The understanding of the pathogenesis ... PRESENTATION... The Role of Serotonin in the Pathophysiology of Irritable Bowel Syndrome

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1 ... PRESENTATION... The Role of Serotonin in the Pathophysiology of Irritable Bowel Syndrome Based on a presentation by Michael D. Crowell, PhD Presentation Summary Coordinated activities of the central, autonomic, and enteric nervous systems modulate intestinal motor, sensory, and secretory activities that may contribute to the triad of dysfunction (altered motility, altered sensation, and psychosocial distress) observed in patients with irritable bowel syndrome (IBS). Autonomic modulation of gastrointestinal (GI) function occurs via the actions of neurotransmitters and neuromodulators such as serotonin (5-hydroxytryptamine, or 5-HT), norepinephrine, and dopamine. Of those modulators, serotonin has received the most attention with respect to disorders of GI function. Serotonin exerts its effects via neurocrine, paracrine, and endocrine pathways. Recent studies have demonstrated that serotonin, acting primarily through 5-HT 3 and 5-HT 4 receptors, is intricately involved in initiating the peristaltic reflex and facilitating intraluminal secretions. Serotonin receptors mediate reflex control of GI motility and secretion and may influence the perception of bowel function and pain under some circumstances. GI motor activity and sensory dysfunction in patients with IBS may be a result of alterations in serotonin levels or associated 5-HT receptors. Serotonin agonists and antagonists such as tegaserod, a 5-HT 4 agonist, may offer new treatments that normalize GI motor and sensory functions in patients with disorders of GI function. The understanding of the pathogenesis of irritable bowel syndrome (IBS) has evolved considerably during the past 50 years. Early mechanistic hypotheses focused primarily on abnormalities of motor function (dysmotility) but were superseded by theories involving visceral hypersensitivity, which was once considered a definitive biological marker for IBS. 1 Recently, a more holistic mechanism of action involving brain-gut interactions has been used to explain the visceral hypersensitivity and abnormal gastrointestinal (GI) motility observed in those with IBS. 1 Alterations in both intrinsic and extrinsic nervous system function may cause altered visceral sensations or hypersensitivity, allodynia, dysfunctions in gastrointestinal motility, and abnormal secretions in the GI tract, all of which may be associated with the symptoms of IBS. The Brain-Gut Interaction Interactions between the brain and the enteric nervous system (ENS) occur via bidirectional neural pathways over both sympathetic and parasympathetic pathways (Figure 1). 2 Coordinated actions of the central nervous system (CNS), autonomic nervous system, and ENS modulate intestinal motor, sensory, and secretory activities. Disruptions of central autonomic integration between the brain and the gut may contribute to symptoms of IBS such as altered motility and sensation in the GI tract. 3 The central autonomic neural network integrates the CNS and the peripheral nervous system. In the periphery, the ENS exerts its effect directly on various effector systems, including muscles, the secretory endothelium, endocrine cells, and the vasculature. The CNS exerts modulatory influences on the ENS via parasympathetic and sympathetic S252 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2001

2 The Role of Serotonin pathways. Autonomic afferent pathways may also influence CNS activation. Local spinal reflexes and vago-vagal reflexes also modulate ongoing neuromuscular activity within the gut via influences on the ENS. 2 The ENS acts directly on effector systems to influence both secretion and motility, whereas intrinsic primary afferents from the effector systems also influence the ENS via local reflex pathways. These effector pathways are modulated by means of a wide array of neurotransmitters and neuromodulators, including serotonin (5-hydroxytryptamine, or 5-HT), norepinephrine, dopamine, acetylcholine, and calcitonin gene-related peptide (CGRP). 2 Serotonin Investigations into the mechanisms involved in these brain-gut interactions have focused primarily on serotonin, which mediates a variety of functions in both the GI tract and the brain and appears to play a major role in the pathophysiologic mechanism of IBS. Serotonin exerts its diverse effects via neurocrine, paracrine, and endocrine pathways and modulates both GI motor and sensory functions. Approximately 95% of all serotonin in the body is synthesized and stored in mucosal enterochromaffin (EC) cells within the GI tract. The remaining serotonin is located within the submucosal and myenteric plexuses and within the CNS. 4 The distribution and density of serotonin and its associated receptors vary significantly in different areas of the gut. Serotonin exerts its diverse effects via activation of numerous receptor subtypes Figure 1. Integration of the Central Nervous System and the Enteric Nervous System Central Nervous System Central Autonomic Neural Network Nodose ganglion Dorsal root ganglion Sympathetic ganglia Parasympathetic Nervous System Sympathetic Nervous System Parasympathetic ganglia Enteric Nervous System (myenteric plexus, submucous plexus) Intermediate cells Effector Systems (muscle, secretory epithelium, endocrine cells, vasculature) VOL. 7, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S253

