Visceral pain perception involves a complex pathway of peripheral and central nervous structures that encode, relay and modify the afferent stimulus.
The enteric nervous system (ENS) is organized into two major plexuses providing the intrinsic innervation of the gut. The plexuses and the nerves connecting them constitute a continuous network around the circumference of the GI tract and along its length. The myenteric plexus, also known as Auerbach's plexus, is situated between the external longitudinal and internal circular muscle layers, and the submucosal plexus (Meissner's plexus) lies between the circular muscle layer and the mucosa. The myenteric plexus is larger and projects fibers primarily to the smooth muscle of the gut controlling motility. Meanwhile, the submucosal plexus projects into the mucosa and submucosa and includes more sensory cells and the neurons that control gland secretion. Although the two intestinal plexuses are separated spatially, interconnections bind the two networks into a functionally unified nervous system. The characteristics of this mesh of sensory fibers, interneurons and motor neurons, enables this mini-brain or 'gut brain' to integrate the sensory information, organize the motor and secretory responses and influence the luminal absorption, producing a functional state that is adapted to the well-being of the individual. Although the ENS receives input from the central and autonomic nervous systems, it can function independently. The ENS performs most of its functions in the absence of central nervous system (CNS) control, locally integrating the information of intrinsic afferent fibers (for example, luminal distension and chemical stimuli) with efferent axons, resulting in motor reflexes or secretory or absorptive responses.
The extrinsic nervous system consists of afferent and efferent fibers connecting the ENS with the CNS. This communication allows the CNS continuously to integrate the information from the gastrointestinal tract with incoming information from other organs and from the environment, in order to initiate an adequate response. Under physiological conditions, most of these processes do not reach the level of conscious perception.21 However, sensations that trigger a particular behavior, including hunger, satiety and need to defecate, reach the cortex. The constant influence of the CNS on the ENS through activation of a subset of vagal and sacral parasympathetic fibers is exemplified by the relation between psychological stress and gastrointestinal response, manifested clinically by the occurrence of vomiting or diarrhea in patients experiencing a stressful event.
The ENS and the brain use multiple neurotrans-mitters for chemical signaling and exchanging of inhibitory or excitatory information. They include excitatory neurotransmitters such as acetylcholine and substance P, and gut inhibitory neurotransmitters such as nitric oxide, ATP, vasoactive intestinal peptide (VIP), cholecystokinin, enkephalins, calcitonin gene-related peptide (CGRP), norepinephrine (noradrenaline), epinephrine (adrenaline) and others. Other neurotransmitters such as serotonin (5-hydroxytryptamine; 5-HT) and histamine have more complex effects. Ninety-five per cent of the total body 5-HT lies within the gut. Of the total gut 5-HT, 90% is found in the granules of the enteroen-docrine cells, and 10% in the neurons of the myenteric plexus.22,23 5-HT plays a role in regulating GI motility and intestinal secretion.22 5-HT receptors appear to participate in mucosal sensory processing within the gut. Distension and stroking of mechanosensitive receptors in the enteroen-docrine cells triggers the release of 5-HT.24 There are at least seven main classes of 5-HT receptor and 22 subclasses that can be differentiated on the basis of structure and function. Four classes have been reported in the human GI tract (5-HTi, 5-HT2, 5-HT3 and 5-HT4).25 Serotonin action is complex, with mixed effects ranging from smooth muscle contraction via cholinergic nerves, to relaxation through stimulation of inhibitory nitric oxide-releasing neurons. Higher levels of serotonin are present in diarrhea-predominant IBS.26 The ENS has the ability to modulate signal transduction by enhancing or inhibiting the activation of nocicep-tors through alteration in smooth muscle tone and contractile activity. Visceral pain may be modulated also at the CNS level by emotional or cognitive factors, providing a rationale for the use of centrally acting agents or cognitive behavioral treatments in functional bowel disorders. Neuroimaging studies have provided information on differences in brain processing of visceral stimuli between normal individuals and those suffering from IBS, revealing an increased activity at the level of the anterior cingulated cortex, prefrontal cortex, insular cortex and thalamus (the areas associated with emotional responses) in patients with IBS compared to asymptomatic indi-viduals.27-29
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