Colonic Motor and Sensory Function and Dysfunction

CHAPTER 98 Colonic Motor and Sensory Function and Dysfunction



Ian J. Cook, Simon J. Brookes, Philip G. Dinning



CHAPTER OUTLINE


Anatomy and Basic Control Mechanisms of the Colon and Anorectum 1660
Macroscopic Structure of the Colon 1660

Structure and Activity of Colonic Smooth Muscle 1660

Ion Channels in Colonic Smooth Muscle 1661

Interstitial Cells of Cajal 1661

Innervation of the Colon 1662
The Enteric Nervous System 1662

Sympathetic Innervation 1664

Parasympathetic Innervation 1664

Extrinsic Afferent Pathways 1664

Anorectal Anatomy and Innervation 1664

Relationships among Cellular Events, Pressure, and Flow 1665

Recognizable Colonic and Anorectal Motor Patterns and Putative Functions 1665
Nonpropagating Motor Patterns 1665

Propagating Motor Patterns 1665

Rectal Motor Complexes 1665

Regional Variation of Propagating Sequences 1665

Regional Linkage among Propagating Sequences 1665

Regulation of Colonic Filling and Transit 1666
Role of the Ileocecal Junction 1666

The Colon as a Storage Organ 1666

Relationships between Colonic Motor Patterns and Flow 1667

Defecation 1668
Rectal Filling, Capacitance, and Accommodation and Motility of the Anal Sphincters 1669

Anorectal Motility during Defecation 1670

Modulators of Colonic Motility 1670
Physiologic 1670

Pharmacologic 1671

Nonpharmacologic 1672

Disorders of Colonic Motility 1672
Constipation 1672

Diarrhea 1673

Irritable Bowel Syndrome 1673

Colonic Motility Disturbances Secondary to Nonmotor Intestinal Disorders 1673

Each day, 1200 to 1500 mL of ileal effluent enter the colon, 200 to 400 mL of which are finally excreted as stool. The colon mixes its contents to facilitate the transmural exchange of water, electrolytes, and short-chain fatty acids and stores stool for extended periods. The mixing process involves rhythmic to-and-fro motions, together with short stepwise movements of contents, resulting in an overall net aboral flow rate that averages approximately 1 cm per hour. When dehydration threatens survival, such as with water deprivation or severe diarrhea, the ability of the colon to reabsorb fluids is of major physiologic significance; appropriate motility patterns are important in achieving this function. For example, the colon has the capacity to increase its fluid absorption five-fold when required, but this ability is greatly impaired when transit is accelerated. Under normal circumstances, viscous contents occasionally are propelled aborally at a rapid rate, and, if circumstances are appropriate, stool is evacuated under voluntary control. Thus, the colon is capable of showing a diverse range of motor patterns that are suited for particular physiologic functions. The generic term motility describes the range of motor patterns and the mechanisms that control them.


Common sensorimotor symptoms, such as constipation, diarrhea, bloating, abdominal pain, or rectal urgency, can arise from disturbances of ileocolonic delivery, colonic propulsion, or stool expulsion. Clearly, these symptoms and dysmotility must be linked, although our current understanding of such linkages is limited, largely because of technical difficulties involved in studying the human colon. Because of differences among species, care is required in extrapolating data from animal studies to humans. For many years, intraluminal motility recordings in humans were obtained mainly from the rectum and sigmoid, but it is now clear that the motor activity of these distal regions is not representative of the colon as a whole. The contents of the colon become increasingly viscous distally, and this alteration complicates the relationship between propulsion and the contractile activity of the smooth muscle. Colonic movements are much less frequent and transit is considerably slower than in other regions of the gastrointestinal tract. The highly propulsive, stereotypical motor patterns that are associated with stool expulsion generally occur only once or twice daily. Hence, study of the motor patterns in the human cannot be achieved using contrast radiography. Prolonged recording techniques must be used to capture such infrequent motor patterns.


