. Parasympathetic and some sympathetic fibers (the function of the latter is unclear) innervate the ciliary muscle. Controlling the regulation of the curvature and thus the refractive power of the lens via this muscle is essentially a parasympathetic function. This innervation allows focusing to occur when an object is close to the eye (accommodation). Of the total number of preganglionic fibers leaving the Edinger-Westphal nucleus, 94% travel to the ciliary muscle, whereas the remaining fibers supply the iris (Cross, 1993b). The accommodation-convergence reflex is necessary during near vision to correct for an unfocused image on the fovea (region of the retina associated with the most acute vision). The reflex response (mediated by CN III) results in an increase in lens curvature, pupillary constriction, and convergence of the eyes.

Knowledge of the innervation of the eye is important because pathologic conditions affecting the autonomic innervation can occur and because these eye functions can be tested in a neurologic examination. Pathologic conditions caused by disruption of parasympathetic fibers include the Argyll Robertson pupil (associated with neurosyphilis), internal ophthalmoplegia, light-near dissociation, and Adie’s pupil (Cross, 1993a). Horner’s syndrome is an example of a condition attributed to a lesion in the sympathetic system (see Clinical Applications).

Innervation of the Lower Urinary Tract

The lower urinary tract consists of the bladder, the neck of the bladder (essentially the internal urethral orifice, which is histologically distinct from the smooth muscle of the bladder wall [Standring et al., 2008]), the urethra, and the urethral sphincter. The lower urinary tract is involved with the process of micturition, which is organized into two phases of bladder function—storage and elimination (voiding) of urine. The neural control of the lower urinary tract is somewhat different than the mechanism by which other viscera are autonomously regulated in that it is dependent on CNS control. The process consists of storage and emptying phases controlled by ‘on’ and ‘off’ neural circuits rather than continual tonic control. It also has a volitional component that becomes operational as the nervous system matures (Fowler et al., 2008). Control of lower urinary tract function occurs by a complex integration and coordination of afferent fibers, sympathetic and parasympathetic efferent fibers, somatic efferent fibers (Fig. 10-23), pontine micturition centers, periaqueductal gray, hypothalamic nuclei, and cortical areas (Carpenter & Sutin, 1983; de Groat & Steers, 1990; Abdel-Azim, Sullivan, & Yalla, 1991; Bradley, 1993; Blok & Holstege, 1998; Shefchyk, 2001, 2002; Fowler et al., 2008). Sympathetic preganglionic neurons originate in cord segments T11 or T12 through L2 and synapse in corresponding ganglia and small ganglia in the superior and inferior hypogastric plexuses. Postganglionic adrenergic fibers course in the vesical plexus (anterior fibers of the inferior hypogastric plexus) to the bladder. Some of these fibers inhibit the smooth muscle (detrusor) of the bladder wall through activation of β₃-adrenergic receptors, but many, and possibly the majority, are also vasomotor, suggesting that sympathetic efferents may have no essential role in micturition. Other sympathetic fibers richly supply (especially in the male) and stimulate the smooth muscle in the neck of the bladder (sphincter vesicae) and urethra by activating α₁-adrenergic receptors. In males, the smooth muscle of the neck of the bladder includes an additional distinct bundle of muscle fibers forming a sphincter (preprostatic sphincter). This is not a urinary sphincter and has a minor, if any, role in urinary continence. During the processes of emission and ejaculation, which are under the control of sympathetic fibers, there is a concomitant stimulation of sympathetic fibers to the bladder neck to contract the sphincter and prevent reflux of ejaculate into the bladder. In females the neck of the bladder is profusely supplied by cholinergic fibers and very few adrenergic fibers. Because the bladder neck does not include an anatomic sphincter, the integrity of the bladder neck in females is more likely to be dependent upon the ligaments surrounding it (Snell, 2001; Fowler et al., 2008; Standring et al., 2008).

The parasympathetic innervation is another important autonomic efferent supply to the detrusor muscle of the bladder. The parasympathetic fibers originate in the S2 to S4 spinal cord segments. The neuron cell bodies are located in the sacral autonomic nucleus and are divided into tonic and phasic types. Dendrites course into lamina I and the dorsal gray commissure. The commissure includes interneurons that are thought to be active during micturition and likely influence the parasympathetic neuron cell bodies (Birder et al., 2010). The parasympathetic fibers pass into the cauda equina, emerge from the S2 to S4 pelvic (ventral) sacral foramina, and travel in the pelvic splanchnic nerves (see Figs. 10-17 and 10-23). These nerves travel within the inferior hypogastric plexus and continue distally into the vesical plexus. These preganglionic fibers synapse with postganglionic neurons located in ganglia within the vesical plexus or within the bladder wall. The postganglionic cholinergic fibers provide excitatory innervation to the detrusor muscle. (A few fibers supply and inhibit the sphincter vesicae, which is mediated by the neural release of nitric oxide.) The acetylcholine (ACh) that is released activates the M₃ muscarinic receptors and causes contraction of the detrusor muscle. The parasympathetic presynaptic nerve terminals at the neuromuscular junction express M₁ and M₄ receptors. Depending on the intensity of neural firing, neurotransmission at this site can be modulated such that activation of these M₁ and M₄ receptors can enhance or suppress, respectively, transmitter release. Some fibers also co-release ATP and cause detrusor muscle contraction through ATP’s action on P2X purinergic receptors (Fowler et al., 2008).

