[MOL] Advances in Basic Science Hold Promise for New therapies in Gastro [00764] Medicine On Line


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[MOL] Advances in Basic Science Hold Promise for New therapies in Gastrointestinal Dysmotility....



Advances in Basic Science Hold Promise for New Therapies in Gastrointestinal Dysmotility

Eamonn M.M. Quigley, MD

Introduction

Symptoms and clinical syndromes associated with disturbances in gastrointestinal motor function continue to pose a major challenge for the clinician. These functional disorders remain poorly defined, are difficult to evaluate, and have proven particularly resistant to successful therapy. Indeed, therapy remains, for the most part, largely empiric and symptomatic. In contrast, there have been tremendous advances in the physiology, neuroanatomy, molecular biology, and pharmacology of gastrointestinal motor function. In a state-of-the-art lecture presented at the 7th United European Gastroenterology Week in Rome, Italy, Dr. Lionel Bueno from the Department of Pharmacology at the INRA Institute in Toulouse, France, described how these advances in basic science may translate into new therapeutic options for patients.[1]

A Neurophysiologic Basis for Motility Therapeutics

Professor Bueno introduced us to the broad concept of brain/gut communications as the template for any understanding of gut-motor dysfunction in disease. This relatively new concept, which has led some to propose that this entire field of effort should be referred to as "neuro-gastroenterology" rather than "motility," emphasizes the inclusion of all elements that may lead to gastrointestinal symptoms. These elements include the smooth muscle of the gut wall, the enteric and autonomic nervous systems, sensory receptors in the gut wall, afferent neurons, and those centers in the spinal cord and brain involved in the reception of stimuli from the gut and in the initiation or modulation of gut motor activity. In this manner, nerve-gut interactions may take place at any one of three levels -- in the central nervous system, at the prevertebral ganglia, and within the enteric nervous system.

Professor Bueno subsequently discussed some experimental models of disease that have provided considerable insight into the pathophysiology and pharmacology of functional bowel disorders, namely altered intestinal reflexes, visceral hypersensitivity and hyperalgesia, immune-mediated gut/brain dysfunction, and abnormal central modulation. The models are not mutually exclusive; indeed, there is considerable evidence for extensive interaction between them.

Abnormal Gut Reflexes in Functional Gastrointestinal Disease: A Basis for New Pharmacological Approaches?

Evidence, primarily from animal models, but supported by some recent data in humans, suggests that dysfunction of gut reflexes may play a role in the pathogenesis of a variety of functional gastrointestinal disorders. The gastroesophageal reflex, initiated by gastric distention, mediated by a vagovagal pathway and leading to transient lower esophageal sphincter relaxation (TLESR), is now regarded as central to physiologic gastroesophageal reflux and gastroesophageal reflux disease (GERD). Nitric oxide (NO), cholecystokinin (CCK)A, and serotonin (5-HT)3 receptors have all been identified as being involved in either the afferent or efferent arms of this reflex. Indeed, the CCKA antagonist, devazepide, has been shown to inhibit TLESR. Given the prevalence of GERD, it is likely that the regulation of TLESR is going to be the subject of major interest in the coming years.

Gastric emptying, tone, and motility are influenced by intestino- and duodeno-gastric reflexes, whose dysfunction has been proposed to play a role in the pathogenesis of symptoms in functional or nonulcer dyspepsia (FD and NUD, respectively). Receptors involved in this reflex include those for CCKA, dopamine (D)2, 5-HT1A, and gastrin-releasing peptide (GRP). A cologastric reflex can also modulate gastric motor function and has been proposed to play a role in both FD and irritable bowel syndrome (IBS). Opioid, substance P (SP), neurokinin (NK1), and peptide YY (PYY) receptors have been implicated in this reflex, and the kappa opioid agonist, fedotozine, has been shown to inhibit the cologastric reflex. Indeed, this drug has been investigated in clinical trials for a number of functional bowel disorders. The rectocolonic reflex has also been implicated in IBS, and has attracted considerable interest recently. Vasoactive intestinal peptide (VIP), SP1, NK1, NK3, and bradykinin (BK)2 receptors have been associated with this reflex, and NK1, NK3, CCKA, BK2 antagonists, calcium channel blockers, trimebutine, and alverine have all been shown to inhibit the rectocolonic reflex.

While the role of the peritoneo-gastrointestinal reflex in functional disease is almost unknown, this reflex, whereby in experimental animals peritoneal stimulation leads to motor inhibition, has provided considerable insight into the pathophysiology of colonic ileus and the pharmacology of gut reflex activity. Receptor types involved in this reflex include NK1, BK2, calcitonin gene-related peptide (CGRP), and corticotropin-releasing factor (CRF)-R1. Experimentally, this reflex can be inhibited by CRF-R1 antagonists, kappa opioid agonists, cyclooxygenase (COX)-2 inhibitors, ICAM (intracellular adhesion molecules) antibodies, and mast cell stabilizers.

Visceral Hypersensitivity and Hyperalgesia in Functional Gastrointestinal Disease

The description of visceral hypersensitivity and hyperalgesia (the phenomenon whereby a previously nonpainful stimulus is now perceived as painful) in several functional gastrointestinal diseases, including noncardiac chest pain, FD, and IBS, has led to a flurry of activity in the areas of gut sensation and perception. While a whole host of receptors, neuropeptides, and neuromodulators is known to be involved at a variety of levels in the mediation of both normal sensation and hyperalgesia, a few have attracted particular interest in view of either their ubiquity and/or apparent key roles. For most visceral sensations, the first-order neuron (primary sensory afferent) synapses with the second-order neuron in the dorsal horn of the spinal cord, which in turn project, thereafter, to the various centers in the brain. Serotonin appears to play a key role. Both 5HT3 and 5HT1A receptor subtypes are involved at different sites in the mediation of gut nociception and several antagonists are currently undergoing study -- some may soon reach the clinical arena.

