Spinal Afferent Fibers

As mentioned, input conveyed through spinal afferent fibers is concerned with visceral sensation, especially visceral nociception. The sensations that reach consciousness are poorly localized and, in the case of pain, may be referred and may produce hyperalgesia (see Appendix II for definitions of terms related to pain), as well. The cell bodies of these fibers are located in the dorsal root ganglia of the thoracic and upper lumbar dorsal roots. These visceral afferent fibers travel from the peripheral receptors in the cardiac, pulmonary, and splanchnic nerves; continue through the sympathetic trunk, white rami communicantes, and dorsal roots; and finally terminate in the spinal cord.

Central Projections and the Referral of Pain

As mentioned, pain of visceral origin differs from somatic pain, both in the neurophysiologic characteristics associated with the production of the pain and more obviously in the clinical presentation to the painful stimuli. Numerous conditions help to define visceral pain. Overdistension of the hollow muscular walled organs, ischemia and the resulting release of chemicals such as bradykinin, and inflammation of the viscera are stimuli that induce pain. However, the severity of the condition resulting in pain is not always a reflection of the severity of the pain experienced. For example, mild pain may be experienced with early appendicitis, whereas severe pain may be present with the fairly normal presence of gas in the GI tract. The least sensitive of the viscera tend to be the solid organs, whereas the serosae of the hollow organs appear to be the most sensitive. Also, a mildly painful or even nonpainful stimulus can result in severe pain (Al-Chaer & Traub, 2002) if an organ is already inflamed or altered pathologically (e.g., irritable bowel syndrome [IBS]). Visceral pain often is described as being either true or referred. True visceral pain is diffuse pain that is perceived as originating from deep, midline structures in the thorax or abdomen. It is often accompanied by the sense of nausea and ill-being. An example of this is during the early stage of appendicitis when the pain is initially felt in the midline. Referred pain also is diffuse but is localized to a distant cutaneous site or to muscles. The following is a list of important clinical characteristics associated with visceral pain:

Autonomic Reflexes

Reflexes are common events mediated by the nervous system. A reflex can be described simply as an involuntary action that occurs fairly quickly, regulates some effector function, and has no direct involvement with the cerebral cortex. The components of a reflex arc include a peripheral receptor and its afferent fiber, which form the sensory limb; an efferent fiber that forms the motor limb; and an effector. Depending on whether the reflex arc is monosynaptic or polysynaptic, the presence of interneurons connecting the afferent and efferent fibers is variable. Both types of afferents (somatic and visceral) and efferents (somatic and visceral) may be involved, thus creating four major kinds of reflex arcs. These are somatosomatic, viscerosomatic, viscerovisceral, and somatovisceral.

Immune System and the CNS

Evidence exists that the immune system communicates with the brain, allowing the brain to monitor the status of invading organisms and react to the immune system as it functions to detect pathogens and other harmful substances. One method is through the blood vascular system. Once pro-inflammatory cytokines (such as tumor necrosis factor [TNF] and interleukin-6 [IL-6]) are in the circulation, they are able to signal the brain humorally by being transported across the blood-brain barrier by saturatable transport systems and by accessing and activating circumventricular organs devoid of the blood-brain barrier such as the area postrema. This important area is located in the region of the floor of the fourth ventricle and is in close proximity to the dorsal motor nucleus of the vagus, the nucleus tractus solitarius (NTS), and the rostral ventrolateral medulla (RVLM). When activated, the area postrema produces and releases prostaglandin E₂. The release of prostaglandins as well as the presence of neural circuits formed by the area postrema, NTS, and RVLM allows for the activation of the HPA axis, mediation of fever, and the activation of the sympathetic system to occur. Cytokines binding to cerebral vascular endothelium also may alter cell function, resulting in the release of neuroactive substances such as prostaglandins into the brain parenchyma (Pavlov et al., 2003; Johnston & Webster, 2009). In addition, other clinical symptoms including anorexia, somnolence, weight loss, and depression (the clinical signs of ‘sickness behaviour’) appear as a result of the brain’s humoral activation by cytokines (Tracey, 2002; Hopkins, 2007; Tracey, 2009).

The second method by which the immune system communicates with the CNS is by the nervous system. Inflammatory mediators released in connective tissues associated with the vagus nerve activate vagal afferent fibers and initiate an anti-inflammatory response. Vagal afferent fibers in the viscera have been shown to be activated by low doses of endotoxin or interleukin-1 (IL-1). Electrophysiologic studies show that vagal afferents can also be activated by TNF and other cytokines released from dendritic cells, macrophages, or other immune cells present at the site of inflammation (Tracey, 2002). Endogenous and exogenous factors associated with inflammation can interact with immune cells such that there is an increase in pro-inflammatory cytokine release, which can activate vagal afferents. This mechanism of activation may occur directly or it may be mediated through glomus (chemoreceptive) cells of numerous paraganglia scattered along the vagus nerve and its branches. The glomus cells are located near fenestrated capillaries and are similar in appearance to those in the carotid body. They are able to detect cytokines in the blood and respond by releasing mediators that in turn activate the vagal afferent fibers (Goehler et al., 1997; Goehler et al., 1999; Goehler et al., 2000; Pavlov et al., 2003; Tracey, 2009). Evidence suggests that information concerning inflammation that courses in vagal afferent fibers may be dependent upon the extent and degree of the response. It has been suggested that vagal input to the CNS is more involved with mild to moderate peripheral inflammatory responses and that the humoral pathway mediates the more acute and vigorous responses (Pavlov et al., 2003). The activation of nociceptors by pro-inflammatory cytokines also leads to the induction and maintenance of pain (Üceyler, Schäfers, & Sommer, 2009). Neural pathways are stimulated, providing another route for the CNS to receive information pertaining to the activity of the immune system (i.e., the inflammatory response). The activation of neural circuitry at the CNS level and the resulting perception of pain will result in the activation of the stress response mediated by the sympathetic division and the HPA axis.

Within the CNS, the vagal afferent fibers terminate primarily in the NTS but also in the dorsal motor nucleus of the vagus and area postrema. Collectively these three areas form the dorsal vagal complex. The NTS, acting as an integration center, sends axons to numerous sites (see section Control of Autonomic Efferents: Central Autonomic Network) including the paraventricular nucleus of the hypothalamus, allowing for the activation of the neuroendocrine arm of the anti-inflammatory pathway (i.e., the HPA axis). NTS axons also synapse in the RVLM, which projects to the locus ceruleus, a brain stem nucleus that is a major source of noradrenergic input to higher centers including the hypothalamus. Also, both the RVLM and locus ceruleus project to sympathetic preganglionic neurons, thus activating the neural connections for an anti-inflammatory response (Pavlov et al., 2003). In addition, and most commonly recognized, is the NTS connection with the nearby dorsal motor nucleus of the vagus.

Efferent Response and the Cholinergic Anti-inflammatory Pathway

When an inflammatory response occurs, anti-inflammatory mechanisms are initiated to modulate the immune response. This limits the acute inflammatory response and prevents widespread inflammation throughout the body, which may cause serious damage to tissues. These mechanisms include both humoral and neural components. The humoral mechanism utilizes diffusible anti-inflammatory mediators that produce a concentration gradient–dependent, slow, and nonintegrated response. The mediators include those that are released at the local site of inflammation such as prostaglandin E₂, spermine, and heat shock proteins and anti-inflammatory cytokines delivered to the local inflammatory site by the bloodstream or by diffusion through tissues. Also, once pro-inflammatory cytokines have interacted with the brain (see text above) hormones such as α-melanocyte-stimulating hormone (α-MSH) and glucocorticoids are released into the bloodstream (Tracey, 2002; Johnston & Webster, 2009). Glucocorticoid (cortisol in humans) released from the cortex of the adrenal gland is the result of the neuroendocrine regulatory mechanism, referred to as the HPA axis. The details of the mechanisms by which these mediators act are beyond the scope of this chapter.