Autonomic postganglionic neuron cell bodies that innervate the lower urinary tract (as well as the reproductive tract and lower bowel) are located in pelvic ganglia. Most of the postganglionic cell bodies are found in the ganglia located at the vesico-ureteric junction but other ganglia are located in the bladder wall, the region of the bladder neck, the trigone, the prostate, and the proximal urethra. Excitatory noradrenergic (NA) and cholinergic fibers, and inhibitory noncholinergic and nonadrenergic fibers, synapse in the ganglia. These neurons, found in groups of up to 20 neurons, show an abundance of acetylcholinesterase. Within the ganglia numerous neurotransmitters and neuromodulators have been identified. Also, data indicate that postganglionic sympathetic fibers terminate within the ganglia as well (Standring et al., 2008; Birder et al., 2010).

Another important muscle involved with normal bladder function is the striated (voluntary) urethral sphincter muscle. This muscle does not contain neuromuscular spindles and consists of slow-twitch fibers. This urethral sphincter is important in maintaining urinary continence because the muscle fibers maintain a contracted state for long periods of time and in doing so contribute to the tone that closes the urethra. Somatic motor neurons in Onuf’s nucleus (S1-S2 cord segments) and possibly other neurons in the ventral horn of the S2 to S4 cord segments innervate this muscle.These neurons travel in the perineal branches of the pudendal nerve to reach the skeletal muscle fibers of the sphincter (Standring et al., 2008).

In addition to the sympathetic, parasympathetic, and somatic efferent innervation to the bladder, there are also afferent fibers that course from the bladder, neck of the bladder, and urethra to the spinal cord. Afferent fibers from the neck of the bladder and urethra travel in the pudendal and hypogastric nerves. Input regarding bladder fullness travels in afferent fibers running in the pelvic splanchnic and hypogastric (lumbar splanchnic) nerves. In animal studies, research shows there are four types of mechanosensitive afferents, which are low-threshold A-delta fibers. These are distributed to the serosa, to the urothelial (transitional epithelial) layer, and throughout the muscle layers of the bladder. Lumbar splanchnic nerves (hypogastric) include afferent fibers primarily from the serosa and muscle layers. Pelvic splanchnic nerves include afferent fibers of all four classes that synapse on interneurons in cord segments S2 to S4. The majority of these are from muscle layers signaling passive distension and active contraction and likely are involved in mediating the micturition reflex via the spinobulbospinal pathway. Other afferents include a small population of unmyelinated C fibers that are distributed in the lamina propria and urothelium (transitional epithelium). These fibers contain peptides such as substance P and CGRP and course in the hypogastric nerve. They are high-threshold fibers that respond to distension and are usually insensitive to muscle contraction. Other unmyelinated C fibers are concerned with nociception and temperature sense. These C fibers are silent during normal bladder filling but will respond primarily to noxious stimuli such as cooling or chemical irritation. These afferent fibers course in pelvic nerves. Afferent fibers enter Lissauer’s tract and terminate on spinal neurons, some of which will mediate segmental reflexes. For example, lamina I neurons receive afferent fibers and project to the IML cell column and to brain stem integration nuclei (Drake et al., 2010). Other entering afferent fibers terminate on interneurons in laminae V to VII and X. Some fibers terminate in the vicinity of the sacral autonomic nucleus and in the dorsal gray commissure. The termination of afferent fibers from the bladder and afferent fibers from the urethra and urethral sphincter overlaps in the lateral and basal part of the dorsal horn and dorsal gray commissure. This may be an integration area that coordinates the functions of the bladder and sphincter (Fowler et al., 2008). Axons from some spinal neurons convey information from the bladder to higher centers and course in the dorsal and anterolateral white columns. In disease states such as malignancies, stones, or inflammation, distension and nociception are brought to one’s consciousness. Because nociceptive information ascends in the anterolateral white, bilateral anterolateral cordotomy results in pain relief. Fibers conveying mechanosensitive information regarding distension ascend in the dorsal column and thus the awareness of bladder fullness and need to void is preserved (Standring et al., 2008).

In addition to the afferent fibers coursing from the bladder to the cord, an intrinsic nerve plexus has been shown to exist immediately below the urothelium in the lamina propria. Fibers of the plexus project into the urothelium. The plexus is especially dense in the region of the bladder neck but is sparse in the bladder fundus and inferolateral walls. It is considered to be an essential component for sensory processing by the urothelium. Also, a population of nonneuronal cells has been identified in animal models that has also been implicated in sensory mechanisms. These are cells that comprise the urothelium and are able to respond to chemical and mechanical stimuli. The cells have unique sensory and signaling properties that allow for communication with underlying nerve fibers, myofibroblasts, smooth muscle cells, and inflammatory cells. One of these properties is the expression of numerous receptors and ion channels that are typically found on nociceptive and mechanoreceptive fibers. Examples of these receptors are purinergic, adrenergic, nicotinic, and muscarinic receptors that are known to mediate responses to stimuli such as stretching and to various signaling molecules. Other unique properties are their close proximity to the afferent and efferent fibers and the ability of these cells to release chemicals that can act on neighboring nerve fibers affecting bladder contraction and vascular flow. These attributes allow the cells to have a bidirectional chemical communication with adjacent nerves in the wall of the bladder. Defects in these mechanisms of sensory transduction may contribute to the pathophysiology of bladder diseases (Fowler et al., 2008; Birder et al., 2010).