Recording of intraluminal pressure, by means of manometric catheters inserted per rectum, requires prior bowel cleansing, which can modify colonic motility. Furthermore, interpretation of intraluminal pressure measurements is complicated, because many contractions of the colonic wall do not occlude the lumen and therefore are detectable manometrically only if they cause significant pressure changes. Measurement of colonic wall tone using a barostat provides information on these nonocclusive colonic wall movements, but it tells us nothing of the spatiotemporal patterning of motility. Smooth muscle electromyography provides insight into the patterning of muscle activity but generally requires access to the muscular wall of the colon, which ethically is problematic in humans. Scintigraphy with suitably high frame rates can resolve discrete movements of the contents but is suboptimal for measuring actual wall motion. In vitro study of the cellular basis of motility using isolated specimens of colon faces fewer technical and ethical limitations; however, data obtained at the cellular level, often under highly nonphysiologic conditions, can be difficult to extrapolate to the more complex integrated responses of the entire organ in vivo. Nonetheless, while recognizing the intrinsic limitations of all these measurement techniques, in combination they have allowed us to piece together a number of concepts that have provided important insights into the relationships among muscle activity, wall motion, intraluminal pressure, and flow.



ANATOMY AND BASIC CONTROL MECHANISMS OF THE COLON AND ANORECTUM



MACROSCOPIC STRUCTURE OF THE COLON


The human colon is just over one meter long and is divided anatomically into the cecum; the ascending, transverse, descending, and sigmoid colon; and the rectum, which lies between the rectosigmoid junction and the anal canal. The outer longitudinal smooth muscle layer forms three thick, cord-like structures called the teniae coli, which are spaced evenly around the circumference of the colon. Between the teniae, the longitudinal smooth muscle is much thinner, allowing the wall to bulge noticeably.


Irregularly spaced circumferential constrictions pinch the colon into a series of pockets, called haustra, which give the colon a sacculated appearance for much of its length. Haustra are not fixed structures and appear to be caused by sustained contractions of the circular muscle. Myogenic activity alone, however, does not seem sufficient to explain haustration, and neural input is likely to contribute to their formation; haustra move, disappear, and re-form during the propulsion of colonic contents.


The teniae fuse to form a continuous outer longitudinal smooth muscle layer at the rectosigmoid junction, which then continues down to the distal margin of the anal canal, insinuating itself between the internal and the external anal sphincters. Throughout the length of the colon, the circular smooth muscle layer consists of thick bundles of cells, which are separated by connective tissue septa. The internal anal sphincter consists of a thickening of the circular muscle layer over the last 2 to 4 cm of the anal canal.


Macroanatomy of the colon is also discussed in Chapter 96.



STRUCTURE AND ACTIVITY OF COLONIC SMOOTH MUSCLE



Structure


Smooth muscle cells in the human colon, as in other muscular organs, are spindle-shaped, nucleolated cells with tapered ends. The surface area of the smooth muscle cell membrane is increased greatly by numerous caveolae, or small pits. Individual smooth muscle cells are connected mechanically to neighboring cells by intermediate junctions and electrically by gap junctions, which allow ions and small molecules—those with molecular weights up to approximately 1000 kD—to diffuse between the cells, thereby ensuring that the cells are functionally coupled to one another. Therefore, the smooth muscle cells do not contract as individual cells; rather, they contract together in a large, coordinated assembly, a syncytium.



Activity


Like smooth muscle throughout the gastrointestinal tract, colonic smooth muscle shows spontaneous, oscillatory electrical activity, even when all neural activity is blocked. Two types of rhythmic myoelectrical activity occur1: myenteric potential oscillations (MPOs) and slow waves.


MPOs are small-amplitude, rapid oscillations, with a frequency of 12 to 20 per minute, that originate from the plane of the myenteric plexus. These small oscillations spread, by means of gap junctions, into both the longitudinal and the circular smooth muscle layers and often reach the threshold potential for generating smooth muscle action potentials in both muscle layers. In the circular muscle layer, MPOs, with superimposed action potentials, generate small phasic contractions of the circular muscle layer. When the muscle is strongly excited by neurotransmitters released by enteric excitatory motor neurons, each MPO evokes an action potential, and the phasic contractions summate into powerful contractions that last several seconds.