3 PRESENTATION Figure 2. Autonomic Integration Model of the Serotonergic and Adrenergic Systems A B C Panel A. Autonomic balance. Panel B. Adrenergic predominance (irritable bowel syndrome with constipation). Panel C. Serotonergic predominance (irritable bowel syndrome with diarrhea). in the brain and in the peripheral nervous system. As many as 14 distinct receptor subtypes have been identified. The distribution and function of serotonin receptors are both species specific and tissue specific. The subtypes of most importance in the GI tract appear to be 5-HT 1A, 5-HT 1P, 5-HT 2, 5-HT 3, and 5-HT 4. Serotonin is released after the activation of a presynaptic neuron or stimulation of mucosal EC cells. Depending on the subtype, number, density, and location of serotonin receptors, a relatively specific physiologic response is initiated. The physiologic response is usually selflimiting. After serotonin has been released, it is subsequently inactivated by reuptake via 5-HT transporters, diffusion into the circulation, and/or metabolization. Additional serotonin release is limited via activation of inhibitory 5- HT 4 autoreceptors located on some presynaptic neurons and by inhibition of EC cell secretion. Abnormal Autonomic Integration in Patients with IBS Altered autonomic integration involving both serotonergic and adrenergic systems may account for both intestinal and extraintestinal symptoms in patients with IBS. The model of autonomic integration of those systems shown in Figure 2 illustrates that hypothesis. Under normal circumstances (Panel A), the primary autonomic systems are balanced. The serotonergic and noradrenergic systems inhibit each other, and both aminergic systems can influence the dopaminergic system via inhibitory or excitatory influences and modulate the availability of acetylcholine. An adrenergic predominance may be involved in some IBS patients with constipation (Panel B). In those cases, the norepinephrine (adrenergic) system predominates and reduces the influence of the serotonergic system, thus increasing the activity of the dopaminergic inhibitory system, reducing the bioavailability of acetylcholine, and reducing the contractility of the GI tract. S254 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2001

4 A serotonergic predominance may be associated with IBS patients with diarrhea (Panel C). In those cases, the predominance of serotonin inhibits the adrenergic system and reduces norepinephrine and the activity of the dopaminergic system. As a result, acetylcholine predominates, particularly in the peripheral nervous system, and increased propulsive activity, increased secretion, and diarrhea may occur. Serotonin Receptor-Mediated Effects The effects mediated by serotonin in the GI tract, such as the control of GI motility and secretion and the modulation of the perception of bowel function and pain, are varied and depend on the receptor subtypes engaged. The 5-HT 3 receptor usually exerts excitatory influences within the GI tract. Unlike all other 5-HT receptor subtypes, the 5-HT 3 receptor is a ligand-gated cation channel rather than a G-coupled protein receptor. Activation of 5- HT 3 receptors enhances GI motility, secretion, and sensation. Therefore, 5-HT 3 antagonists slow colonic transit and increase fluid absorption, thus improving symptoms in some IBS patients with diarrhea. The 5-HT 3 antagonists may also attenuate visceral nociception resulting from colorectal distension. 5 However, these effects likely resulted from increased colorectal compliance after the administration of 5-HT 3 antagonists. Such findings strongly suggest that these new compounds are beneficial in the treatment of IBS with diarrhea. The 5-HT 4 agonists are G-coupled proteins that exert both excitatory and inhibitory effects within the GI tract, depending on the location and density of the receptors. These agonists may directly excite or inhibit neural and smooth muscle cells and may also inhibit the release of additional serotonin from neurons and EC cells. 6 The 5-HT 4 agonist tegaserod enhances the peristaltic reflex in response to intraluminal stimulation, which in turn stimulates intestinal and colonic transit. 6 Tegaserod also stimulates the camp-dependent intraluminal secretion of chloride; improves overall symptoms of abdominal pain, discomfort, and bloating; and increases the frequency of bowel movements in IBS patients with constipation. 6,7 Serotonin Initiates the Peristaltic Reflex Serotonin is directly involved in the initiation of the peristaltic reflex mediated by the ENS (Figure 3). The peristaltic reflex is triggered by a bolus that moves through the lumen and causes distension, mucosal stimulation, and the release of 5-HT from EC cells. Serotonin then binds to and activates 5-HT 4 receptors located on intrinsic primary afferent neurons (IPANs) containing CGRP. IPANs synapse with both ascending and descending interneurons in the myenteric plexus. Figure 3. Initiation of the Peristaltic Reflex by Serotonin Orad Motor Neuron Ascending Contraction ACh/SP/NKA Interneuron Myenteric Plexus 5-HT 4 Receptor CGRP IPAN Bolus Interneuron 5-HT The Role of Serotonin EC Cells Caudad Motor Neuron Descending Relaxation VIP/NO/PACAP ACh = acetylcholine; CGRP = calcitonin gene-related peptide; EC = enterochromaffin; IPAN = intrinsic primary afferent neuron; NKA = neurokinin A; NO = nitrous oxide; PACAP = pituitary adenylate cyclase activating polypeptide; SP = substance P; VIP = vasoactive intestinal polypeptide. VOL. 7, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S255