In addition to the areas in the spinal cord gray matter involved with lower urinary tract function, there are many higher centers also involved in controlling the bladder, urethra, and urethral sphincter. These include the raphe nuclei in the medulla, the locus ceruleus, and the noradrenergic (NA) A5 cell group in the brain stem, which project to the cord and act as nonspecific ‘level-setting’ mechanisms. Other areas involved with the micturition response include the pontine micturition center (PMC; also known as Barrington’s nucleus), periaqueductal gray (PAG), hypothalamic nuclei, amygdala, and regions of the cerebral cortex such as the anterior cingulate gyrus, insula, and prefrontal cortex. These supraspinal areas are interconnected and regulate the bladder and lower urinary tract function by sending projections to the lumbosacral spinal cord via multiple pathways (Fowler et al., 2008).

As mentioned previously, micturition consists of two phases involving the bladder: filling/storage and voiding. The neural circuits involved with this system are organized as ‘on-off’ switching circuits interrelating activity in the bladder with the outlet structures (i.e., neck of the bladder, urethra, and urethral sphincter). In general the spinal cord circuitry is involved with the filling of the bladder whereas the circuitry mediating the voiding process is organized in the higher centers. Afferent information is processed in the spinal cord, establishing a reflex response and activating tract neurons. The tracts include the fasciculus gracilis, spinoreticular, spinothalamic, and spinohypothalamic. The axons ascend in the dorsal column, and the dorsolateral funiculus and lateral funiculus, and give off collateral branches as they terminate in higher centers. One of these areas is the periaqueductal gray (PAG) matter located in the midbrain, which controls the primary input to the pontine micturition center (PMC). The PMC neurons subsequently transmit signals back to the sacral spinal cord. The PMC, which also receives ascending projections from the spinal cord directly, has two components: the medial or ‘M’ center and the lateral or ‘L’ center. The ‘L’ center (pontine storage center) is thought to project to Onuf’s nucleus in the sacral cord and to facilitate the contraction of the external (striated) urethral sphincter. The ‘M’ center projects to the sacral autonomic nucleus to activate parasympathetic neurons and possibly inhibit Onuf’s nucleus. This spinobulbospinal voiding-reflex pathway functions as a switch. It is in the ‘off’ position for filling (storage) and is in the ‘on’ position for voiding. During bladder filling, afferents from stretch receptors project into the cord where interneuronal circuits function as a gating mechanism and reflexively inhibit parasympathetic innervation to the detrusor muscle; also, some sympathetic fibers facilitate bladder filling by causing inhibition of the detrusor muscle whereas many fibers cause contraction of the sphincter vesicae. In addition, through input from the ‘L’ center, somatic motor neurons fire and maintain the external urethral sphincter muscle in a tonically active state. The sum of all of these urethral reflex circuits that promote continence is known as the ‘guarding reflex’. During a critical level of bladder distension, bladder afferent activity reaches a specific threshold, sensory fibers activate ascending pathways to higher centers including the brain stem, and the pathway is switched on. Descending fibers from the ‘M’ pontine micturition center course through the lateral funiculus of the cord and, via interneurons, cause inhibition of somatic motor neurons, resulting in relaxation of the external urethral sphincter followed a few seconds later by excitation of sacral preganglionic parasympathetic neurons, resulting in detrusor muscle contraction (Blok & Holstege, 1998; Shefchyk, 2001, 2002; Fowler et al., 2008). Although the pontine center coordinates the micturition process, it in turn is strictly modulated by the cerebral cortex, allowing for voluntary control. The decision to void is based on numerous factors that include one’s emotional state, input from the bladder, and one’s environment. The PAG has a dominant role in this process, acting as a hub by interconnecting with cortical regions and providing the major input to the PMC. Afferent signals from the bladder terminate in the PAG and from here axons project to the cortex where conscious awareness of the bladder sensation occurs. Additional input may ascend in the fasciculus gracilis and spinothalamic tract. The prefrontal cortex, especially the medial and dorsolateral areas and often more on the right side (Drake et al., 2010), projects back to the PAG to influence its activation of the PMC: during filling the PAG firing is suppressed and voiding is prevented; if voiding is desired, excitation by the PAG is allowed. Other areas of cortex involved with bladder function have also been identified in functional magnetic resonance imaging (fMRI) studies. During bladder filling the PAG not only is activated but also appears to project, possibly via the thalamus, to the insula (especially the right), which is shown to be very active during bladder filling. Visceral sensations including the desire to void are thought to be mapped in the insular cortex. The PAG also interconnects with the anterior cingulate cortex, which likely determines one’s attentiveness to bladder sensation and deciding whether to initiate or delay voiding, and the prefrontal cortex. The prefrontal cortex in turn has connections with the anterior cingulate cortex, the hypothalamus, and other autonomic control centers. It functions as the CEO of the brain, orchestrating complex cognitive behaviors, including those that are socially acceptable, and providing the mechanisms that allow one to be aware of a situation and respond appropriately. It is possible that through its connection with the PAG, the prefrontal cortex has a tonic suppressive effect on voiding that is reduced when voiding is desired (de Groat & Steers, 1990; Bradley, 1993; Blok & Holstege, 1998; Fowler et al., 2008). This descending cortical input not only allows voluntary control of voiding but also allows one to start and stop micturition on demand. The connections between the spinal cord and brain stem forming the spinobulbospinal reflex are instrumental for sustaining detrusor muscle contraction and relaxing the striated sphincter during micturition. In an excellent review, Drake and colleagues (2010) proposed a working model for the control of bladder function by higher centers. Sphincter relaxation and detrusor contraction are under the control of the PMC, which in turn receives input from the hypothalamus and, seemingly more important, the PAG. The PAG acts as an integrative center and modulates the activity of the PMC based on the input it has received from bladder afferents and higher centers. The higher centers that project to the PAG and are most understood include the insula (which maps and processes visceral sensations), the anterior cingulate gyrus (which monitors stress and conflict and initiates the correct autonomic response), and the medial prefrontal cortex (which evaluates information from all of the sensory cortices and makes a decision taking into account the current emotional and social state of the individual). Other areas of the brain that project to the PAG are the basal ganglia and cerebellum.