There is also a neural component that is involved with the anti-inflammatory response. Activation of sympathetic fibers produces a powerful anti-inflammatory action upon the innate immune system. In general, immunomodulation of the immune system is mediated by sympathetic innervation of lymphoid tissue. Norepinephrine (NE) released from postganglionic neurons exerts an immunosuppressive response by binding to adrenoceptors expressed on lymphocytes and macrophages such that pro-inflammatory cytokine synthesis is inhibited and anti-inflammatory cytokine synthesis is stimulated. (See following section on Sympathetic Innervation of Lymphoid Tissue). In addition, preganglionic sympathetic fibers coursing in the greater splanchnic nerve innervate the chromaffin cells of the medulla of the adrenal gland with subsequent release of epinephrine (E) and some NE. These catecholamines act as hormones and have a widespread effect on effector tissues. The increase of E and NE levels can inhibit macrophage activation and the pro-inflammatory cytokine TNF synthesis. The activation of the β-adrenergic receptor has been shown to not only suppress TNF production but also up-regulate the production of the anti-inflammatory cytokine IL-10 (Tracey, 2002; Pavlov et al., 2003; Nance & Sanders, 2007; Johnston & Webster, 2009).

Evidence that has accumulated over the last decade indicates that there appears to be a cholinergic component to the anti-inflammatory mechanisms utilized by the central nervous system. This component is mediated through efferent fibers coursing within the vagus nerve. Vagal afferent fibers provide input into the CNS and the vagal efferent fibers serve as the efferent arc of an inflammatory reflex. This provides a direct, localized, and rapid response to inflammatory effects on the body—an advantage that allows for containing immune activation at the critical period of the initiation of the response. This theory is the conclusion of experiments showing that the vagal efferent fibers appear to have an immunosuppressive effect on pro-inflammatory cytokines, such as the potent cytokine TNF, produced by innate immune cells found in tissues innervated by the vagus nerve such as the spleen, liver, GI tract, and heart. Evidence supporting the presence of an anti-inflammatory pathway mediated by vagal efferent fibers includes data concerning the utilization of the tetravalent guanylhydrazone CNI-1493 drug, which activates the vagus nerve; the use of cholinergic agonists and antagonists as well as antisense and gene knockout methods in mice; and the investigation of the anti-inflammatory pathway in experimental models of disease including sepsis, endotoxemic shock, hemorrhagic shock, ischemia/reperfusion injury, subcutaneous inflammation, postoperative ileus, pancreatitis, and inflammatory bowel disease (Pavlov et al., 2003; Tracey, 2007; Gallowitsch-Puerta & Pavlov, 2007; Tracey, 2009). Because the major neurotransmitter used by parasympathetic/vagal efferents is acetylcholine (ACh), the pathway was named the ‘cholinergic anti-inflammatory pathway’. It was also determined that the receptor that was activated by ACh in the cholinergic anti-inflammatory pathway, resulting in the inhibition of cytokine synthesis, was the nicotinic acetylcholine receptor α7 subunit (α7nAChR) (Borovikova et al., 2000; Wang et al., 2003). The receptor is expressed on macrophages, monocytes, B and T cells, keratinocytes, endothelial cells, and dendritic cells. It has been determined that the signaling transduction mechanisms used by these receptors on immune cells and on neurons are different (Gallowitsch-Puerta & Pavlov, 2007; Tracey, 2009). Also, it has been shown that although ACh binds to muscarinic receptors, some of which are expressed on cytokine-producing cells, these receptors are not required for modulating cytokine production via the cholinergic anti-inflammatory pathway (Johnston & Webster, 2009). This mechanism is different than the one used by parasympathetic fibers to modulate effector tissues in other physiologic systems. However, muscarinic receptors are found in the CNS (NTS and dorsal motor nucleus) and may be involved in cholinergic activation. Through their activation, they have been shown to inhibit systemic inflammation in endotoxemic rats and also to significantly increase the activity of vagal efferent neurons, implicating a possible function, at least in the rat model, of modulating the cholinergic anti-inflammatory pathway (Gallowitsch-Puerta & Pavlov, 2007).

Macrophages and monocytes, important cells of the immune system and components of the reticuloendothelial system, target foreign pathogens. Their actions are essential during the early innate immune response. They reside in the spleen, liver, lungs, and other tissues. Microorganisms and their products, such as bacterial endotoxins, localize to macrophages primarily in the spleen and liver and when the macrophages are activated they are capable of secreting pro-inflammatory cytokines. The spleen is the major source of hepatic and systemic TNF during endotoxemia and its relationship with the vagus nerve has been studied. Data (Huston et al., 2006) show that TNF production in the liver and spleen, but not in the lung, was significantly decreased when the vagus nerve was stimulated. It was also shown that the spleen is a major source of the pro-inflammatory cytokine TNF and that the suppression of its production after stimulation of vagal fibers requires the α7nAChR. Therefore it appears that the cholinergic anti-inflammatory pathway may be hardwired through the spleen as a route by which it regulates suppression of TNF production and limits the magnitude of the inflammatory response (Huston et al., 2006; Rosas-Ballina et al., 2008). The spleen is a major source of ACh and it has been shown that large quantities of ACh are released into the tissue and splenic vein as a result of splenic nerve activation. It is possible that this process may allow the spleen to control the movement of immune cells to distant sites (Saeed et al., 2005; Huston et al., 2006; Tracey, 2009). However, it has also been established that there are no cholinergic fibers terminating in the spleen and in fact the innervation of the spleen is by catecholaminergic fibers (splenic nerve) originating in the celiac-superior mesenteric ganglion. It becomes problematic because the receptors that are activated in order to suppress TNF production via the cholinergic anti-inflammatory pathway have been shown to be nicotinic receptors specific for ACh. The vagus nerve does play a role in the innervation of the spleen in that the right vagus nerve gives off a large celiac branch that ends within the celiac plexus and it also sends small branches into the splenic plexus (Standring et al., 2008). Research studies indicate that the celiac branches of the vagus nerve terminate in synaptic-like structures around main cells in the celiac-superior mesenteric ganglia (Berthoud & Powley, 1993; Berthoud & Powley, 1996; Szurszewski & Miller, 2006; Rosas-Ballina et al., 2008), which is the location of the sympathetic postganglionic catecholaminergic fibers of the splenic nerve. ACh can be synthesized, stored, and released from nonneuronal cells. These cells include vascular endothelial cells and lymphocytes (primarily T cells). It has been suggested (Kawashima & Fujii, 2003; Kawashima & Fujii, 2004) that a resident population of these interacting lymphocytes in lymphoid tissue may be involved in a local cholinergic system that regulates immune function. The spleen includes populations of these cells, which also have been shown to be innervated by catecholaminergic fibers. The synthesis and release of ACh from these cells and subsequent binding to the α7nAChR expressed on immune cells such as macrophages suppress TNF production (Mignini, Streccioni, & Amenta, 2003; Wang et al., 2003; Rosas-Ballina et al., 2008; Tracey, 2009). From these studies it can be hypothesized that the wiring of the cholinergic anti-inflammatory pathway consists of the vagus nerve activating postganglionic noradrenergic fibers coursing in the splenic nerve. These fibers cause the release of ACh from immune cells such as lymphocytes in the spleen; the ACh binds to the α7nAChR on macrophages and down-regulates pro-inflammatory cytokine release (Fig. 10-29).