Although the functions of the colon circular smooth muscle are well understood, the role that the longitudinal muscles play in colonic motility, mixing, and propulsion is a matter of some controversy. The longitudinal muscle probably acts in an antagonistic role to the circular muscle, contracting largely in concert with it and thus preventing excessive lengthening when the circular muscle contracts, which would be mechanically disadvantageous. It might also contribute to propulsion by pulling the colon over its contents, so that circular muscle contractions gain more purchase on them. Some evidence from modeling suggests that it also might play a role in mixing of liquid contents, at least in the small intestine.


A second pacemaker region is located at the submucosal border of the circular muscle. This region produces larger-amplitude, slower myogenic oscillations in membrane potential called slow waves, which also spread through the thickness of the circular smooth muscle by means of gap junctions. Slow waves also often reach the threshold for triggering smooth muscle action potentials and can evoke strong contractions. Slow waves occur throughout the human colon at a frequency of approximately 2 to 4 per minute. In the small intestine, a gradient of slow wave intrinsic frequencies causes slow waves to propagate predominantly aborad. This is not the case in the colon: Slow waves propagate over short distances up or down the colon, and complex interactions occur as waves coming from different initiation sites collide, leading to mixing of contents with little propulsion.


The currents produced by pacemaker cells at the myenteric and submucosal borders decay as they spread through the thickness of the circular muscle layer. Thus, operating in the middle of the circular smooth muscle layer is complex spontaneous electrical activity consisting of a mixture of MPOs and slow waves, with superimposed smooth muscle action potentials. Most of the time, slow waves determine the contractile activity of the smooth muscle and cause nonpropulsive mixing movements. During times of strong enteric neuronal activity, however, MPO-related contractions summate, giving rise to powerful patterned contractions of much longer duration than those produced by slow waves. These contractions can propagate for long distances along the colon and are known as propagating sequences. Action potentials in the smooth muscle can be recorded in vivo with electrodes attached to the serosal surface, thereby giving a high-resolution measurement of myoelectric activity or spike bursts.



ION CHANNELS IN COLONIC SMOOTH MUSCLE


The membrane of colonic smooth muscle cells contains a variety of ion channels, including several types of potassium channels, calcium channels, chloride channels, and nonselective cation channels.2 Although the exact physiologic roles of many of these ion channels are unknown, the high-threshold, voltage-operated calcium channels (l-type calcium channels) do play a crucial role in colonic muscle contractility. These channels open when the membrane potential of smooth muscle cells is depolarized beyond a voltage threshold, and they are responsible for the rapid upstroke of smooth muscle action potentials. The influx of calcium through l-type calcium channels during action potentials is a major trigger for activation of the contractile apparatus. It is not surprising that pharmacologic blockade of l-type calcium channels by dihydropyridine drugs such as nifedipine can reduce the contractility of colonic smooth muscle substantially. Release of calcium from intracellular stores, which is triggered by excitatory neurotransmitters, also may play a role in muscle contraction.



INTERSTITIAL CELLS OF CAJAL


Since 1991, the interstitial cells of Cajal (ICC) have been shown to play at least two important roles in the control of gastrointestinal motility: control of myogenic activity and mediating or amplifying the effects of motor neurons on the smooth muscle apparatus. ICC are non-neuronal in origin and are derived from common progenitors of smooth muscle cells. Mutant mice and rats that are deficient in ICC have profoundly disturbed intestinal motility, an observation that provides insight into the roles of ICC in the human gastrointestinal tract.


In the human colon, three types of ICC are recognized and are named according to their locations: ICC in the plane of the myenteric plexus (ICCMY), ICC near the submucosal plexus (ICCSM), and intramuscular ICC located between the circular and the longitudinal muscle layers (ICCIM). ICCMY and ICCSM form extensive networks along the colon and are electrically coupled to one another and to the smooth muscle layers by gap junctions (Figs. 98-1 and 98-2). ICCMY probably are the pacemakers for the small, rapid (12-20/min) oscillations in membrane potential (MPOs) of longitudinal and circular smooth muscle layers. ICCSM are the pacemakers for the large-amplitude slow waves (2-4/min) originating in the plane of the submucosal plexus; these slow waves have a powerful influence on the patterning of circular muscle contraction.