The functional and clinical relevance of the connections of the prefrontal cortex with the brain stem is exemplified in pathologic conditions that include this region (both cortex and underlying white matter) such as in stroke and normal pressure hydrocephalus (NPH). In NPH, which is often misdiagnosed as Parkinson’s or Alzheimer’s disease, three distinguishing characteristics are recognized: abnormal gait, dementia, and urinary incontinence. Imaging scans show enlarged anterior horns of the lateral ventricles, which are located in the frontal lobe. The frontal lobe is also the site of the descending fibers of the prefrontal cortex (as well as the connections between the basal ganglia and the frontal lobe) (Victor & Ropper, 2001). Studies of other frontal lobe pathologies resulting in urinary dysfunction (Drake et al., 2010) have shown the lesion to be localized anterior to the tips of the ventricles and the genu of the corpus callosum. Patients with acute hemispheric strokes that present with urinary dysfunction commonly show infarcts in the frontal lobe. In these cases, the cognitive abilities of the individual are normal and the act of voiding is normal. However, when the patient is sleeping the result of the lesion is incontinence. When the patient is awake, the loss of higher control causes frequency and extreme urgency of the voiding response. Because of the lesion, the individual is unaware of the sensation of normal gradual bladder filling and the sensation that voiding is about to occur. This often results in embarrassing and humiliating situations.

There is also a synergistic physiologic relationship between the lower urinary tract and other pelvic organs. Studies on animals show that the sensory input from a distended rectum inhibits the efferent arc of the micturition reflex (i.e., voiding response). Data indicate that many neurons in the pontine micturition center have a dual connection with neurons controlling colon and bladder activity whereas only a few center neurons have separate connections. Also, in spinal cord injury patients, low level stimulation of S3 roots by implanted electrodes results in the contraction of the external urethral and anal sphincters and pelvic floor muscles. Stimulation of the S3 roots at high levels results in detrusor muscle contraction and subsequent bladder emptying when the sphincter muscle is relaxed (Birder et al., 2010). Other studies have shown that a small percentage of lumbosacral afferent neurons dually innervate both the colon and the bladder. It is thought that this bidirectional communication may be involved in the enhancement of reflex activity in one when the other is chemically irritated (de Groat, 2006). This mechanism is referred to as cross-organ hypersensitivity (see section on Visceral Afferents).

Innervation of Reproductive Organs

The innervation of the reproductive organs, which is similar to that of the bladder, consists of sympathetic, parasympathetic, and somatic fibers (de Groat & Steers, 1990; Seftel, Oates, & Krane, 1991; Stewart, 1993). This section is primarily concerned with the innervation of male reproductive organs, although innervation to homologous female organs is somewhat similar.

The sympathetic preganglionic fibers originate from approximately the T10 to L2 cord segments (Fig. 10-24). The route of these fibers varies. Some preganglionic fibers synapse with postganglionic neurons in the sympathetic chain. The axons of these postganglionic neurons enter into the hypogastric nerves and continue into the inferior hypogastric (pelvic) plexus. Other preganglionic fibers travel in the superior hypogastric plexus and synapse in ganglia scattered in the inferior hypogastric plexus (Seftel, Oates, & Krane, 1991). In both cases the postganglionic fibers coursing within the inferior hypogastric plexus continue distally into the prostatic plexus. These fibers then leave the plexus as the cavernous nerve and innervate erectile tissue of the penis and smooth muscle in the seminal vesicles, prostate gland, vas deferens, and the nonstriated sphincter in the bladder neck. Parasympathetic preganglionic fibers originate from S2 to S4 and course in the pelvic splanchnic nerves (see Fig. 10-24). The pelvic splanchnic nerves synapse in ganglia in the inferior hypogastric (pelvic) plexus. Postganglionic fibers, in conjunction with postganglionic sympathetic fibers, continue to (and are the primary innervation of) erectile tissue, as well as glandular tissue in the seminal vesicles, prostate gland, and urethra.

The somatic nervous system is also involved with sexual function. The pudendal nerve contains sensory fibers that course from the penis to sacral cord segments. It also contains motor fibers that travel from the spinal cord to the bulbocavernosus and ischiocavernosus skeletal muscles. These motor neurons originate in the ventral horn of the S2 to S4 cord segments.