It is interesting and somewhat surprising that the vagus nerve has been implicated as having this uncharacteristic role of providing the ‘hard-wiring’ for an inflammatory reflex arc and suppressing the inflammatory response. Classically, the function of the vagus has been associated with the regulation of physiologic systems such as the cardiovascular, respiratory, and GI systems through its sensory and motor innervations of the viscera. Research continues to produce data elucidating in more molecular detail the types of receptors located on various cell populations and their mechanisms of action. In light of this information, it perhaps makes sense that the vagus nerve is involved because it is well-positioned anatomically throughout the body to interact with cells that are involved with providing an immediate immune response (and producing pro-inflammatory cytokines) to pathogens, such as the nonneuronal cells residing in the organs (e.g., spleen, liver, and lung) of the reticuloendothelial system. In fact, it has been proposed (Tracey, 2007), based on evidence of endotoxemia studies in mice, that the vagus nerve, through its ability to suppress cytokine production, may provide the means by which the CNS is able to continuously and precisely modulate and control the extent of the inflammatory response, that is, “…maintain homeostasis by limiting the inflammatory responses within the healthy, protective, and non-toxic range” (Tracey, 2009). Studies of mice (van Maanen et al., 2009) subjected to collagen-induced arthritis indicated that the cholinergic anti-inflammatory pathway has a suppressive effect on arthritis. Although the vagus nerve does not directly innervate peripheral sites (e.g., joints of the extremities) that might be involved with the anti-inflammatory responses, there is evidence of vagus nerve involvement in animal models of induced peripheral inflammation (Borovikova et al., 2000). It is theorized that the suppressed inflammatory response seen in these models is the result of a decrease in cytokine production and a redirection of immune cells away from the site of peripheral inflammation possibly through the association of the vagus nerve with the spleen and the obstruction of endothelial cell activation (see earlier text) (Saeed et al., 2005; Huston et al., 2006; Tracey, 2007).

The parasympathetic and sympathetic divisions of the ANS have distinct anatomic features and specific interactions with the effector tissues such that traditionally they are often described as being separate and as functioning antagonistically. However, this classical description is not entirely true. Anatomically, it has been shown that the splenic nerve, consisting of catecholaminergic fibers, can be stimulated either by sympathetic preganglionic neurons or, in the case of the cholinergic anti-inflammatory pathway, by vagal preganglionic neurons. Also, peripheral effector cells modulated by vagus nerve activation express nicotinic receptors and not the traditional muscarinic receptor. Homeostatic control mechanisms that act daily in an individual are not functioning in isolation but are the result of the composite activity of many neural networks including the sympathetic and parasympathetic divisions. For example, activation of only sympathetic fibers to the heart results in an increase in heart rate and an increase in cardiac output. Parasympathetic activity in an isolated setting results in decreased heart rate and decreased cardiac output. In an intact organism, when both divisions are activated simultaneously, the net increase in cardiac output is greater than when the sympathetic fibers are firing in isolation because the decreased heart rate allows the blood to fill the heart more efficiently (Tracey, 2009). Thus, when the two divisions work synergistically the overall result is a more beneficial response. This is also the case regarding the modulation and monitoring of the body’s defense system against pathogens such that the traditional ‘rules’ are changed both anatomically and physiologically. As mentioned earlier, the cholinergic anti-inflammatory pathway is neither sympathetic nor parasympathetic because it contains neural components of each division. Both sympathetic (see Sympathetic Innervation of Lymphoid Tissue) and parasympathetic (via the vagus nerve) divisions are activated by immunogenic stimuli. Stimulation of vagal afferent fibers results in activation of the NTS, which has the capability to signal not only vagal efferent fibers in the dorsal motor nucleus but also the RVLM and locus ceruleus with subsequent firing of sympathetic neurons in the cord, as well as activating the HPA axis. Both function synergistically through the innervation they provide to the thymus, spleen, heart, liver, lungs, GI tract, pancreas, and kidneys, allowing for the co-regulation of the production of cytokines by immune and nonimmune cells (Pavlov et al., 2003).

Clinical Relevance

The discovery of the cholinergic anti-inflammatory pathway opens up the avenue for designing therapeutic protocols to treat inflammatory diseases by altering vagus nerve activity or targeting the components of the pathway. Also, understanding the mechanism of the cholinergic anti-inflammatory pathway may explain why current treatments and activities that result in anti-inflammatory responses occur. Examples of the clinical relevancy of the pathway are briefly described next.

Sympathetic Innervation of Lymphoid Tissue

As mentioned previously, the sympathetic division has a very important role in mediating immune system functions. Research shows that sympathetic efferent fibers innervate primary (bone marrow and thymus) and secondary (lymph nodes, spleen, and peripheral) lymphoid tissue. Two adrenergic receptor subtypes are shown to be expressed on immune cells regulated by sympathetic neurons and NE: α (1 and 2) and β (1 and 2). These belong to a G protein–coupled receptor superfamily and are further classified into subgroups (Pavlov et al., 2003). In humans and rodents the β₂ receptor is the primary subtype. Cell activation, cytokines, hormones, and neurotransmitters can influence and regulate the number of these receptors expressed. Cells involved in the innate immune response express the β₂ and the α₁ and α₂ receptors. The β₂ receptor is exclusively expressed on cells involved in the adaptive immune response (Nance & Sanders, 2007). NE has an anti-inflammatory effect by binding to adrenoceptors on lymphocytes and macrophages. Relative to the inflammatory response, a decreased production and release of inflammatory mediators such as TNF-α, IL-1β, interferon γ, and NO and an elevation in the levels of anti-inflammatory cytokines IL-6 and IL-10 via β₂ receptors were seen in stress-induced situations such as endotoxemia and hemorrhagic shock in which the sympathetic division was activated (Pavlov et al., 2003). In vivo activation of the sympathetic division by stress or by central inflammatory stimuli results in a potent anti-inflammatory response in the spleen inhibiting the production and release of TNF-α from macrophages (Nance & Sanders, 2007). It appears that the mechanism by which both NE and E (released from the adrenal medulla) inhibit pro-inflammatory cytokines and stimulate anti-inflammatory cytokines is through the activation of the β₂-adrenoceptor–cAMP–protein kinase A pathway. This activation may occur at synapse-like junctions similar to those in the spleen or at a distant site subsequent to the diffusion of NE through the tissue. The latter type of activation plays the dominant physiologic role. The release of NE can be presynaptically regulated through the effects of chemical mediators such as neuropeptide Y, ACh, dopamine, prostaglandins, and other microenvironmental factors (Pavlov et al., 2003). Although activated sympathetic fibers have an overall anti-inflammatory effect relative to the innate immune system response, in the beginning of some inflammatory responses, sympathetic firing may activate a local response including the accumulation of neutrophils. Also, during the acquired immune response, activated sympathetic fibers may enhance or inhibit cellular activity possibly by altering gene expression for cytokines and antibodies (Nance & Sanders, 2007). The dual role of sympathetic modulation on cellular activity may be dependent upon the peripheral receptor expressed on the effector cell and its affinity for NE, the tissue in which it is located, and its local concentration in the synaptic cleft (Koopman et al., 2011).

The thymus has a rich sympathetic innervation. Preganglionic neuron cell bodies are located in the intermediolateral cell column of T1 to T7 cord segments and postganglionic cells bodies are located in the cervical ganglia and the first two or three thoracic ganglia. Fibers entering the thymus along blood vessels travel through the capsule and septa to enter the cortex and medulla and terminate near immune cells such as thymic epithelial cells and thymocytes (Mignini, Streccioni, & Amenta, 2003; Nance & Sanders, 2007). Both of these cells have been shown to express both muscarinic and nicotinic receptors and to synthesize and release ACh. It is possible that this population of cells forms a cholinergic system that regulates and modulates thymic function (Kawashima & Fujii, 2004). Sympathetic fibers innervating bone marrow course as perivascular plexuses that enter nutrient foramina and terminate in the vicinity of hemopoietic and lymphopoietic marrow cells. This may indicate a sympathetic function of modulating hemopoiesis (Mignini, Streccioni, & Amenta, 2003).