5 PRESENTATION Ascending excitatory motor neurons release acetylcholine and tachykinins (substance P and neurokinin A) at the myocyte, which results in circular muscle contraction orad to the intraluminal bolus. Simultaneously, descending inhibitory interneurons signal the myocytes caudal to the bolus to release vasoactive intestinal polypeptide, nitric oxide, and pituitary adenylate cyclaseactivating polypeptide, which results in circular muscle relaxation. Thus increased intraluminal pressures from the contraction behind the bolus and decreased intraluminal pressures that precede the bolus cause a net forward movement of the luminal contents. 8 Recent in vitro data from human, rat, and guinea pig intestines suggest that 5- HT 4 receptors are primary mediators of the peristaltic reflex. 8 Those data indicated that stimulation of isolated compartmented segments from human jejunum, rat colon, and guinea pig colon with nanomolar concentrations of the 5-HT 4 agonists tegaserod and prucalopride facilitated both ascending contraction and descending relaxation. When tissues were pretreated with antagonists of CGRP or 5-HT 4, both the ascending and descending responses were significantly reduced. Antagonism of the 5-HT 3 receptor had no significant effect. The data clearly demonstrate that 5-HT 4 receptors, which are located on primary sensory CGRP neurons, are involved in the peristaltic reflex. The Role of Visceral Hypersensitivity in Patients with IBS Altered visceral sensation in the form of hypersensitivity or allodynia plays a significant role in the pathogenesis of IBS. 9 The increased perception of visceral afferent stimulation observed in patients with IBS may occur in response to both normal GI function and to noxious or higher-level stimuli. Increased sensitivity to or perception of painful stimuli may result in abdominal pain or discomfort. Evidence suggests that an exaggerated response to a normal stimulus or allodynia may be involved in this increased sensitivity to pain. The many potential mediators involved in this response include serotonin, bradykinin, tachykinins, CGRP, and neurotrophins. The increased level of psychological distress in patients with IBS can lead to increased anxiety and hypervigilance that results in a generalized hypersensitivity. Investigations of pain thresholds in IBS patients compared with those in healthy controls suggest that patients with IBS have a specific (rather than a general) visceral hypersensitivity. Although a significantly higher proportion of patients with IBS report pain in response to rectosigmoid balloon distension than do normal controls, determinations of somatic pain thresholds in the periphery have shown either elevated pain thresholds in IBS patients or no differences in the pain thresholds of IBS patients and those of controls. 10,11 Under normal conditions, pain signals are transmitted from the periphery outside the CNS to the spinal cord via primary nociceptive afferents (C fibers and A-δ fibers), which release neurotransmitters from the presynaptic junction. The neurotransmitters usually involved include glutamate and substance P, both of which activate receptors on the postsynaptic membrane. Under normal circumstances, the primary receptor for glutamate is an alpha-amino-3-hydroxy- 5-methyl-4-isoxazole propionic acid receptor, and the primary receptor for substance P is the neurokinin-1 receptor. Glutamate also activates the N-methyl-daspartate (NMDA) receptor under special circumstances, but that receptor does not play a role in normal nociceptive transmission because the channel is blocked by magnesium. Under basal conditions, the 5-HT 3 and 5-HT 4 receptors also do not appear to be directly involved in nociceptive transmission. After sensitization of the primary afferent fibers, however, significant changes occur in the postsynaptic membrane that can lead to a hyperresponsive state. After inflammation, for example, the receptors involved in normal pain S256 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2001