The erection phase of sexual function can be initiated by stimuli such as visual, auditory, imaginative, and tactile. Evidence from spinal cord–injured patients indicates that there are two types of erection reflexes: psychogenic and reflexogenic. In healthy individuals, both types of reflexes probably act synergistically. Reflexogenic erections are sacral spinal reflexes consisting of afferent fibers in the pudendal nerve activating sacral parasympathetic efferent fibers (a small number of afferent fibers ascend in the dorsal columns to higher centers). Psychogenic erections begin in supraspinal centers, including the limbic system and the hypothalamus. The hypothalamus has been implicated as the integration center for the erection response (de Groat & Steers, 1990; Stewart, 1993).

Fibers from these supraspinal centers descend through the brain stem and the lateral white column (funiculus) of the spinal cord to synapse on lower thoracic and lumbar preganglionic sympathetic neurons and the sacral preganglionic parasympathetic neurons. The parasympathetic fibers initiate the erectile response by causing dilation of the arteries within the erectile tissue. However, the sympathetic fibers contribute to this reflex because they also can initiate a psychogenic erection (possibly through the use of different neurotransmitters) when the parasympathetic preganglionic neurons are lesioned (de Groat & Steers, 1990; Seftel, Oates, & Krane, 1991).

Emission and ejaculation are also a part of sexual function. Cortical modulation occurs, but the mechanism is complex and unclear. Emission is sympathetically controlled by neurons originating in the T10 to L2 or L3 cord segments (see previous discussion for the route of these sympathetic preganglionic and postganglionic fibers). This event includes the smooth muscle contraction of the vas deferens, seminal vesicles, prostate gland, and nonstriated sphincter vesicae (to prevent reflux of semen into the bladder during ejaculation), resulting in the deposition of semen into the prostatic urethra. The process of ejaculation consists of propelling the semen from the prostatic urethra through the membranous and penile parts of the urethra and out the urethral orifice. The bulbocavernosus and ischiocavernosus skeletal muscles, which are innervated by the pudendal nerve, contract during this event. The coordination of emission and ejaculation probably occurs by the integration of sensory afferent fibers, descending supraspinal input, and motor efferents in an ejaculation center located in the T12 to L2 cord segments (Seftel, Oates, & Krane, 1991).

Exercise

Other than the muscular system, the major systems involved in exercise are the cardiovascular and respiratory systems. During exercise, the active skeletal muscles have a tremendous increase in their demand for oxygen, which arrives by way of the bloodstream. During rest, metabolic demand is low and therefore some capillaries in muscle tissue have little blood flow in them. When exercise begins, all capillaries are opened and the demand for blood flow increases. A decrease in available oxygen in the muscle tissue causes local vasodilation in the arterioles attributable to increased flaccidity in the arteriolar wall and the release of vasodilator substances. Chemical vasodilators released locally from cells to allow increased perfusion through the muscle include bradykinin, adenosine, potassium, carbon dioxide, lactate, and ATP. In addition, nitric oxide released from endothelial cells in response to the increased shear stress resulting from the increased flow also contributes to the vasodilation. While the higher centers of the CNS initiate contraction of the skeletal muscles, they also activate the vasomotor center in the brain stem. This area initiates a mass sympathetic discharge (and inhibits parasympathetic innervation to the heart) that affects other parts of the body. This leads to an escalation in heart rate and contractile force via cardiac nerves; vasoconstriction of peripheral arterioles located in the noncontracting muscles and nonparticipating tissues (coronary arteries and cerebral arteries are exempt), thus redirecting blood to the active muscles; and vasoconstriction of the veins, which increases venous return to the heart. Vasoconstriction occurs both directly through sympathetic innervation to the blood vessels and indirectly through sympathetic innervation of the medulla of the adrenal gland by the greater splanchnic nerve. The adrenal medulla releases norepinephrine, which causes vasoconstriction, and epinephrine, which increases cardiac output. The extensive increase in sympathetic stimulation to the heart and blood vessels raises cardiac output, supports arterial blood pressure, and provides significantly increased blood flow to the working muscles. In addition to these adaptive changes to provide increased oxygen and nutrient supply to the working muscles, there must also be increased blood flow directed to peripheral subcutaneous regions as part of the thermoregulatory response to shed the additional heat being generated by the working muscles. Temperature-regulating centers in the hypothalamus are activated to inhibit sympathetic fibers directed to peripheral subcutaneous vessels to cause vasodilation and allow increased blood flow to these regions for the purpose of heat dissipation. In addition, the thermoregulatory response will stimulate sympathetic cholinergic fibers that innervate sweat glands to activate heat dissipation by evaporation of the sweat from the skin surface.

The respiratory system functions to deliver and remove the oxygen and the carbon dioxide, respectively, to the bloodstream that flows through the lungs. As higher centers signal the start of muscle contraction and activate the vasomotor center, the brain stem respiratory center also receives excitatory input, which results in the increase in ventilation experienced during exercise. In fact, it appears that a large percentage of the total ventilatory increase occurs immediately at the initiation of exercise, indicating that the brain is able to anticipate the subsequent increase in oxygen consumption and carbon dioxide generation. Respiratory center neurons inhibit parasympathetic neurons and activate sympathetic neurons. The effects of sympathetic fibers that directly innervate bronchiolar muscle tissue are minimal. It is the innervation to the adrenal medulla and subsequent release of epinephrine and norepinephrine into the blood that is more effective. The result is dilation of the bronchial tree primarily through the effect of epinephrine, which has a greater stimulatory effect through its binding to bronchial β-adrenergic receptors.