Secondary lymphoid tissue includes lymph nodes, spleen, and other regions that contain lymphatic tissue. These tissues are the sites where immune responses occur. Sympathetic fibers course along blood vessels and innervate lymph nodes located in the specific area of distribution of the nerve fibers. Studies indicate the fibers travel to the parenchyma in T-cell–rich regions such as the paracortical and cortical areas but not in B-cell–containing areas such as the nodular regions and germinal centers. Postcapillary venules have also been found to have nerve fibers associated with them, possibly for regulating the movement of lymphocytes into the lymph node (Panuncio et al., 1998; Mignini, Streccioni, & Amenta, 2003).

The spleen, another secondary lymphoid organ, and its sympathetic innervation have already been discussed relative to the inflammatory response. The preganglionic neuron cell bodies of this pathway are located in the T1 to T12 cord segments whereas the postganglionic neuron cell bodies are located in the celiac-superior mesenteric ganglion. The postganglionic efferent fibers form the splenic nerve and course with blood vessels to the hilum. Studies of the feline spleen have shown that it is innervated by approximately 12,000 sympathetic fibers. When the weight of the spleen is compared with the weight of the kidney, the number of splenic sympathetic fibers is three times the number supplying the kidney. The fibers to the spleen appear to be different from sympathetic renal fibers, which function as vasoconstrictors. Although splenic fibers have the functions of capsular contraction and vasoconstriction, some splenic fibers appear to function independently from arterial baroreceptor input and are activated reflexively to sensory input from the spleen, as well as the GI tract. These splenic fibers may be involved with immune system regulation. Studies alluded to in previous sections indicate the important functional connection the spleen has with the immune system. Studies in rats show the alteration of various immune functions in the spleen with sympathetic nerve stimulation. These alterations include changes of cellular elements involved in immune responses after sympathectomy; decreased number of immune responses after splenic nerve stimulation; and activation of certain other immune responses (e.g., stimulation of a specific hypothalamic region results in splenic nerve activity that correlates with the suppression of cytotoxic activity of splenic natural killer cells) (Jänig & Häbler, 2000). Sato (1997) used anesthetized rats and looked at the effect of pinching the hindpaws and brushing and pinching the skin on sympathetic activity in the spleen. The results showed a reflex response that included vasoconstriction and a decrease in cytotoxic activity of the natural killer cells. Evidence from studying the cellular characteristics of splenic innervation shows that when the fibers traverse the capsule and enter the white pulp, they terminate in proximity of immune cells such as macrophages, T and B lymphocytes, and plasma cells that are located in specific regions of the white pulp (see Mignini, Streccioni, & Amenta [2003]). Scattered fibers along the trabeculae in red pulp also are present. Because of the various immune cells involved, their variety of receptors, and a possible local lymphocytic cholinergic regulating system (Kawashima & Fujii, 2004), modulation of aspects of both the innate and the adaptive immune systems, such as lymphocyte proliferation, antibody secretion, and cytokine production, may occur (Mignini, Streccioni, & Amenta, 2003).

Enteric Nervous System and the Immune System

There is also an important relationship between the immune system of the GI tract and the enteric division of the ANS, which regulates GI motility, blood flow, and secretion (see Enteric Nervous System). The immune system of the gut is comprised of a diverse population of immune cells and inflammatory cells such as lymphocytes, macrophages, dendritic cells, and mast cells. These cells provide a security system in case the mucosal lining is breached by any one of a number of potentially harmful substances such as dietary antigens, parasites, viruses, and bacteria that appear in the intestinal lumen. The immune/inflammatory cells release chemical mediators and signal enteric neurons as well as vagal and spinal afferent fibers. Of these cells the mast cell has been studied the most. Antigenic activation of the mast cells results in the release of chemical mediators such as histamine, IL-6, serotonin, leukotrienes, platelet activating factor, adenosine, IL-1β, and mast cell proteases. These mediators are involved in the activation of the enteric neural circuitry that runs the defense program. This program is designed to eliminate the injurious agent from the lumen by the coordination of increased secretion and blood flow followed by powered propulsive motor activity. Because receptors for inflammatory mediators such as mast cell proteases, bradykinin, and prostaglandins are expressed on spinal afferent fibers, it has been suggested that activation of these receptors may result in the sensitization of nociceptors and the recruitment of silent nociceptors. The clinical manifestations of these neuronal processes, which are often seen in individuals with IBS, are cramping abdominal pain, fecal urgency, and watery diarrhea. It is also known that symptoms seen in functional gut disorders such as IBS can be exacerbated by psychological stress. Because of the similarity in symptomology to the gut’s response seen in inflammatory conditions such as infectious enteritis, it is thought that there may be a connection between the brain and mast cells. Psychological states in the brain could activate a neural pathway that stimulates the release of chemical mediators from mast cells, resulting in the activation of the same neural circuitry used in response to a breach in the mucosal lining (Wood, 2007).

Ganglionic Transmission

As stated, the ganglion is the location of postganglionic cell bodies, and therefore the site in which preganglionic neurons synapse. Functionally it is the location in which information from the CNS (via preganglionic neurons) and the periphery (via collateral branches of afferent neurons, releasing substance P and CGRP [Iversen, Iversen, & Saper, 2000]) is integrated and then distributed to the peripheral effectors via postganglionic neurons. Each preganglionic neuron diverges onto many postganglionic neurons (divergence) and each postganglionic neuron in turn receives input from more than one preganglionic neuron (convergence) (see Fig. 10-4). The divergence occurring in the sympathetic system traditionally is thought to be greater compared with the divergence in the parasympathetic system so that the sympathetic system can produce widespread responses. This concept has been used to delineate the two systems. However, some authors suggest that the difference in divergence ratios should not be used to characterize the sympathetic and parasympathetic systems, but rather should be noted as the means by which small targets with distinct functions are regulated (limited divergence) and extensive effectors (targets) acting in unison are regulated (vast divergence) (Wang, Holst, & Powley, 1995; Jänig & Häbler, 2000). Each postganglionic cell is inhibited via dendrodendritic synapses with other postganglionic cells and interneurons, the latter being excited by preganglionic fibers (see Fig. 10-4) (Kiernan, 2009). The primary neurotransmitter released by preganglionic neurons at their synaptic boutons is ACh (Fig. 10-30). This binds to and activates nicotinic receptors (so-named because the effect can be reproduced using the drug nicotine) found on the postganglionic neurons. In addition to postganglionic neurons, nicotinic receptors also are found on skeletal muscle cells and CNS neurons. The binding causes depolarization and the generation of a fast excitatory postsynaptic potential (EPSP). Use of the nicotine receptors is regarded as the main mechanism for transmission in both sympathetic and parasympathetic divisions of the ANS (Iversen, Iversen, & Saper, 2000). However, if the preganglionic neuron is stimulated repeatedly, ganglionic ACh also binds to muscarinic receptors on postganglionic cells. These are G protein–coupled receptors that evoke slow EPSPs and inhibitory postsynaptic potentials (IPSPs). Neuropeptides such as enkephalins, neurotensin, somatostatin, substance P, VIP, and neuropeptide Y (Iversen, Iversen, & Saper, 2000; Bear, Conners, & Paradiso, 2001) are colocalized with (contained in) cholinergic preganglionic neurons. These molecules are important in helping to determine the overall activity of the postganglionic neuron. They act by modulating the postsynaptic membrane such that the membrane will reach threshold more easily when activated via a fast EPSP (Iversen, Iversen, & Saper, 2000; Bear, Conners, & Paradiso, 2001). Animal studies on sympathetic ganglia also show variability among postganglionic neurons in paravertebral (sympathetic chain) ganglia versus those in prevertebral ganglia. Paravertebral ganglia cells have consistent properties (i.e., each preganglionic neuron evokes an EPSP via nicotinic receptor channels and an action potential always is produced). On the other hand, prevertebral ganglia cells do not have uniform properties, but instead can be divided into three groups based on their electrophysiologic, anatomic, and neurochemical differences (Jänig & Häbler, 2000). The transmission of information coursing through this site is complex and likely modulated and controlled based on the structure of the ganglion and the chemical diversity at the level of the preganglionic and postganglionic synapse and at the synapse of the interneuron pool.