6 The Role of Serotonin transmission continue to be active, but additional receptors that facilitate pain transmission may become available. Inflammation often results in the increased release of serotonin and in the activation of 5-HT 3 and 5-HT 4 receptors. The translocation and increased expression of receptors sensitive to neurotrophins and tachykinins also occur. In addition, NMDA phosphorylates the magnesium block, which opens the NMDA receptors. Those receptors are then capable of receiving their respective transmitters when the sensitized neuron is stimulated, which dramatically increases afferent signaling. The Role of Receptor Subtypes in Pain Processing Serotonin appears to play a major role in the visceral hypersensitivity seen in patients with IBS. Serotonin is released by EC cells after colonic distension or intraluminal stimulation, both of which result in the subsequent activation of 5- HT 3 and 5-HT 4 receptors on intrinsic and extrinsic afferent fibers (Figure 4). Under inflammatory conditions, mast cells are also stimulated; this promotes the release of inflammatory agents and an increase in the level of serotonin. Data that delineate the role of 5-HT receptor subtypes in visceral hypersensitivity have now been published. It is possible that 5-HT 3 receptors are involved in visceral nociceptive transmission via primary spinal afferent neurons. 12 * Nociceptive colonic distension causes the increased expression of the protooncogene c-fos in the dorsal horn neurons of the spinal cord and specific brain structures. C-fos is a specific and reliable marker of central neuronal activation after visceral stimulation, including pain. In the spinal cord, the superficial layers (laminae I and II) are most associated with spinal nociceptive *Note: The labeling changes for alosetron and its subsequent removal from the US market were implemented after the symposium upon which this article is based was held. Alosetron is, however, currently being considered for reintroduction to the market. afferents and pain processing from the viscera. Antagonism of the 5-HT 3 receptors has been shown to inhibit spinal c-fos when administered prior to colorectal distension. 12 A dose-dependent reduction in c- fos was noted in laminae I and II, thus suggesting the involvement of 5-HT 3 receptors in the transmission of nociceptive information from the periphery to the dorsal horn of the spinal cord. Although recent data 13,14 suggest a significant involvement of 5-HT 4 receptors in visceral sensation and perception, the exact mechanism of action is unknown. The 5-HT 4 agonist tegaserod was shown to inhibit afferent electrical activity from sacral spinal fibers in a spinalized, decerebrate feline model. 13 Isobaric colorectal distension induced a dose-dependent increase in the firing rate of rectal afferent fibers in S2 and S3 of the sacral cord that was significantly and dose-dependently inhibited by clinically relevant concentrations of tegaserod. Tegaserod produced no significant effect on rectal compliance in this model; this suggests that tegaserod exerts a direct effect on visceral afferent fibers. Similar findings have been reported in a well-established rodent model of visceral pain. 14 The frequency of abdominal contractions during colorectal distension in that model was shown to be directly related to the intensity of stimulation. The investigators demonstrated a dosedependent decrease in the frequency of abdominal contractions during colorectal balloon distension after pretreatment with tegaserod (1 mg/kg). Differential Processing of the Sensation and Perception of Pain Consistent with the brain-gut hypothesis, alterations in the sensation and perception of pain in patients with IBS may occur at many levels, including higher CNS centers such as the brain. Evidence has shown that patients with IBS appear to differ in their CNS integration and processing of afferent signals from the gut. Pain transmission is initiated in the periphery by the increased stimulation of VOL. 7, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S257

7 PRESENTATION A-δ and C fibers that traverse the dorsal root ganglion and synapse with neurons in laminae I, II, and V of the dorsal horn of the spinal cord (Figure 5). These impulses then cross to the contralateral side and ascend in spinothalamic and spinoreticular tract formations to the brain through ascending pathways that involve numerous neurotransmitters. Pain perception and the activation of inhibitory and facilitory pathways occur at the level of the brain stem. From the higher brain centers, descending pathways may activate the nuclei of the periaqueductal gray, the nucleus raphae magnus, and the local ceruleus. The descending inhibitory and facilitory pain pathways involve serotonin and norepinephrine, which probably exert their effects through final pathways involving opiate receptors. Recent studies 15 have demonstrated differential central processing of colorectal stimulation in patients with IBS compared with that in healthy controls. Using positron emission tomography (PET) to identify areas of increased blood flow, Silverman et al 15 demonstrated that the perception of acute rectal pain during noxious rectal distension and during the anticipation of rectal pain was associated with the activation of the anterior cingulate cortex in healthy subjects. This area is rich in opiate receptors and is thought to be involved in the modulation of descending spinal path- Figure 4. Role of Serotonin in Pain Transmission Abdominopelvic (greater, lesser, and least) splanchnic nerves Vagus nerve (X) Nodose ganglion to brain Pain 5-HT 3 A-δ 5-HT 3 5-HT 4 CGRP Celiac ganglion 5-HT Distension stimulation Enteric plexuses of gut EC cells Mast cells CGRP = calcitonin gene-related peptide; EC = enterochromaffin. S258 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2001