image

Figure 98-1. Schematic cross section of the muscularis externa of the human colon. The outer longitudinal smooth muscle layer (LM) is thickened at the teniae. In the plane of the myenteric plexus (not shown) is a network of interstitial cells of Cajal (ICC), which generate a rapid myenteric potential oscillation (ICCMY; see lower waveform on the right). The circular muscle layer (CM) is innervated by axons of enteric motor neurons with transmitter release sites (clusters of clear vesicles) that are associated with specialized intramuscular ICC (ICCIM). At the outer border of the circular muscle is another network of submucosal ICC, which generate slow waves (ICCSM; see upper waveform on the right). Also present are axons of motor neurons in the longitudinal muscles and ICCIM (not shown in this cross section). The tiny white squares represent gap junctions, which electrically couple cells.


image

Figure 98-2. Micrographs of interstitial cells of Cajal (ICC) in the human colon, labeled by c-Kit immunohistochemistry. A, ICC in the plane of the myenteric plexus (ICCMY) have an irregular shape, form a dense network of cells, and probably function as pacemakers. B, A different plane of focus of the same region shows spindle-shaped intramuscular ICC (ICCIM) in the overlying circular muscle layer. These cells probably are involved in neuromuscular transmission to the smooth muscle.


(Courtesy of Liz Murphy and David Wattchow.)


The exact ionic basis of rhythmicity in ICCMY and ICCSM that gives rise to MPOs and slow waves is not entirely clear; however, oscillations in membrane potential are an intrinsic property of both ICCMY and ICCSM. Intramuscular ICC (ICCIM) are a major target of neurotransmitters released from the axons of excitatory and inhibitory enteric motor neurons. Acetylcholine and nitric oxide (and probably several other motor neuron transmitters) evoke changes in the membrane potential of ICCIM, which then spread through the smooth muscle by means of gap junctions. ICCIM also may be involved in amplifying the slow waves as they spread through the muscle layers. Thus, these cells appear to be key players in integrating non-neuronal pacemaker activity and neuronal inputs to the smooth muscle.


The discovery that cellular mechanisms long considered to be the properties of smooth muscle cells actually are mediated by ICC may have important clinical implications. For example, in the distal bowel, reduced numbers of ICC, or a reduction in the total volume of ICC, has been associated with anorectal malformations, colonic manifestations of Chagas’ disease, and possibly some cases of slow-transit constipation.3 Some reports have suggested that the density of ICC may be reduced in aganglionic segments of colon in Hirschsprung’s disease and that this deficit might contribute to diminished propulsive activity; this finding, however, has not been consistent between studies.3



INNERVATION OF THE COLON1



THE ENTERIC NERVOUS SYSTEM


Direct neuronal control of colonic motility is mediated mostly by the enteric nervous system (ENS). Although the ENS is capable of expressing a diverse repertoire of motor patterns, its functions are modulated by sympathetic, parasympathetic, and extrinsic afferent pathways (Fig. 98-3). In terms of numbers of nerve cells, the ENS is by far the largest component of the autonomic nervous system, with considerably more neurons than those of the parasympathetic and sympathetic divisions combined. The nerve cell bodies of the ENS are located in plexuses of myenteric ganglia (Auerbach’s plexus), which lie between the longitudinal and the circular muscle layers of the muscularis externa, or in the submucosal ganglia, which lie between the circular muscle and the mucosa (Fig. 98-4).