Neuroeffector Transmission

Postganglionic neurons innervate the smooth muscle, cardiac muscle, and glands of the body. The axons are approximately 1 µm in diameter and typically are unmyelinated. Studies on the terminal endings of primarily sympathetic postganglionic axons show that they are different from somatic efferent fibers. The motor neurons that innervate skeletal muscle fibers do so at the neuromuscular junction at specialized regions on the postsynaptic membrane called the motor end plate. The neurotransmitter is released at this one site and binds to the receptors. On the other hand, postganglionic autonomic fibers branch extensively near the effector muscle cells, thus regulating the function of numerous muscle fibers. These fibers are arranged in bundles and some smooth muscle fibers are directly innervated, whereas the rest are electrically linked to the directly innervated cells by gap junctions. There are no well-defined presynaptic and postsynaptic specializations, nor just one transmission site. Instead the ends of the terminal branches of the postganglionic neurons are varicosed (i.e., they have a beaded appearance) (Fig. 10-31). Each of these beads or swellings (numbering from 10,000 to more than 2 million/mm³) (Hamill, 1996) is called a varicosity, and it contains mitochondria and vesicles of stored neurotransmitters (100 to 1000 per varicosity in adrenergic fibers). Each varicosity is approximately 0.3 to 1 µm in diameter and is located approximately 4 µm from its neighboring varicosity (Hirst et al., 1996; Bennett, 1998). The membrane of each varicosity is devoid of its Schwann cell neurilemma. Because there are no postsynaptic specializations, the varicosities are dynamic and may move along the axons (Standring et al., 2008). Because these are strung out along the terminal fiber ending, the receptors are also spread over the surface of the effector cell membrane and each varicosity is a possible site for neurotransmission onto muscular (or glandular) tissue. The neurotransmitter, which is released typically during passage as the action potential travels along the axon, crosses the synaptic cleft and may diffuse a distance (as many as several hundred nanometers) before reaching its target receptors (Iversen, Iversen, & Saper, 2000). The synaptic cleft varies considerably in size among tissues, ranging from as little as 20 nm in densely innervated effector tissues (e.g., ductus deferens) to 1 to 2 µm in large elastic arteries (Standring et al., 2008).

The traditional description of chemical transmission at the neuroeffector junction has been based on the release of the “conventional” transmitters ACh, released by the parasympathetic postganglionic fibers, and NE, released by sympathetic postganglionic fibers (see Fig. 10-30). In general, these neurotransmitters are released and then bind to and activate their specific receptors, which in turn release intracellular chemical messengers. In turn, these messengers initiate a cascade of cellular reactions; however, other chemical substances have been found to be involved with neurotransmission. For example, ATP is a cotransmitter with NE in adrenergic neurons, although its concentration relative to NE varies in different fibers. Neuropeptides are common substances that colocalize with both NE- and ACh-containing neurons and function to modulate neurotransmission. Neuropeptide Y is found in approximately 90% of postganglionic adrenergic fibers. It facilitates responses by acting postsynaptically on effector cells located more than 60 nm away. On densely innervated target cells that are 20 nm away, neuropeptide Y acts on the presynaptic membrane and dampens effector activity by inhibiting the release of ATP and NE. Neuropeptide Y often is associated with other neuropeptides such as galanin and dynorphin. The few sympathetic neurons that are cholinergic (e.g., to sweat glands) have been shown to often contain CGRP and VIP. Adenosine also modulates transmission of sympathetic neurons at both the presynaptic and postsynaptic junctions (Iversen, Iversen, & Saper, 2000).

Parasympathetic postganglionic neurons have been found to colocalize VIP with ACh. VIP is a vasodilator that may function to assist effector activity by increasing blood flow, which is necessary in the process of glandular secretion (Iversen, Iversen, & Saper, 2000). Other populations of neurons use ATP or nitric oxide (or both) as cotransmitters. In addition, nitric oxide, which has been implicated in the mediation of smooth muscle relaxation, and ATP have been recognized as chemical substances associated with nonadrenergic, noncholinergic (NANC) fibers (Standring et al., 2008).

The actual physiologic response of effector tissues to postganglionic neuron activation is dependent on the neurotransmitter (and possible cotransmitters and comodulators) released. More importantly, the response also is dependent on the presence and distribution of ligand receptors at the neuroeffector junction to which the neurotransmitter will bind. Depending on the physiologic status of the target cell, the concentration of receptors found on its postsynaptic membrane can be modified by the cell inserting or removing receptors into its cell membrane (up-regulation or down-regulation, respectively), thus affecting the binding capability of neurotransmitter and the resulting activity of the target cell.

NE is the primary neurotransmitter that sympathetic postganglionic fibers release, although fibers that innervate merocrine sweat glands release ACh (apocrine glands associated with hair follicles are innervated by adrenergic fibers) (Standring et al., 2008). NE binds to adrenergic receptors, of which there are two major types, α (alpha) and β (beta). The α type is further subdivided into an α₁ type, which is subdivided into three subtypes (A, B, D), and an α₂ type, which is also subdivided into three subtypes (A, B, C) (Insel, 1996). The β receptor is divided into β₁, β₂, and β₃ types. Each type of adrenergic receptor is linked preferentially to specific subclasses of G proteins located in the cell membrane. Each G protein in turn is linked to specific effector molecules within the cell. For example, phospholipase C_β and adenylyl cyclase are examples of such effector molecules. Activation of the effector molecules in turn leads to changes in intracellular concentrations of second messengers (e.g., cyclic adenosine monophosphate [cAMP]), which results in the modulation of cellular activities (Insel, 1996).

The primary neurotransmitter that parasympathetic postganglionic fibers release is ACh. At the neuroeffector junction, ACh binds to muscarinic receptors. These receptors are so-named because administration of the alkaloid muscarine (derived from the Amanita mushroom) was found to mimic specific actions of the parasympathetic system. Muscarinic receptors found at the neuroeffector junction are subdivided into three major classes: M₁, which is excitatory to postganglionic neurons and when activated modulates NE release; M₂, which decreases heart rate and contractility; and M₃, which causes smooth muscle contraction and increased glandular secretion (Hamill, 1996). Two other classes, M₄ and M₅, have been identified but their functions outside of nervous tissue are unclear (Eglen, 2005). Table 10-3 summarizes major functions of the adrenergic and cholinergic receptors.

Adrenergic and muscarinic receptors are located on both presynaptic (postganglionic) and postsynaptic (target cell) membranes (Fig. 10-32). More specifically, M₁, M₂, and M₃ receptors are located on the postsynaptic membranes. Some muscarinic receptors are located on sympathetic neuron presynaptic membranes and these receptors inhibit the release of NE. Others are located on parasympathetic presynaptic membranes. When stimulated, these inhibit the further release of ACh. α₁-Adrenergic receptors are located on postsynaptic membranes and when activated mediate smooth muscle contraction in peripheral small arteries and large arterioles, dilator pupillae muscle, GI sphincters, the bladder neck, and the vas deferens. α₂ receptors are located on sympathetic presynaptic membranes (as autoreceptors involved with an auto-feedback loop regulating NE release) and on neighboring parasympathetic presynaptic membranes. In both cases, when activated, neurotransmitter release is inhibited. β₁ receptors found on postsynaptic membranes cause an increase in heart rate and force of contraction, and those found on cells in the kidney cause the secretion of renin. Renin is part of the pathway that forms the vasoconstrictor peptide angiotensin II. β₂ receptors are activated by epinephrine (released from the medulla of the adrenal gland) and by locally released NE. These receptors are postsynaptic and cause relaxation of tracheal and bronchial smooth muscle and the ciliary muscle of the eye, and they initiate glycogenolysis and gluconeogenesis in the hepatocytes of the liver. β₂ receptors also are found on presynaptic adrenergic fiber membranes acting as autoreceptors and causing the release of NE (FitzGerald & Folan-Curran, 2002). β₃ receptors are located in brown adipose tissue. When activated, these receptors are thought to promote lipolysis and heat production in fat (Insel, 1996). Table 10-1 lists the effector tissues and their adrenergic receptor type.