Stress Response

In order to survive and maintain the well-being of the individual, physiologic responses are required to maintain homeostasis while the body is challenged by various stressors. In general, stress can be defined as “an actual or anticipated disruption of homeostasis or an anticipated threat to well-being” (Ulrich-Lai & Herman, 2009). Combating stress requires activation of the neuroendocrine system and the ANS. Some forms of stress (called eustress) are helpful in preparing the body to meet challenges whereas other forms of stress (called distress) can be damaging. An increase in body temperature is an example of a stressor, and through the control of just a limited number of effector tissues (i.e., sweat glands and smooth muscle in the cutaneous blood vessels), sympathetic nerves can restore the normal body temperature. In cases of distress where the challenge is chronic or extreme, resulting from severe and uncontrollable situations of physical and emotional stress, normal homeostatic mechanisms are insufficient. These situations can result in a sequence of changes to maintain the physiologic integrity of the body. This is sometimes referred to as the adaptive stress response or the general adaptation syndrome (Tortora & Derrickson, 2009). The ANS provides the most immediate response to stress. It is initiated by inputs into the brain indicating homeostatic disturbances. In some cases such as blood loss, infection, or pain, the immediate response is reflexive through connections in the rostral ventrolateral medulla of the brain stem and the intermediolateral cell column of the spinal cord. In other cases, the stressor may be psychogenic or nonphysical. In this case, the input is processed in areas of the limbic forebrain, which includes the amygdala, hippocampus, and medial prefrontal cortex. These areas have received input from other regions of the brain that are involved in higher-order sensory processing, attention and arousal, and memory. From here, most connections are made with various hypothalamic nuclei for integration and necessary modulation based on the current physiologic status of the individual. Output is relayed to the paraventricular nucleus (PVN) of the hypothalamus, which has been suggested as being the principal integrator of stress signals (Ulrich-Lai & Herman, 2009). This nucleus sends signals to various nuclei in the brain stem and to the spinal cord. The involvement of the sympathetic neurons results in a simultaneous mass discharge of sympathetic output to widespread areas of the body by utilizing both postganglionic peripheral fibers and preganglionic fibers that innervate the medulla of the adrenal glands (the sympathoadrenomedullary connection), causing the release of epinephrine and norepinephrine into the blood. The immediate goal of the activation of the sympathetic system is to ensure that there are increased amounts of glucose and oxygen transported to essential tissues for the necessary increased rates of cellular metabolism for immediate action (increase in muscle strength and increased mental activity). To achieve this, the innervation of numerous tissues and organs is modulated and their functions coordinated. This response demonstrates the widespread connections of the sympathetic nervous system throughout the body. Some of the more obvious organs and tissues that are involved include the heart (increase in heart rate and force of contraction), peripheral blood vessels in nonessential tissues (redistribution in blood flow), lungs (vasodilation and bronchial dilation), liver (glycogenolysis), and kidneys (reduced renal blood flow resulting in the release of renin). At the same time that sympathetic neurons are activated, parasympathetic neuronal activation is modulated. CNS areas such as the PVN and the prelimbic cortex influence the parasympathetic neurons in the nucleus ambiguus and dorsal motor nucleus of the vagus directly or possibly through connections with the nucleus tractus solitarius (NTS). This connection alters vagal tone to the heart and lungs and helps to limit the duration of the response (Ulrich-Lai & Herman, 2009). In addition to the activation of the ANS for an immediate response, the neuroendocrine system is employed through the hypothalamic-pituitary-adrenal (HPA) axis. The brain stem and circumventricular areas also provide input into the PVN as well as the limbic forebrain structures mentioned previously. The PVN secretes releasing hormones such as corticotropin-releasing hormone (CRH), which acts on the anterior pituitary gland. It also synthesizes arginine vasopressin, which is released in the posterior pituitary. These hormones stimulate the release of adrenocorticotropic hormone (ACTH), which acts on the adrenal cortex to initiate the synthesis and release of glucocorticoids (e.g., cortisol) into the blood. Glucocorticoids quickly mobilize stored amino acids and fats so they are available for synthesizing other necessary molecules such as glucose, and in general protect against acute hypoglycemia. If these neuroendocrine responses are insufficient to maintain homeostasis, the body’s organ systems may incur pathologic changes. Research indicates that the brain’s continual effort of attempting to combat chronic stress can result in plastic changes in areas such as the amygdala, hippocampus, medial prefrontal cortex, and PVN. These include changes in dendritic morphology, changes in glucocorticoid receptor expression, increased corticotropin-releasing hormone expression and release, and increased stress excitability. Studies suggest that the excitability of the HPA axis and the sympathoadrenomedullary pathway seems to be enhanced by chronic stress (McEwen, 2007; Ulrich-Lai & Herman, 2009). In addition, it appears that the activation of neural pathways from the brain attributable to psychological stress and negative life experiences may cause degranulation of mast cells in the gut and exacerbate symptoms in patients with gut disorders such as IBS and colitis. Mast cell degranulation results in the activation of the same enteric defense program of the gut that normally is activated when there is a threatening circumstance within the intestinal lumen, such as the presence of dietary antigens, bacteria, toxins, parasites, and viruses. The defense program (i.e., coordinated mucosal secretion and power propulsion) is manifested clinically by the symptoms of abdominal pain, fecal urgency, and diarrhea, which are present in GI disorders such as IBS (Wood, 2007).