image

Figure 98-3. The extrinsic innervation of the human colon. Parasympathetic efferent pathways (filled cell bodies) arise from the dorsal motor nucleus of the vagus in the brainstem and pass through the vagus nerve and prevertebral sympathetic ganglia, through the lumbar colonic nerves to the proximal colon. Parasympathetic pathways also extend from nuclei in the sacral spinal cord that run through the pelvic nerves and either synapse in the pelvic plexus ganglia or run directly into the bowel wall. Sympathetic pathways (open cell bodies) consist of preganglionic neurons in the thoracic spinal cord that synapse with sympathetic postganglionic neurons either in the inferior mesenteric plexus or in the pelvic plexus. Enteric nerve cell bodies in the colon receive input from both parasympathetic and sympathetic pathways. Viscerofugal enteric neurons project out of the bowel to the prevertebral ganglia. Afferent pathways consist of vagal afferent neurons from the proximal colon with cell bodies in the nodose ganglia. In addition, spinal afferent neurons with cell bodies in lumbar dorsal root ganglia (DRG) run through the lesser splanchnic and colonic nerves to the colon and mediate nociception. Another population of spinal afferents, with cell bodies in the sacral DRG, runs through the pelvic nerves and pelvic ganglia to the rectum; these include sensory neurons that transmit non-nociceptive information about the distention of the rectum. The striated muscles of the pelvic floor (including the external anal sphincter) are supplied by motor neurons with cell bodies in the spinal cord and axons that run in the pudendal nerves. Triangles represent transmitter release sites; combs represent sensory transduction sites.


image

Figure 98-4. Diagram showing the layers and components of the intestinal wall. The lumen is at the top and the longitudinal muscle layer is at the bottom. Auerbach’s myenteric plexus and the submucosal plexuses (Meissner’s and Schabadasch’s plexuses) are shown, along with some of their major classes of enteric neurons. The networks of interstitial cells are shown in Figure 98-1.


The submucosal plexus is divisible into at least two networks: Meissner’s plexus, which lies closer to the mucosa, and Schabadasch’s plexus, which lies adjacent to the circular muscle. Some authors have identified an additional intermediate plexus. Internodal strands that contain hundreds of axons run within and between the different plexuses. Finer nerve trunks innervate the various target tissues of the intestinal wall, including the longitudinal muscle layer, circular muscle, muscularis mucosae, mucosal crypts, and mucosal epithelium. Within the ganglia of each plexus, different functional classes of enteric nerve cell bodies are intermingled, although differences in the proportions of cell types among the plexuses have been observed. It has become clear that an exquisite degree of organization is characteristic of the ENS, each class of nerve cell making highly specific and precise projections to its particular target.


The ENS uses many transmitters in addition to the major transmitters acetylcholine and nitric oxide, including tachykinins, purines, numerous other modulatory peptides, and some amines. Many other substances, released from neural and non-neural cells, also modulate neuronal and muscular excitability, including gaseous mediators (carbon monoxide and hydrogen sulfide) and, in inflammation, prostanoids, cytokines, purines, bradykinin, H+ ions, and neurotrophins.



Primary Afferent Neurons


Much of the motor and secretory activity of the intestine can be conceptualized as a series of reflexes evoked by mechanical or chemical stimuli. These reflexes involve activation of enteric primary afferent neurons, integration by interneurons, and execution of appropriate responses by motor neurons. The first neurons in these reflex circuits are primary afferent neurons (sometimes called “sensory” neurons, although they do not give rise to conscious sensation). These neurons are located in both myenteric and submucosal plexuses and characteristically have several long axonal processes. Some primary afferents fire action potentials in response to stretch or tension in the bowel wall; others are activated by chemical or mechanical stimuli of the mucosa. These mucosal stimuli probably work, at least in part, by activating specialized enteroendocrine cells in the mucosal epithelium, such as the serotonin-containing enterochromaffin cells. The primary afferent neurons then release synaptic transmitters, such as acetylcholine or tachykinins or other peptides, to excite other classes of enteric neurons in nearby ganglia. Enteric primary afferent neurons also make excitatory synaptic contacts onto other neurons of their own class, so that they fire in coordinated assemblies.



Motor Neurons


Enteric motor neurons typically have smaller cell bodies than afferent neurons, with a few short dendrites and a single long axon. Separate populations of motor neurons innervate the circular and longitudinal muscle layers. Excitatory motor neurons synthesize acetylcholine, which they release from their varicose endings in the smooth muscle layers; some also release the tachykinin peptides, substance P and neurokinin A, which excite smooth muscle. Typically, axons of excitatory motor neurons project either directly to the smooth muscle close to their cell bodies or orad for up to 10 mm.4 Once in the smooth muscle layers, the axons turn and run parallel to the smooth muscle fibers for several millimeters; they branch extensively and form many small varicosities, or transmitter release sites, closely associated with intramuscular ICC (ICCIM).


