Disease Basis

6.29.2.1 Basic Neurophysiology of the Gastrointestinal Tract 6.29.2.1.1 Neuronal control of gastrointestinal function

Consisting of as many neurons as are found in the spinal cord (~ 100 million),37'38 the enteric nervous system (ENS), composed of the myenteric and submucosal plexuses,39 can micromanage peristaltic and secretory reflexes of the intestines in an essentially independent manner (i.e., in the absence of control from the brain, spinal cord, dorsal root ganglia, or cranial nerve ganglia)40; it thus often is referred to as the second brain.41-44

To organize and manage the behavior patterns of the intestines, the ENS must possess the ability to sense the conditions prevailing in the enteric lumen (e.g., pressure, pH, nutrient status). In the absence of nerve fibers in the GI lumen, sensory signaling occurs transepithelially via enteroendocrine cells. An example of these is the enterochromaffin (EC) cells, the primary storage sites for serotonin (or 5-hydroxytryptamine (5HT)). Approximately 95% of the 5HT produced by the body is found in the bowel.40 The release of 5HT from EC cells is a pivotal first step in the initiation of gut motility and secretion.40

Although able to perform its basic functions in isolation, neural regulation of the ENS is composed of both intrinsic and extrinsic components.43,45-47 Intrinsically, gut activity is monitored by intrinsic primary afferent neurons (IPANs) located in the submucosal and myenteric plexuses. IPANs are the first neurons to receive the signal from transmitters such as 5HT released from enteroendocrine cells and enable the ENS to mediate reflex responses independently of the central nervous system (CNS) influence. The CNS uses peripheral sensors to monitor the environment and transmits the information to the brain via dorsal root and cranial nerve ganglion cells. Similarly, IPANs are the first neuronal component in the intrinsic sensory system of the bowel responding to luminal stimuli. However, a key difference between CNS primary afferent nerves and IPANs is that the latter do not directly sense the luminal content. IPANs work by transmitting information from the enteroendocrine cell sensors (e.g., EC cells) to the motor neurons of the submucosal and myenteric plexuses. Submucosal IPANs, which secrete calcitonin gene-related peptide (CGRP) and acetylcholine (ACh), appear to be critical for mucosal-related actions, including peristaltic and secretory reflexes. Unlike the case with dorsal root and cranial nerve sensory ganglion neurons, IPANs are innervated, allowing them both to act as interneurons and initiate gut-related reflexes.40

Extrinsic innervation of the gut is composed of the two anatomically integrated branches of the autonomic nervous system (sympathetic and parasympathetic), with sensory afferent nerves traveling along the efferent fibers in the same nerve bundles.41'49 The spinally directed afferent neurons travel primarily with the sympathetic pathway, composed of splanchnic (spinal) primary afferent neurons, but also in the pelvic nerve alongside parasympathetic fibers innervating the colon. These nerves are involved in the transmission of sensory signals that are perceived (e.g., pain, bloating, discomfort), and the overall action of the sympathetic efferent limb is to reduce GI activity via stimulation of contraction of sphincteric muscle and relaxation of nonsphincteric muscle. The vagal afferent fibers travel in parallel with the vagal efferent fibers in the vagus nerve. The vagal afferents relay primarily nonperceived (chemosensory, motor) gut-related physiological activity to the brain (although nausea is also mediated via signals beginning in the vagus nerve), and parasympathetic efferents exert an excitatory influence on enteric neurons (stimulate GI activity). Overall, the parasympathetic nervous system provides stimulatory activation of nonsphincteric muscle.

6.29.2.1.2 Key roles of 5-hydroxytryptamine in gastrointestinal function

Serotonin is a major player in the overall functioning of the bowel, with 95% of the serotonin produced by the body found in the GI mucosa, from which it is released as the pivotal first step in the initiation of gut motility and secretion.40 Because evidence exists for a disruption of serotonin signaling in the GI tract as a pathophysiological factor in IBS and other GI diseases (discussed next) and because the major therapeutic agents currently used in the treatment of patients with IBS act upon the serotonin system, it is important that we consider this system in some detail in this review of the IBS disease area.

Of numerous neurotransmitters involved in communication along the brain-gut axis, 5HT is a common link in several key processes of the GI tract, including GI motility, intestinal secretion, and perception of pain (Table 2).45,50-52

Motor and secretory reflexes (e.g., peristalsis) are initiated via intrinsic ENS neurons, whereas bowel-related sensations (e.g., bloating, pain) are initiated via extrinsic afferent nerves.5,45,53-57

6.29.2.1.2.1 5-Hydroxytryptamine and gastrointestinal motility and secretion

5HT is involved in initiating and maintaining a cascade of coordinated events that comprise the peristaltic reflex (Figure 1),51'52'5«'59 which is triggered by distension of the gut lumen and/or mechanical disturbance of intestinal villi by a food bolus. These stimuli result in release of 5HT from the EC cells. There has been debate in the literature around the subtype of receptor responsible for the initiation of the ensuing enteric reflexes (see Section 6.29.2.1.2.3),

Table 2 Key mediators of gut function5'

Motility

Secretion

Visceral sensation

Serotonin Acetylcholine Nitric oxide Substance P

Vasoactive intential peptide Cholecystokinin

Serotonin Acetylcholine

Vasoactive intestinal peptide

Serotonin Tachykinins

Calcitonin generelated peptide

Neurokinin A

Enkephalins

Proximal

Movement of Distal gut content

Interneurons

Motor neurons (contraction)

Interneurons

SybP

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