In addition to the adrenergic and cholinergic receptor categories, there also are receptors for nitric oxide. These receptors function to relax vasculature smooth muscle. In addition, there are receptors that bind adenosine and ATP (called purinergic P₁ and purinergic P₂, respectively). Adenosine modulates sympathetic activity by activating presynaptic receptors that prevent further release of ATP and NE after intense sympathetic activation. It also inhibits cardiac and smooth muscle activity that is in direct opposition to NE-produced excitation. ATP is a cotransmitter with NE and is involved with the fast and slow responses observed in smooth muscle (Iversen, Iversen, & Saper, 2000).

Notice that controlling the activity of the target cell is dependent on the concentration and availability of neurotransmitter present in the synaptic cleft. This is linked to the release and removal of that neurotransmitter. The release is determined by the frequency of action potentials and the influx of calcium ions, which in turn controls the release of neurotransmitter. In addition, noradrenergic presynaptic membranes include receptors that modulate the release of NE. These are the β₂- and α₂-adrenergic receptors (see the preceding text) and receptors for histamine, prostaglandin E₁, 5-hydroxytryptamine, ACh (all of which may decrease NE release), and angiotensin II (which promotes release of NE). The removal of NE at the synaptic cleft (and therefore the cessation of its action) occurs primarily by inactivation through either diffusion or uptake. Neuronal reuptake of NE results largely in the restorage of NE into vesicles, although some NE is degraded by monoamine oxidase (MAO). Uptake by the effector cell (extraneuronal) results in the degradation of NE, by MAO and catechol O-methyltransferase (COMT), into inactive metabolites. The inactive metabolites subsequently diffuse out of the cell and into the capillaries. Because of the large synaptic cleft, NE also is able to diffuse away from the junction and into capillaries. Removal by neuronal uptake occurs, the majority of the time (70%), in densely innervated tissues compared with removal by extraneuronal uptake (20%). However, diffusion and extraneuronal uptake may be more important in sparsely innervated tissues (Bray et al., 1994; Weisbrodt, 1998).

The control of ACh concentration is similar to that of NE in that action potentials trigger the release of ACh into the synaptic cleft. However, the removal of ACh is via degradation of ACh by acetylcholinesterase into choline and acetate. Subsequent reuptake returns choline to the nerve terminal. Also, ACh is removed by its diffusing away from the junction (Bray et al., 1994; Weisbrodt, 1998).

In summary, the mechanism of neurotransmission that occurs in the ANS is more complex than the simple traditional description of a sympathetic division, which uses NE, and a parasympathetic division, which uses ACh, to control the activities of visceral tissues of the body. Research has resulted in information that reveals concepts illustrating the complexity and versatility of ANS neurotransmission. Some of these advances, which have been discussed in the previous section, indicate that nerve fibers can release more than one neurotransmitter (cotransmission); that neuromodulation of neurotransmitter release and action can occur at either the presynaptic or the postsynaptic membrane; and that the neuroeffector junction has structural and functional attributes that suit the overall functioning of the ANS and differ from the skeletal neuromuscular junction (Standring et al., 2008). Other factors contributing to the complexity of autonomic neuronal transmission are the presence of NANC fibers, which use peptides and modulate the function of the major neurotransmitters (FitzGerald & Folan-Curran, 2002); the presence of afferent neurons that release neurotransmitter from their peripheral endings (called sensorimotor nerves) and function in the autonomic control of the GI system, heart, lungs, ganglia, and vasculature; the discovery of integrative circuitry found not only in the enteric nervous system but also in peripheral intrinsic ganglia associated with the heart, bladder, and respiratory structures; and the plasticity (the ability to change) of autonomic neurons (demonstrated by variations in the expression of neurotransmitters, cotransmitters, and receptors) that occurs not only during normal development and aging processes but also in response to hormones and nerve growth factors released as a result of injury, surgery, and disease states (Williams et al., 1999).

Pharmacologic Applications

The synapse between preganglionic and postganglionic neurons, and between postganglionic fibers and effectors, is of interest pharmacologically. Various agents, some of which are produced synthetically, can produce numerous effects. Some mimic the actions of sympathetic (sympathomimetic) stimulation, and others mimic the actions of parasympathetic (parasympathomimetic) stimulation. Many agents block receptor sites or alter the deactivation mechanism of the neurotransmitter. Examples of blocking agents are high concentrations of nicotine, which act at the ganglion level and sustain postganglionic depolarization; atropine, which binds to muscarinic receptors (used to dilate the pupils and increase heart rate by blocking the effects of postganglionic parasympathetic stimulation); phenoxybenzamine, which blocks α-adrenergic receptors; propranolol, which blocks β-adrenergic receptors (used to treat hypertension); and reserpine, which inhibits NE synthesis and storage (Snell, 2001).

Some pharmacologic agents also inhibit or inactivate acetylcholinesterase. Because ACh is not deactivated, it continues to stimulate cholinergic fibers. Examples of reversible anticholinesterase drugs are physostigmine and neostigmine, used in treating glaucoma and myasthenia gravis. Irreversible anticholinesterase drugs are also produced. Some of these are toxic, such as “nerve gas” (Carpenter & Sutin, 1983).

Pharmacologic agents can also mimic autonomic function by stimulating receptors. Phenylephrine (Neo-Synephrine; used to decrease nasal secretions) and isoproterenol (Isuprel; used as a bronchodilator during attacks of asthma) activate α and β beta receptors, respectively. Pilocarpine can mimic parasympathetic activity and also is used in the treatment of glaucoma (constriction of the sphincter pupillae muscle allows drainage of the anterior chamber of the eye by opening the canals of Schlemm).

Denervation Hypersensitivity

Although total disruption of the innervation to skeletal muscles prohibits contraction from occurring, many viscera are autoregulated, and lesions of preganglionic and postganglionic fibers to these autonomic effectors may not cause total cessation of function. However, the autonomic effector may not function in the most efficient manner under these circumstances. Depending on its location, a lesion would likely eliminate the release of neurotransmitters either between the preganglionic and postganglionic neurons or between the postganglionic neuron and effector. When this occurs, the denervated structures show an increase in sensitivity to their neurotransmitters, which at times may be found in the circulation. This hypersensitivity is possibly caused by an increase in the number of cell membrane adrenergic receptor sites or by alterations in the reuptake mechanism of certain neurotransmitters (e.g., epinephrine) (Carpenter & Sutin, 1983; Snell, 2001). The effectors show greater sensitization as a result of sectioning postganglionic fibers rather than sectioning preganglionic fibers (Carpenter & Sutin, 1983).

An example of the effects of denervation hypersensitivity may be observed in the pupils of individuals who have Horner’s syndrome, which is caused by a disruption of sympathetic fibers (see the following discussion). If the individual’s sympathetic nervous system is stimulated (e.g., overexcitement), epinephrine and NE are released from the medulla of the adrenal gland into the blood and cause the pupil to dilate (paradoxic pupillary response), even though the sympathetic innervation to the iris has been interrupted (Noback, Strominger, & Demarest, 1991). Administration of sympatheticomimetic agents to individuals with Horner’s syndrome also produces this same pupillary response (Cross, 1993a).