Opioids acting as mu, gamma, and kappa receptors appear to be involved at the peripheral receptor in primary afferents and in dorsal root ganglia, as well as in the spinal cord and the central nervous system. Substance P and NKA also appear to be involved at a number of levels, whereas CGRP has been localized to primary sensory afferents.

Professor Bueno placed considerable emphasis on gut hyperalgesia and, in particular, on the role of inflammatory mediators in sensitizing primary afferent neurons. A variety of experimental models have demonstrated that inflammatory mediators will lead to the development of pain in response to a level of gut distention that previously did not elicit this sensation. Several peptides, including BK, CGRP, tachykinins, VIP, 5HT, adenosine, noradrenaline, eicosanoids (including prostaglandin (PG)E2, cytokines [interleukin {IL}-1, IL-8], tumor necrosis factor-alpha [TNF-alpha], and growth factors [nerve growth factor or NGF]), have all been shown to be involved in the sensitization process.

A fascinating development has been the realization that such peripheral events can lead to both short- and long-term changes in neural activity in the spinal cord and central nervous system. For example, peripheral sensitization of sensory neurons may alter the membrane properties of the second-order neurons originating in the dorsal horn of the spinal cord through N-methyl-d-aspartate (NMDA) receptors, leading to long-lasting adaptation. SP, dynorphins, and glutamate may also be involved. Thyrotropin-releasing factor (TRF), vasopressin, CCK8, SP, IL-1, TNF-alpha, norepinephrine, dopamine, 5HT1A, and PGE2 have all been shown to modulate the central mediation of events initiated at peripheral sensitization.

Motility-Immune Reactions

The potential role of gut-immune interactions in the pathogenesis of functional gastrointestinal disorders is, perhaps, best illustrated by the phenomenon of the postinfective IBS. It is now evident that prior exposure to bacterial gastroenteritis may lead to the development of full-blown IBS in a proportion of exposed subjects. Such dysfunction may persist for months or even years after the infectious agent has completely cleared. This observation has stimulated intense interest in the potential interactions between inflammation, intestinal muscle, and the enteric, autonomic, and central nervous systems.

Professor Bueno reviewed three animal-based models of disease that have provided considerable insight into these interactions: hypermastocytosis (related to experimental helminthic infestation), lipopolysaccharide-induced allodynia (a model of systemic sepsis), and peripheral inflammation. NK2 receptor antagonists appear to be active in each model, and the NK2 antagonists, SR 48968 and MEN 11420, have been shown to reduce the pain induced by visceral distention in hypermastocytosis models, such as the rat infected with Nippostrongylus brasiliensis, or in experimentally induced inflammation. BK1 and BK2 antagonists, as well as 5HT1A antagonists, such as WAY 100425, also have efficacy in the lipopolysaccharide-induced allodynia model. Serotonin, NK, and BK antagonists appear to hold particular promise for efficacy in the latter setting.

Central Input

It has been stressed repeatedly that many proposed mechanisms of abnormal nerve-gut responses may include alterations in neurotransmission at the level of the spinal cord and brain. There are other circumstances where gut-motor dysfunction appears to originate centrally. The clinician will immediately recognize the profound effects of stress, be it short- or long-term, on such motor functions as gastric emptying and small bowel transit. Indeed, animal studies and experiments in humans have demonstrated the ability of stimuli of central origin to modulate and disrupt a host of motor and sensory activities in the gastrointestinal tract.

Similarly, central nervous system activity may modulate incoming signals from the periphery initiated by physiologic or pathologic events, including inflammation. Many of the receptors identified as active in the peripheral regulation of gut motor activity appear to be at least as important in central regulation. These receptors include 5HT, CRF, NK, CCK, and SP. Cytokines, such as IL-1 and TNF-alpha, also appear to be centrally active. It should come as no surprise, therefore, that the efficacy of some of the newer motility agents that are currently undergoing clinical evaluation may be exerted, at least in part, through effects on the central nervous system. For example, the 5HT4 agonist, HTF 919 (or tegaserod), has been shown to reverse stress-induced delay in gastric emptying.

Summary: Implications for Clinical Practice

  • An understanding of the pathophysiology of functional bowel disease should be based on modern concepts of nerve-gut interactions.

  • Experimental animal models have provided tremendous insights into the regulation of a variety of gut motor functions, and have led to the identification of many of the receptors involved.

  • Gut reflexes, visceral hypersensitivity, and hyperalgesia, as well as stimuli of central origin, may all have a role in generating symptoms in functional bowel disease and are likely to interact.

  • Sensitization of visceral afferents by local inflammation, leading to hyperalgesia, may explain some functional bowel disorders.

  • Interventions targeted at serotonin, NK, CCK, and opioid receptors appear to provide the most immediate promise for clinical application in functional bowel disorders.

Reference

  1. Bueno L. New and future drugs in nerve-gut dysfunctions. State-of-the-Art Lecture. Program and abstracts of the 7th United European Gastroenterology Week; November 13-17, 1999; Rome, Italy.


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