Review Article: The Role of Serotonergic Agents in the Treatment of Patients With Primary Chronic Constipation

B.D. Cash; W.D. Chey

Disclosures

Aliment Pharmacol Ther. 2005;22(11):1047-1060. 

In This Article

The Brain-Gut Axis and the Role of Serotonin in Gastrointestinal Function

The ENS regulates motor, secretory and sensory functions through an extensive neural network contained within the GI tract. It functions semiautonomously but is influenced by bidirectional communication with the central nervous system (CNS) through the autonomic nervous system. The ENS is composed of 'intrinsic' and 'extrinsic' neurones. Intrinsic pathways consist of primary afferent neurones (IPANs), which respond to physiological stimuli such as distension and inflammation and mediate motor and secretory reflexes. IPANs are located in the submucosal and myenteric plexuses and, along with interneurones and motor neurones, form integrated local circuits.[21,22,23,24] Extrinsic pathways relay information to and from the CNS through the autonomic nervous system. Sympathetic neurones within spinal afferent and splanchnic pathways primarily convey sensory information to the CNS but also can exert inhibitory influence on the motor activities of the gut. Conversely, parasympathetic neurones located in vagal and sacral afferents facilitate communication from the CNS to the ENS and also exert a predominantly stimulatory motor influence to the gut (Figure 1). The aggregate of these neuronal pathways serves as the foundation of what is referred to as the brain-gut axis.[25]

Bidirectional brain-gut interactions. Originally published in Am J Health Syst Pharm 2005; 62: 700-11. © 2005, American Society of Health-System Pharmacists, Inc. All rights reserved (reprinted with permission; R0515). ENS, enteric nervous system; CNS, central nervous system; ANS, autonomic nervous system; IPANs, intrinsic primary afferent neurones.

As in the CNS, molecular messengers are responsible for selective neuronal activation in the ENS. Numerous neurotransmitters and neuropeptides have been identified in the ENS, including calcitonin-gene receptor protein (CGRP), substance P, vasoactive intestinal peptide, nitric oxide, adenosine triphosphate, acetylcholine (ACh) and serotonin (5-HT). Of these, serotonin has been found to be most relevant to the neural pathways involved with motility, secretion and sensation within the GI tract, and significant physiological evidence demonstrates its effects on these functions.[26]

Serotonin is a prominent neurotransmitter and mucosal signalling molecule associated with a wide variety of physiological actions within the human body. Although widely distributed, virtually all plasma serotonin originates from EC cells located within the gut. In fact, more than 90% of the body's total serotonin content localizes to the GI tract.[25]It should come as no surprise then that serotonin plays an important role in a broad range of functions in the gut.[26,27] To date, 14 serotonin receptor subtypes have been identified. Of these, type 1 (5-HT1), type 2 (5-HT2), type 3 (5-HT3), type 4 (5-HT4) and type 7 (5-HT7) have been implicated in the function of the GI tract.[21,28] The greatest knowledge related to GI health and disease has been accumulated on the 5-HT3 and 5-HT4 receptor subtypes.[21]

The 5-HT3 receptors, which can be found in both the ENS and the CNS, are vital to GI motility, secretion and sensation. Stimulation of these ligand-gated ion-channels results in a fast inward current responsible for mediating a subset of fast excitatory postsynaptic potentials in the ENS (most are mediated by ACh).[27] 5-HT3 receptors have been localized to emetic pathways, providing an explanation for the antiemetic properties offered by 5-HT3 receptor antagonists such as ondansetron and granisetron. Peripherally, these receptors can be found on intrinsic and extrinsic neurones of the myenteric plexus. Blocking these receptors at this level with 5-HT3 receptor antagonists alters the colonic peristaltic reflex, decreases postprandial colonic motility,[29,30] delays colonic transit and alters colonic compliance.[31] Another important role of 5-HT3 receptors is to transmit sensory information to primary spinal afferent nerves and higher CNS levels. Serotonin release from EC cells appears to stimulate 5-HT3 receptors on vagal afferents, potentially resulting in nausea and other non-painful gut sensations such as bloating and abdominal fullness. Antagonism of 5-HT3 receptors may thereby reduce symptoms associated with altered visceral sensation, as can be the case in patients with IBS.[27,32,33,34] With this as background, it makes intuitive sense that 5-HT3 receptor antagonists are most appropriate for patients with IBS whose primary bowel symptom is diarrhoea. Alternatively, it is conceivable that a 5-HT3 agonist might be of benefit to patients with IBS whose primary bowel symptom is constipation.