Horner’s Syndrome

Horner’s syndrome is primarily an acquired pathologic condition but rarely may occur as a congenital condition. This syndrome is caused by the interruption of the sympathetic innervation to effectors located in the head. Characteristic signs seen in Horner’s syndrome are those associated with the ipsilateral loss of sympathetic innervation to the following structures: smooth muscle of the dilator pupillae muscle of the iris, producing pupillary constriction (miosis), which is more apparent in dim light; smooth muscle (Müller’s or superior tarsal muscle) of the upper eyelid, producing ptosis; sweat glands of the face, causing anhidrosis; and smooth muscle of the blood vessels, resulting in vasodilation (this makes the skin flushed and warm to the touch). The patient also may appear to have enophthalmos (“sunken eye”). This feature actually is caused by the narrowed palpebral fissure after denervation of the upper eyelids. Because of its denervation, the dilator pupillae muscle also is hypersensitive to circulating adrenergic neurotransmitters (see previous discussion).

The neuronal pathway that supplies the effector tissues involved in Horner’s syndrome includes a central pathway, preganglionic neurons, and postganglionic neurons. An interruption of any part of these components may result in Horner’s syndrome. The central pathway is ipsilateral and polysynaptic and includes interconnected fibers from the insular cortex, amygdala, hypothalamus (hypothalamospinal fibers), and brain stem nuclei. Although the exact location is unclear, the hypothalamospinal fibers have been shown to descend in the lateral aspect of the brain stem and lateral funiculus of the cord and terminate in the region of the intermediolateral cell column (Fig. 10-36, A). Interruption of these fibers can be caused by tumors, multiple sclerosis, trauma, or vascular insufficiency, such as that seen in lateral medullary (Wallenberg’s) syndrome. Preganglionic and postganglionic sympathetic fibers also can be disrupted, resulting in Horner’s syndrome. Preganglionic fibers originating from the upper three thoracic segments enter the sympathetic chain, ascend, and synapse in the superior cervical ganglion. Postganglionic fibers to the effectors travel with the external and internal carotid arteries. Therefore an interruption of preganglionic fibers (along their pathway in the ventral roots or in the cervical sympathetic chain) or postganglionic fibers may also result in Horner’s syndrome (see Fig. 10-36, A).

The preganglionic neuron axons are anatomically related to the spine, apex of the lung, cervical pleura, subclavian artery, common carotid artery, internal jugular vein, thyroid gland, and upper ribs. Lesions of any of these structures could affect the preganglionic fibers, resulting in Horner’s syndrome (Amonoo-Kuofi, 1999). Examples of these lesions include an apical lung (Pancoast) tumor pressing on the stellate ganglion (Fig. 10-36, B), surgical trauma to the thorax or neck (e.g., during the anterior surgical approach to the lower cervical vertebrae [Ebraheim et al., 2000]), severe whiplash, and a cervical spine fracture or dislocation (Cross, 1993a). Postganglionic fibers may be disrupted in the neck or within the cranium. A lesion distal to the superior cervical ganglion may produce a variation in the clinical signs and symptoms presented by the patient, because the postganglionic fibers use several different arteries to travel to their effectors. Therefore the signs and symptoms depend on which postganglionic fibers have been damaged. The majority of sudomotor fibers to the face travel along the external carotid artery and its branches. The fibers to the eyelid, eyeball, and orbit course with the internal carotid artery and its plexus. Because this artery may be the site of an aneurysm or dissecting lesion, the postganglionic fibers become susceptible to disruption. Also, as the fibers pass by the trigeminal ganglion to enter the ophthalmic division of the trigeminal nerve, they may be lesioned as a result of irritation of the trigeminal nerve. This syndrome, known as Raeder’s (paratrigeminal) syndrome, presents with ptosis, miosis, and enophthalmos. It can be differentiated from Horner’s syndrome by the presence of ipsilateral facial pain (from irritation of the trigeminal ganglion) and the preservation of facial sweating. Raeder’s syndrome also can be caused by aneurysms or dissections of the internal carotid artery, head trauma, parasellar masses, hypertension, vasculitis, and migraines (Amonoo-Kuofi, 1999).

Raynaud’s Disease

Raynaud’s disease is the result of vasospasms in the digital arteries and arterioles of the fingers (most frequently). Although rarely affected alone, the toes may become involved in conjunction with the fingers. Induced by cold, this painful episodic condition presents bilaterally as changes in skin color caused by vasoconstriction and later a reactive hyperemia. This phenomenon also may be present secondary to other disorders, such as thoracic outlet syndrome, carpal tunnel syndrome, connective tissue disorders, and occupational trauma (e.g., operating air hammers or chain saws). Although conservative treatment should be attempted first, the administration of sympathetic pharmacologic blockers (e.g., reserpine) or even sympathectomy may be necessary to treat serious cases (Carpenter & Sutin, 1983; Khurana, 1993; Snell, 2001).

Hirschsprung’s Disease

Hirschsprung’s disease (megacolon) is a congenital condition affecting the enteric nervous system. It occurs as a result of neural and glial stem cells not migrating from the neural crest appropriately, which results either in a reduction or in the absence of ganglionic neurons populating the myenteric plexus. The amount of involvement of the large intestine varies but the most common site is in the lower and middle rectum. The rectum, sigmoid colon, descending colon, and often the proximal colon can be involved in severe cases. Because of the absence of the myenteric plexus, peristalsis is unable to occur and the affected segment of colon is left in a state of constriction. This subsequently blocks evacuation of the bowel and causes the region proximal to the constriction (which is normal) to become immensely dilated, thus giving the condition its name, megacolon. In infants, this condition results in vomiting, a distended abdomen, constipation, and a slowing in the passage of meconium. In a minority of cases, a very short region of the rectum just proximal to the anorectal junction is affected (‘ultra-short segment Hirschsprung’s disease’). In this case the amount of functional obstruction is very small and clinical signs and symptoms present later in life (Standring et al., 2008).

Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is a neurogenic pain condition that most commonly occurs in either an upper or a lower extremity, and that may be either localized or include the entire limb. This disorder is divided into two types: CRPS I, which was formerly known as reflex sympathetic dystrophy; and CRPS II, which was known as causalgia. CRPS I is the result of a minor injury (e.g., sprain, bruising), bone fracture (the most common precipitating event), or surgery of the affected limb. In CRPS I there is typically no detectable nerve damage and the symptoms are not confined to any specific nerve distribution. CRPS II develops after a major peripheral nerve, or one of its branches, is damaged. The classic example for this type of injury is a bullet wound to a major nerve, but any similar trauma may produce CRPS II. CRPS should be regarded as a disorder in which psychological, behavioral, and pathophysiologic factors are intricately and complexly interrelated. It may be mild and short lived or chronic, in which case the disorder results in long-term suffering and has a severe impact on the patient’s quality of life. Statistics show the disorder interferes with ability to work (about 62% are disabled), mobility (about 86%), self-care (about 57%), and sleep (96%). Although CRPS may develop in children, the majority of patients are between 50 and 70 years of age, mainly Caucasian and Japanese, and more often (two to three times) women (Shipton, 2009).

