Chapter 41 Antispasmodic Agents
Definitions
Brain–Gut Axis
The term brain–gut axis refers to the bidirectional neural processing of information between the central nervous and digestive systems. The brain–gut axis plays an essential role in the regulation of gastrointestinal (GI) motility, secretion, digestion, absorption, and blood flow; in the regulation of appetite, energy balance, and metabolism; and in the modulation of mucosal immunity (see Chapter 1). In turn, the brain receives interoceptive input (i.e., endogenous stimuli) from the GI tract, integrates this information with other systems input, and transmits integrated feedback back to the end-organs of the GI tract. The brain–gut axis is designed to optimize homoeostasis during minor physiologic perturbations and to adapt GI function to the overall state of the animal.1 In health, the great majority of interoceptive input does not reach the level of consciousness in the brain, but serves primarily as input to an autonomic reflex pathway. Brain–gut dysfunction underlies the clinical signs of the functional GI disorders such as irritable bowel syndrome, and it might mediate the development of stress-induced relapses in inflammatory bowel disease (IBD).1
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a human chronic GI tract disorder of unknown origin that is characterized by abdominal pain and altered bowel habits in the absence of detectable biochemical or structural abnormalities.2 IBS is one of the most common functional GI disorders with an estimated prevalence of 10% to 15% in Western adult populations. Direct and indirect costs of IBS reach up to $30 billion per year in the United States alone.2 IBS is commonly subdivided into different phenotypes, depending upon the most prevalent bowel habit: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), and mixed features IBS (IBS-M).3 Symptom complex differentiation is an important strategy in the diagnosis and treatment of the disorder. Because of the inability of animal species to describe clinical signs such as abdominal pain and discomfort, IBS is not as well-defined in veterinary medicine. Nonetheless, recurring vomiting and diarrheal disorders are seen in companion animals, abdominal discomfort is readily detected on physical examination, the clinical features are unaccompanied by mucosal morphologic change, and the pathogenesis is assumed, therefore, to be of functional or physiologic origin.4
Pathophysiology of Irritable Bowel Syndrome
The pathophysiology of IBS is incompletely understood, although it is considered to have both peripheral and central mechanisms.1
Peripheral Mechanisms
Primary Afferent Pathways
Acute inflammation is associated with peripheral sensitization and visceral hyperalgesia. Inflammation-induced peripheral sensitization is usually transient and resolves after inflammation subsides. The role of sensitized primary sensory afferents in the symptoms of persistent or chronically recurrent abdominal pain states is not known. Evidence from mucosal biopsies of IBS patients, however, suggests neuroplastic remodeling of the epithelium. Such neuroplastic changes may affect the response properties of spinal and vagal afferent neurons.1,5
Infection and Microflora
A bacterial etiology of persistent abdominal pain has long been suspected (including a relationship between Helicobacter pylori infection of the stomach and functional dyspepsia, and the development of IBS-like symptoms following infectious gastroenteritis). Although in the great majority of patients a causal relationship between abdominal pain and acute or chronic infection cannot be established, it has been suggested that host–microbial interactions in vulnerable individuals during the early phase of the disorder may result in permanently altered immune or host cell responses, which then continue to play a role in the persistence of symptoms in the absence of the infection or inflammation. Several studies have reported the onset of IBS-like symptoms following established bacterial or viral infections of the GI tract. This so-called postinfectious IBS occurs in 10% of human patients with bacterial gastroenteritis.1,6
Epithelial-Immune Activation
Leukocyte infiltration and mucosal inflammatory cytokines are generally not found in the GI mucosa of the IBS patient. Instead, enhanced release of neuropeptides from primary sensory nerve endings (such as substance P and calcitonin gene-related peptide), as well as the release of mast cell mediators (including serotonin, histamine, and proteases), has been implicated in the sensitization of primary afferent pathways. The release of nerve growth factor has also been impugned in the neuroplastic and morphologic changes of sensory and motor neurons of the colon. Such neuroplastic changes may play a role in the long-term symptoms of IBS long after the initial immune activation subsides.1,5
Mast Cells
Increased mast cell numbers or density, alterations in mast cell–nerve interactions, and increased release of mast cell mediators have been reported in the epithelial biopsy samples of IBS patients.1,7 Mast cells can be activated by immunoglobulins, neuropeptides, and cytokines to secrete mediators without degranulation. They can release many signaling molecules, including histamine, serotonin, corticotropin-releasing factor (CRF), and proteases. Alterations in these signaling systems have been implicated in the pathophysiology of IBS, and mediator-specific receptor antagonists have been suggested as possible therapies. A particularly interesting aspect of mast cell regulation is the close juxtaposition of mast cells with noradrenergic, cholinergic, and peptidergic nerve endings in the villus epithelium (see Fig. 1-17). Persistent alterations in the spatial and functional relationships between mast cells and nerve endings are a plausible mechanism for recurrent abdominal pain.1,7
Epithelial Permeability
Increased epithelial permeability has been reported in many IBS patients, including animal species.8 Multiple mechanisms of increased permeability have been proposed with differing underlying trigger mechanisms, including stressors and mucosal inflammation. Mast cell mediators, such as CRF and proteases, have been implicated in mediating permeability changes in the GI tract and in pain sensitization.1,9
Dysmotility
The concept that exaggerated and dysregulated contractile activity of the GI tract plays a role in the pathophysiology of chronic abdominal pain states has long been a central theme of IBS pathophysiology.1 Colonic motor dysregulation has been unequivocally demonstrated in experimental canine IBD,10 but not yet IBS.
Central Mechanisms
Enhanced Stress Responsiveness
First-symptom onset or symptom exacerbation in IBS has been linked to psychosocial stressors and enhanced visceral perception. Upregulation of central stress and arousal circuits has been postulated.1,11 Central CRF-CRF1 receptor signaling has been impugned in mediating some forms of acute and chronic stress-induced visceral hyperalgesia. Increased responsiveness of stress and arousal circuits is likely to contribute to the increased activity of the sympathetic nervous system observed in IBS patients, and may play a role in altered mast cell function.7
Central Pain Amplification
There are multiple mechanisms by which the central nervous system can modulate afferent signals from the viscera, including increased activity of endogenous pain facilitation and reduced engagement of endogenous pain inhibition. Endogenous pain modulation systems are likely to mediate the effects of affect, mood, and environmental context on pain perception.11
Neuroimmune Activation in the Spinal Cord
Visceral hyperalgesia is associated with activation of the glia following a psychological stressor. Activation of the glia can produce proinflammatory cytokines, such as tumor necrosis factor-α, and can result in the downregulation of the glutamate transporter on astrocytes, which, in turn, may lead to elevated synaptic glutamate. Both effects may result in an upregulation of the glutamate/N-methyl-D-aspartate receptor signaling system, thereby contributing to the development of central sensitization.1,12
Enhanced Brain Responses to Visceral Distention
In IBS patients, evidence for both increased engagement of endogenous pain facilitatory mechanisms and compromised engagement of endogenous pain inhibitory mechanisms have been reported.1,13
Enhanced Brain Responses to Expectation of Visceral Pain
Future-oriented worry and anxiety about abdominal symptoms play a prominent role in many human IBS patients. Alterations in prefrontal modulation of stress and arousal circuits may comprise the neurobiologic substrate underlying anxiety.1,14
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