In contrast to 5-HT3 receptors, 5-HT4 receptors are G protein-coupled receptors found on smooth muscle cells, EC cells, myenteric plexus neurones and IPANs.[21] Although they are not directly involved in initiating the peristaltic or secretory reflex, 5-HT4 receptors work in conjunction with other 5-HT receptors to augment peristalsis and secretion by mediating the release of other neurotransmitters directly involved in GI motility, such as ACh and CGRP. The peristaltic reflex is typically initiated in response to food or luminal distension, and serotonin release from EC cells is an initiating event in this process. Once released, serotonin stimulates 5-HT1P receptors on the presynaptic nerve endings of IPANs in the submucosal plexus. The signal from the 5-HT1P receptor is communicated to 5-HT4 receptors, which are located on the terminals of submucosal IPANs. Secondary messengers (ACh and CGRP) then activate a unique neuromuscular cascade in which excitatory neurotransmitters are released in an orad direction and inhibitory neurotransmitters are released caudally. These differing regional effects lead to coordinated proximal smooth muscle contraction and distal smooth muscle relaxation, resulting in effective peristalsis (Figure 2).[21]

The peristaltic reflex (adapted from Grider et al. Gastroenterology 1998; 115: 370, Baker Am J Health Syst pharm 2005; 67: 700 and Gershon J Clin Gastroenterol 2005; 39(4): S184). 5-HT, serotonin; ENS, enteric nervous system; CNS, central nervous system; CGRP, calcitonin gene-related peptide; Ach, acetylcholine; VIP, vasoactive intestinal peptide; NO, nitric oxide; NKA, neurokinin A; PACAP, pituitary adenylate cyclase-activating peptide; IPAN, intrinsic primary afferent neurone, ESN, extrinsic sensory neurone.

In addition to promoting peristalsis, the effect of stimulation of colonic 5-HT4 receptors on other gut functions makes them an attractive mechanistic target for agents directed at treating constipation. These receptors also modulate stool fluid content through cyclic adenosine monophosphate-mediated release of chloride from colonocytes such that stimulation increases the water content of stool.[35] There is also preliminary evidence that 5-HT4 receptor agonists can decrease visceral hypersensitivity.[36,37,38] For example, tegaserod (a 5-HT4 receptor agonist) was able to (i) inhibit rectal distension-induced responses and limbic system c-Fos expression in rats with experimentally induced visceral hypersensitivity,[36] (ii) decrease the firing rate of rectal sensory nerves after visceral distension in a cat model[37] and (iii) inhibit the RIII reflex, a human model of visceral nociception, in humans,[38] and it has been shown to reduce abdominal pain/discomfort in patients with IBS-C or chronic constipation.[39] The postulated mechanisms for these effects include modulation of primary spinal afferent transmission or inhibition of descending bulbospinal pathways; however, the precise mechanism(s) remains to be clearly defined.[40] Whether these emerging data using experimental models will translate into meaningful effects on pain in clinical practice remains to be determined.

         In recent years, a number of serotonergic agents have been developed for use in patients with GI conditions (          Table 2          ),[39,41,42,43,44,45,46,47,48,49,50,51,52] such as chemotherapy-induced, radiation-induced, and postsurgical nausea and vomiting, and with GI motility disorders. These agents, which function as selective 5-HT3 and 5-HT4 receptor antagonists and/or agonists, have markedly different actions, both physiologically and clinically.        

As in the CNS, serotonin levels in the perineural spaces of the ENS are regulated by the serotonin reuptake transporter (SERT), a plasma membrane protein that deactivates and degrades serotonin and whose function has been likened to a serotonin 'off' switch.[27] The presence of the SERT protein represents a physiological mechanism by which serotonin levels (and, thus, activity) are regulated. Abnormalities in SERT would be expected to result in disturbed GI motility. It has been suggested that impaired SERT activity (reduced uptake) could result in excessive serotonin-mediated receptor stimulation, manifesting clinically as diarrhoea. Eventually, as a result of excessive exposure, the sensitive G protein-coupled 5-HT4 receptors may undergo desensitization, resulting in constipation. Preliminary evidence from animals and humans appears to support this hypothesis. Mice devoid of the SERT gene have been observed to exhibit a cyclic diarrhoea-constipation sequence similar to that seen in a subset of patients with IBS and mixed bowel pattern.[53] Crowell et al.[40] and Coates et al.[54] have demonstrated that patients with IBS-C, IBS with diarrhoea and ulcerative colitis all have reduced mucosal serotonin and SERT mRNA expression compared with controls. Similar studies in patients with chronic constipation are not yet available.

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