General Considerations

Although the ANS is considered by some to consist primarily of an efferent limb, visceral afferent fibers have an important relationship with the efferent fibers. Visceral afferent fibers, which since 1894 have been known to accompany autonomic efferents (Cervero & Foreman, 1990), provide information about changes in the body’s internal environment. This input becomes integrated in the CNS and may participate in reflexes via autonomic and somatic efferents. These reflexes, such as the regulation of blood pressure and the chemical composition of the blood, aid the ANS in the control of homeostasis. However, visceral afferent fibers also mediate some conscious feelings, such as the visceral sensations of hunger, nausea, and distension. Although receptors of visceral afferent fibers do not respond to stimuli such as cutting or burning (as cutaneous receptors do), a pathologic condition or excessive distension produces visceral nociception. The continual barrage of impulses via visceral afferent fibers on the CNS is a probable cause of an individual’s feeling of well-being or of discomfort.

Visceral afferent fibers convey information from peripheral receptors called interoceptors. These endings, which may be encapsulated or free nerve endings, are found in the walls of the viscera, glands, adventitia of blood vessels, epithelium, mesentery, and serosae. Some are polymodal nociceptors, which are predominantly free nerve endings of unmyelinated fibers. They are located throughout the GI and respiratory tracts and respond to various stimuli such as noxious chemicals or damaging mechanical stimuli (Standring et al., 2008). Others are described as mechanoreceptors and include numerous pacinian corpuscles. These are located in the abdominal mesenteries. Additional mechanoreceptors are found in the serosal covering of the viscera and also in the blood vessels, and they may be stimulated by movement or distension. Still others, found in smooth muscle layers such as that of the bladder and gut, monitor both contraction and distension. In addition, chemoreceptors and baroreceptors are special interoceptors that are located specifically in the aortic arch and the bifurcation of the left and right common carotid arteries.

Receptors of somatic afferent fibers show a clear distinction between those detecting noxious stimuli and those that detect innocuous stimuli. This distinction is not as clear regarding visceral afferent receptors. For example, GI and pelvic spinal afferents, which are mechanosensitive, express receptors that function in visceral nociception. Also, unlike somatic receptors, those expressed on visceral sensory neurons may respond to more than one stimulus—for example, GI mucosal afferents respond to both light brushing and chemical irritants and muscle afferents in the wall of the gut respond to distension but may also fire in response to chemical stimuli (Christianson et al., 2009). The visceral afferent fibers (excluding the enteric nervous system afferent fibers that have already been discussed) travel with the autonomic efferents of both the sympathetic and parasympathetic divisions. (To be clear, the terms sympathetic and parasympathetic refer only to efferent fibers.) The vast majority are unmyelinated, with the exception of those from the pacinian corpuscles located in the mesentery (see previous discussion). There are numerous receptors expressed on visceral afferent fibers that are involved with nociception, including the adenosine and 5-HT₃ receptors. Another is the P2X receptor to which ATP binds. ATP is a mediator released from epithelial cells in response to cell injury and plays a role in nociception and inflammation. The P2X receptors have been identified on vagal C afferent fibers innervating the lung and esophagus and spinal afferent fibers in the bladder and colon. The transient receptor potential (TRP) family of transmembrane cation-permeable channels has also been identified on visceral afferents. Members of this group of receptors have been implicated in being involved in visceral nociception and inflammation and may also play a role in the development of hypersensitivity (Christianson et al., 2009). Although many of these afferent fibers are purely sensory, some fibers also have an efferent function. These fibers, sometimes called sensory-motor nerves, have the ability to release neurotransmitters such as substance P, CGRP, and ATP from their peripheral endings during the axon reflex. The release of these chemicals results in neurogenic inflammation, which includes vasodilation, increased vascular permeability, altered smooth muscle contractility, and functional changes in cells typically involved with the inflammatory response, such as degranulation of mast cells. This event appears to be a widespread phenomenon that occurs in autonomic tissues within the cardiovascular, respiratory, and GI systems (Standring et al., 2008). The cell bodies of visceral afferent fibers that travel within the glossopharyngeal (CN IX) and vagus (CN X) nerves are located in the inferior (petrosal) ganglion of CN IX and the superior (jugular) (Christianson et al., 2009) and inferior (nodose) ganglia of CN X. The dorsal root ganglia of the second, third, and fourth sacral roots house visceral afferent cell bodies of fibers that travel with pelvic parasympathetic efferents in pelvic splanchnic nerves. These are referred to as pelvic afferent fibers. Cell bodies of afferent fibers associated with sympathetic fibers are located in the dorsal root ganglia of the thoracic and upper lumbar dorsal roots. These fibers course from the periphery along with sympathetic efferent fibers in the splanchnic nerves, pass through the prevertebral ganglia without synapsing, and enter the sympathetic trunk (Fig. 10-25). Then they pass through the white rami communicantes into the dorsal root and terminate in the cord segment from which the accompanying preganglionic efferent fibers originate. These afferent fibers are referred to as spinal afferent fibers. Some general characteristics of somatic afferent fibers apply to visceral afferent fibers. Both course with efferent fibers, the cell bodies are located in sensory ganglia, and there is only one sensory fiber that extends from the receptor into the CNS. One unique feature relative to the sensory innervation of the viscera is that for each organ the origin of the sensory input is from two well-defined sources and each has a different role in sensory processing. The thoracic and abdominal viscera are supplied both by fibers of cell bodies located in the dorsal root ganglia (spinal afferents), which appear to be involved with acute nociceptive function, and by fibers of cell bodies located in the ganglia of the vagus (predominantly) and glossopharyngeal nerves. The fibers within these cranial nerves function more often in the realm of normal physiologic states and in the related sensations of well-being. The pelvic viscera are supplied by fibers of cell bodies located in the dorsal root ganglia of sacral cord segments (pelvic afferents) and thoracolumbar cord segments. These appear to function in sensitizing processes such as the postinflammatory state but not in the initial process of nociception (Christianson et al., 2009).