8 The Role of Serotonin ways and the inhibition of pain, as well as with cognition and the attentional aspects of perception. In patients with IBS, rectal distension failed to activate the anterior cingulate cortex but instead elicited slight changes in the left prefrontal cortex. These results suggest that in patients with IBS, central descending inhibitory pathways may not be activated; this results in up-regulated neuronal activation in the dorsal horn centers associated with pain transmission. In summary, patients with IBS may process information differently from those without the condition and may lack the descending stimulus necessary to inhibit the function of pain pathways. Recently, Mertz et al 16 used functional magnetic resonance imaging (MRI) to further investigate differences in pain processing. In contrast to the results of PET studies, 15 functional MRI data suggested that patients with IBS may have a normal pattern of activation but a heightened pain sensitivity in the brain-gut axis. The study also demonstrated that colorectal stimulation led to activation of the anterior cingulate gyrus in most nor- Figure 5. Processing of Pain Information Pain Descending pain pathway (5-HT and NE) PAG NRM Spinal sensory (dorsal root) ganglion Laminae I, II, and V Ascending pain pathway Spinothalamic tract A-δ fibers C fibers NE = norepinephrine; NRM = nucleus raphae magnus; PAG = periaqueductal gray. VOL. 7, NO. 8, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S259

9 PRESENTATION mal subjects as well as in those with IBS. In addition, activation was also observed in most subjects in the prefrontal cortex, the insular cortex, and the thalamus, which is also involved in descending inhibitory pathways. However, in patients with IBS, a greater activation of the anterior cingulate cortex was noted after painful stimuli as opposed to nonpainful stimuli. Patients with IBS also reported greater intensity of pain during rectal distension than did controls. These results differ from earlier studies and suggest a heightened central sensitivity to visceral afferent signals in patients with IBS. Technical differences among these studies may account for the difference in results. Current intensive investigation in this exciting arena will provide more information about the CNS processing of visceral sensation in the near future. Summary Altered CNS integration involving serotonin and norepinephrine may cause intestinal and extraintestinal symptoms in those with IBS. Serotonin directly and indirectly affects intestinal motor and secretory functions at the level of the ENS, and abnormalities of those nervous system functions may lead to constipation or diarrhea. Serotonin significantly modulates sensation and the perception of visceral stimuli at both peripheral and central sites via its effect on primary afferent fibers and acts in conjunction with other neurotransmitters and neuromodulators to produce these effects. Specific 5-HT receptor subtypes also modulate intraluminal chloride secretion, water secretion, and fluid absorption within the lumen of the GI tract. The 5-HT 3 and 5-HT 4 receptors have a pivotal role in the motor, sensory, and secretory regulation of the GI tract and in the pathophysiologic effects of IBS.... REFERENCES Drossman DA. Review article: An integrated approach to the irritable bowel syndrome. Aliment Pharmacol Ther 1999;13(suppl 2): Goyal RK, Hirano I. The enteric nervous system. N Engl J Med 1996;334: Coulie B, Camilleri M. Irritable bowel syndrome: Epidemiology, mechanism, and management. Clin Perspect Gastroenterol 1999;2: Gershon MD. Review article: Roles played by 5- hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther 1999;13(suppl 2): Prior A, Read NW. Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5-HT 3 - receptor antagonist, in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1993;7: Scott LJ, Perry CM. Tegaserod. Drugs 1999;58: Stoner M, Arcuni J, Lee J, Kellum JN. A selective 5HT 4 receptor agonist induces c-amp mediated Clefflux from rat colonocytes [abstract]. Gastroenterology 1999;116:A Grider JR, Foxx-Orenstein AE, Jin JG. 5- Hydroxytryptamine 4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998;115: Bueno L, Fioramonti J, Delvaux M, Frexinos J. Mediators and pharmacology of visceral sensitivity: From basic to clinical investigations. Gastroenterology 1997;112: Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome: Physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 1980;25: Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology 1990;98(pt 1): Kozlowski CM, Green A, Grundy D, Boissonade FM, Bountra C. The 5-HT 3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat. Gut 2000;46: Schikowski A, Mathis C, Thewiben M, Ross H- G, Pak MA, Enck P. Dose-dependent modulation of rectal afferent sensitivity by a 5HT 4 receptor agonist [abstract]. Gastroenterology 1999;116:A Coelho AM, Rovira P, Fioramonti J, Bueno L. Antinociceptive properties of HTF919 (tegaserod), a 5- HT 4 receptor partial agonist, on colorectal distention in rats [abstract]. Gastroenterology 2000;118:A Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997;112: Mertz H, Morgan V, Tanner G, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology 2000;118: S260 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2001