Diagnosis of CRPS is based mainly on history, clinical examination, and laboratory findings. Changes in the criteria have resulted in four diagnostic criteria to be met, allowing the disorder to be more easily identified (Harden et al., 2007). It is characterized initially by signs and symptoms localized to the affected extremity. However, the signs and symptoms typically increase in severity and number over time, and the disease ultimately may spread to other ipsilateral areas or even to the contralateral limb. The signs and symptoms, in order of general occurrence and progression, are as follows:

These clinical features of CRPS may be devastating. In addition to these signs and symptoms, a distinguishing feature of this condition is that its symptoms are disproportionate to the severity of the original insult (Walker & Cousins, 1997; Wasner, Backonja, & Baron, 1998; Schwartzman & Popescu, 2002; Turner-Stokes, 2002; Wasner et al., 2003). In addition, the clinical presentation and severity of CRPS vary. The pathophysiologic mechanism underlying the disorder is still uncertain and under investigation, but it appears that there is abnormal processing of noxious stimuli at a number of sites (Shipton, 2009). One of these is in the periphery, where the body’s response to peripheral trauma is a local neurogenic inflammatory response typically occurring when primary afferent nociceptors have been activated. These unmyelinated fibers are capable of releasing inflammatory mediators peripherally in response to tissue damage. In CRPS patients, the concentrations of the inflammatory neuropeptide mediators substance P, calcitonin gene–related peptide (CGRP), and bradykinin have been shown to be elevated in the blood. It is thought that the neurogenic inflammation is amplified by the sensitization of nociceptors by cytokines released as an immune response and by growth factors released to repair the damaged tissue. White blood cells and nonspecific antibodies also migrate to the inflamed region. Another location is in the spinal cord, where central sensitization occurs. Continued activation of polymodal nociceptors and the firing of primary afferent fibers result in a state of hyperexcitability and disinhibition (sensitization) of wide dynamic range dorsal horn neurons. These sensitized neurons then can be activated by innocuous cutaneous mechanoreceptors, resulting eventually in touch being perceived as pain (allodynia).

A third site where processing of nociception is altered is in the cortex, where cortical reorganization or plasticity occurs (Shipton, 2009). In CRPS patients, the cortical sensitization and reorganization of sensory and motor units may occur as the result of continuous firing of primary afferent fibers conveying nociception. It appears that a number of cortical areas are reorganized, including the parietal cortex, prefrontal cortex, and motor cortex. In some cases of CRPS, patients over a long period of time actively attempt to suppress motor and sensory activity in the affected painful limb, which results in a deficit in the attention to and awareness of the limb. That is, sensory input from the limb does not become incorporated into the body schema, resulting in a type of neglect syndrome. This continued attempt to suppress normal neuronal activity may explain the data from studies of cortical areas including those involved in the processing of emotional, autonomic, and pain perception that show the relationship between the volume of whole-brain gray matter and white matter anisotropy is disrupted (Shipton, 2009).

In CRPS patients showing abnormal or altered activity to real or imagined motor tasks and tactile stimuli, studies such as fMR imaging indicate that the posterior parietal cortex, which integrates visual and proprioceptive input, may be altered and central motor circuits may be rewired. fMR imaging studies also show a change in the somatotopic mapping in the somatosensory and motor cortices. In upper limb CRPS, the area of the somatosensory cortex designated for the affected hand has been shown to be remapped and decreased. The area of primary motor cortex for the affected upper limb has been shown to be increased on the contralateral side compared to the ipsilateral primary motor cortex. It is thought this difference in the remapping of sensory and motor cortices is because more cognitive processing is likely necessary for initiating and maintaining required motor activity and therefore more motor cortical units are stimulated. Also, the level of pain experienced by CRPS patients and the amount of cortical plasticity have been shown to be directly correlated. When the somatotopic remapping of the somatosensory cortex begins to reverse, the perceived pain is reduced.

A dysfunctioning sympathetic system can also be involved in CRPS. This results in an imbalance in regulating the blood vascular system and sweat gland activity, leading to hyperhidrosis, trophic changes, and vasoconstriction-related coldness. The hyperactivity of the skin reflexes may be the result of new sympathetic fibers sprouting in the dermis or in the dorsal horn. Although the sympathetic innervation to the sweat glands and blood vessels is abnormal, the density of adrenoreceptors is greater in the affected skin area. It has been suggested that a primary cause for the adrenoreceptor up-regulation and sensitization is due to a temporary decrease in sympathetic activation. Sympathetically maintained pain (SMP) may also be present. In SMP, pain is provoked by sympathetic output via sympathetic-afferent coupling. In this case, after acute tissue damage the primary afferent nerve endings of already sensitized nociceptors also become sensitive to catecholamines and up-regulate adrenergic receptors. The release of NE from sympathetic fibers or circulation of NE in the blood can activate these receptors located in the dorsal root ganglion, the periphery, and possibly the lesioned nerve. Based on this scenario, two mechanisms may be involved in the occurrence of painful sensations in SMP: (1) hyperactivity or increased sympathetic output and (2) normal sympathetic output but abnormally sensitive adrenergic receptors (Shipton, 2009). Sympathetic afferent coupling occurs not only in cutaneous locations but also in deep somatic tissues, resulting in patients experiencing painful bone, muscle, or joint tissues. The mechanism appears to be an indirect coupling involving the capillary bed and nonneuronal elements such as mast cells and macrophages (Jänig & Baron, 2003). SMP and sympathetic dysregulation are considered to be components of the clinical presentation in a significant number of patients with CRPS but they are not always present. Sympathetic blockade is commonly administered for the treatment of CRPS and generally relieves SMP. Because both vasomotor and thermoregulatory instability respond to sympathetic blockade, relief of these associated conditions is considered to be diagnostic for SMP. However, in placebo-controlled studies, data show that the responses to sympathetic blockades and placebo blocks are about the same (Pontell, 2008). In addition to SMP, some patients also present with non–sympathetically-mediated or sympathetic-independent pain (SIP). Often the two exist simultaneously; however, in other cases SMP is present initially and converted to SIP over the progression of the disease (Albazaz et al., 2008; Pontell, 2008). Although it is theorized that SMP is mediated by the sympathetic system, the actual pathophysiologic mechanism of CRPS is still unclear. Campero and colleagues (2010) performed microneurography on 24 CRPS I and II patients, looking for interactions between sympathetic efferent fibers and C nociceptors. Their results showed no evidence that activation of C fiber nociceptors was related to activated sympathetic efferent fibers. They also concluded that “the pain in CRPS I is not in general maintained by a peripheral nociceptive input, whether involving sympathetic outflow or not, so the source must lie elsewhere.”

CRPS is a complex disorder that appears to be a chronic neuropathic condition that involves both PNS and CNS components. The exact mechanisms explaining its pathophysiology and unpredictable clinical course are still not fully understood. There is consensus that CRPS patients should be managed by a multidisciplinary approach that includes psychological, pharmacologic, interventional, and rehabilitation components (Shipton, 2009). The treatment of CRPS is primarily to relieve pain and to rehabilitate the affected limb. Based on clinical studies of a patient population in the Netherlands, treatment protocols included pharmacotherapy (90%), noninvasive therapy (physiotherapy) (89%), intravenous therapy (45%), and nerve blocks (18%) (De Mos et al., 2009). Some research suggests that CRPS patients may benefit from surgical or chemical sympathectomy, a procedure that is used to interrupt the sympathetic nervous system. Chemical sympathectomies use alcohol or phenol injections to destroy nervous tissue of the sympathetic chain. Surgical sympathectomy can also be performed and involves open removal or electrocoagulation of the sympathetic chain. Less invasive procedures exist in which thermal or laser interruption is utilized. Nerve regeneration is a common occurrence in either chemical or surgical ablation; however, regeneration may take longer following surgical ablation. Unfortunately, the long-term effectiveness of sympathectomy has not yet been demonstrated; this, compounded with the reality that sympathectomy also carries the risk of potentially serious complications, has led current researchers to suggest that sympathectomy be used with great caution outside of a research setting, if at all (Straube et al., 2010). Because there has been inadequate research on the treatment of CRPS, protocols remain unclear. However, when a sympathectomy procedure is used it appears that the earlier the treatment begins the better the prognosis.

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