Electron microscopic and retrograde tracing methods show that a low density of fibers innervates the viscera in comparison to the innervation of the skin. Feline studies demonstrate that approximately 16,000 spinal afferent fibers exist, and 6000 to 7000 of these are found in the greater splanchnic nerves (Cervero & Foreman, 1990). However, the total number of afferent fibers represents less than 20% of all fibers in these nerves and approximately 2% of the fibers located in dorsal roots of thoracic and lumber spinal nerves. An obvious disparity is noticed when the vagal and pelvic afferent fibers are enumerated. Feline visceral afferent fibers in the vagus nerve number approximately 40,000 and pelvic afferent fibers approximately 7500. Of the total number of fibers in the vagus, 80% are afferent. In the pelvic nerves 50% of the fibers are afferent (Cervero & Foreman, 1990). In general, concerning the two groups of mixed nerves (i.e., the vagus and splanchnic nerves), the vagus nerve consists predominantly of afferent fibers and the splanchnic nerves consist predominantly of efferent fibers. The specific functional differences between these two major groups of afferent fibers are not clear. The vagal, primarily, and pelvic afferent fibers generally are thought to transmit input concerning physiologic activity of the viscera, such as GI motility and secretion. By monitoring the activity, these afferent fibers are able to mediate reflexes necessary for the proper regulation of visceral function. The spinal afferent fibers appear to be concerned with sensations arising from the viscera, especially the sensation of pain (Cervero & Foreman, 1990). However, Kollarik and colleagues (2010) have introduced the concept that there is a subset of vagal afferent fibers referred to as “putative vagal nociceptors” that convey nociception. These have characteristics similar to nociceptors in somatic tissues. Although it is possible that these vagal afferent fibers are yet to be identified in other viscera, two regions that do show evidence of these are the lungs and the esophagus. In the lungs, putative vagal nociceptors are bronchopulmonary C fibers. These comprise the majority (75%) of the lung afferent fibers and innervate all components of the lungs. They are inactive in healthy lungs and are activated by exogenous noxious factors such as cigarette smoke, environmental pollutants, ozone, and particulate matter, and by endogenous inflammatory mediators. When activated, reflexes such as coughing, tachypnea, and mucus secretion are induced in order to remove or limit the effects of the noxious stimulus. Both peripheral (induced by inflammatory mediators such as prostaglandin E₂) and central sensitization have been described. Although tension mechanosensors comprise a large number of receptors in the esophagus, there exists another population of distension-sensitive afferent fibers that can be characterized as putative vagal nociceptor fibers. These fibers have a different response pattern to distension and express membrane receptors that respond directly to noxious chemicals, are peripherally sensitized by inflammatory mediators, and are likely to be sensitized at the central level. The vast majority have a conduction rate that corresponds to C fiber conduction speeds.

Vagus, Glossopharyngeal, and Pelvic Afferent Fibers

Afferent fibers coursing in the vagus nerve relay input from many sources (Standring et al., 2008). A partial list includes the following:

The glossopharyngeal nerve conveys visceral afferent information from the posterior region of the tongue, upper pharynx, tonsils, and the carotid sinus and carotid body.

The cell bodies of afferent fibers for both the vagus and glossopharyngeal nerves are located in their respective sensory ganglia. These ganglia are located adjacent to the jugular foramen of the skull. The afferent fibers of both CNs IX and X synapse in the nucleus of the tractus solitarius, which is located in the medulla oblongata of the brain stem. From here, axons project to numerous areas in the central autonomic network of the brain stem and diencephalon (see Control of Autonomic Efferents: Central Autonomic Network and Figs. 10-33 and 10-34) and the cerebral cortex. The projections to the cerebral cortex travel by way of the thalamus. These cerebral projections allow for conscious awareness of sensations, such as hunger. When appropriate, reflexes also may be elicited. Examples include the swallowing, cough, cardiovascular, and respiratory reflexes.

Visceral afferent fibers from the pelvic viscera and distal colon enter the spinal cord via pelvic splanchnics. Based on their structure and function at the peripheral level, the endings of these fibers act primarily as mechanosensors monitoring stretch in the hollow viscera. The extent of their participation in mediating nociception originating in the bladder and colon is unclear (Carpenter & Sutin, 1983; Cervero & Foreman, 1990; Knowles & Aziz, 2009).