Inhibitory motor neurons typically are slightly larger than excitatory motor neurons, and there are fewer of them. They also have short dendrites and a single axon but, unlike excitatory motor neurons, they project aborally to the smooth muscle layer for distances of 1 to 15 mm in the human colon.4 Once the axon reaches the smooth muscle, it branches extensively to form multiple varicose release sites. Inhibitory motor neurons release a cocktail of transmitters that inhibit smooth muscle cells, including nitric oxide, adenosine triphosphate (ATP), and peptides, such as vasoactive intestinal polypeptide (VIP) and pituitary adenyl cyclase-activating peptide (PACAP). The varicose transmitter release sites of inhibitory motor neurons also are associated with ICCIM, just as are the release sites of excitatory motor neurons. Interstitial cells probably mediate a large component of the electrical effects on smooth muscle of neurotransmitters released by enteric motor neurons. Inhibitory motor neurons usually are tonically active, modulating the ongoing contractile activity of the colonic circular smooth muscle. Inhibitory motor neurons are particularly important in relaxing sphincteric muscles in the ileocecal junction and the internal anal sphincter.



Interneurons


When a region of colon is stimulated, such as by a bolus that distends it, intrinsic primary afferent neurons (IPANs) are activated. These neurons then activate excitatory and inhibitory motor neurons, which, because of their polarized projections, cause contraction of the muscle orad to the bolus and relaxation aborally. These effects tend to propel the contents aborally. From the new position of the bolus, another set of polarized reflexes is triggered, and peristaltic propulsion results. The ascending excitatory reflex and the descending inhibitory reflex sometimes are called “the law of the intestine.” These reflexes spread farther than is predicted by the projections of the excitatory and inhibitory motor neurons, because interneurons also are involved in these reflex pathways. Ascending cholinergic interneurons in the human colon have axons that project up to 40 mm orad and extend the spread of ascending excitatory reflex pathways. In addition, several classes of descending interneurons are present in the human colon, with axons that project up to 70 mm aborally. Some of these interneurons are involved in spreading descending inhibition along the colon, but others are likely to be involved in the propagation of migratory contractions. It also is likely that some interneurons are themselves stretch sensitive, thereby functioning as primary afferent neurons. In addition to the sensory neurons, interneurons, and motor neurons, viscerofugal nerve cells project to the sympathetic prevertebral ganglia, vasomotor neurons innervate blood vessels, and secretomotor neurons stimulate secretion from the colonic epithelium.



SYMPATHETIC INNERVATION


The major sympathetic innervation of the proximal colon arises from the inferior mesenteric ganglion and projects through the lumbar colonic nerves to the ascending and transverse colon (see Fig. 98-3). A small number of sympathetic neurons in the celiac and superior mesenteric ganglia, in the paravertebral chain ganglia, and in the pelvic plexus ganglia also project to the colon (see Fig. 98-3). These neurons receive a powerful cholinergic drive from preganglionic nerve cell bodies in the intermediolateral column of the spinal cord (segments L2-L5). This is a major pathway by which the central nervous system modifies bowel activity, such as during exercise. Sympathetic efferent neurons also receive input from the enteric viscerofugal neurons and from extrinsic, spinal sensory neurons with cell bodies in the dorsal root ganglia, forming several reflex loops with the distal bowel.


Sympathetic nerve fibers from prevertebral ganglia cause vasoconstriction of the mucosal and submucosal blood vessels. Other cells project to the enteric ganglia, where they cause presynaptic inhibition of synaptic activity in the ENS and thus depress reflex motor activity. Another target for sympathetic axons is the circuitry of the submucosal plexus (largely Meissner’s plexus) involved in controlling epithelial secretion. Hence, these pathways inhibit colonic motor activity, reduce blood flow, and inhibit secretion to limit water loss from the body during times of sympathetic activation. In addition, some sympathetic axons innervate the smooth muscle directly, particularly the ileocecal junction and internal anal sphincter, where they cause contraction; these effects also are consistent with closing down enteric motor activity during sympathetic arousal.



PARASYMPATHETIC INNERVATION

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May 31, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Colonic Motor and Sensory Function and Dysfunction

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