- Email: [email protected]
The metamorphosis of motility: From squiggles to neuroscience
Comment From the Editors The Metamorphosis of Motility: From Squiggles to Neuroscience
T
he last two decades of motility research were devoted to descriptive characterization of clinical syndromes in which a motor component had long been suspected.The ability to place soft multilumen extrusions into any region of the gastrointestinal tract enabled recordings to be made with perfusion tubes and a pneumohydraulic, low-compliance infusion system. New insights were gained, and derangements have been documented in disease processes: lowamplitude intestinal contractions with infiltrative processes, simultaneous prolonged contractions when the lumen is obstructed, and the more frequent giant contractions of the colon before defecation in patients with functional diarrhea or their absence in colonic inertia. Yet two facts of life continue to bedevil the lives of “motorologists.” First, motor disturbances do not account for the symptoms in many patients with functional disorders because correction of the disturbance did not always relieve symptoms. Second, the mechanisms responsible for the disturbed function are largely unknown. Recent advances suggest the field is at the threshold of a significant metamorphosis, projecting “motility” and gastroenterology into the field of neuroscience. In whole humans, study of the perception of visceral stimulation has been facilitated by the application of controlled distention. At the brain and gut ends of the brain-gut axis, the level of psychosensory arousal and visceral tone influence the perception of mechanosensory stimuli in humans.The pathways or centers of relay (e.g., dorsal horn neurons) are being extensively studied in animal models. More specific pharmacological agents that can “probe” the pathways and mechanisms controlling gut motor and sen-
sory function, e.g., NK1 antagonists, k-opiate agonists, and serotonergic antagonists. Positron emission tomography and other functional brain imaging are defining the anatomic regions involved during visceral stimulation. Thus, there may be unusual central projection of afferents during rectal stimulation in patients with irritable bowel syndrome. These data require confirmation, but they indicate the neuroanatomic basis of limbic activation and possibly explain the association of affective disorders with functional gastrointestinal diseases. The second series of advances accrue from the combination of morphological and molecular biology approaches,providing insights into the pathogenesis of motor disorders. Models of pyloric stenosis or megacolon in strains of rats deficient in interstitial cells of Cajal (the pacemaker cells of the intestinal tract) or a neurotrophic factor that results in a complete absence of the enteric nervous system show the importance of these control mechanisms. However, targeted gene description in experimental pathology is only useful if the deletions are not lethal,and the phenotype is an approximation of the human condition.The experimental models studied to date are not an adequate representation of human disease but, ultimately, may lead to a greater understanding of the suffering patients who are knocking on our office door everyday for help! Morphological and electrophysiological studies of human tissue from patients with motility disorders are needed to better characterize the role of enteric neuronal subpopulations in disease. Human conditions are characterized by more subtle disturbances than the experimental animal models. The potential roles of ion channel dysfunction or altered intracellular translation in enteric nerves and smooth muscles require elucidation in health and disease. The way forward must surely involve a wide range of approaches.
Knockouts of the genes controlling the expression of each transmitter or receptor will provide insights on the role of that transmitter; however, single deletions may be less relevant in view of the redundancy of transmitters in nature and the fact that a single transmitter may not have an impact on integrated organ functions. In contrast, the human model continues to be a powerful alternative: selective antagonists or agonists to peptide or amine transmitters are still the best therapies we have until gene therapy becomes safe, feasible, and effective. Epidemiological studies have documented the high prevalence and economic impact of functional gastrointestinal disorders, in which sensorimotor dysfunction is a key player. Given the importance of its clinical impact and the promise of imminent progress of gastrointestinal neuroscience, “motility” needs a higher priority in federal funding support, just as the discipline needs to attract the talents of the “best and the brightest.” The descriptive studies of the past two decades have provided investigators with the tools to investigate the mechanisms that control motor and sensory functions. Studying the whole human, warts and all, is a sine qua non if the new biology is to have a real impact on health. These efforts should not be to the exclusion of basic investigation. Patient-based investigators must continue to apply rigorous science and bridge the gap toward the basic scientists because patientbased investigators can best appreciate the potential of these exciting discoveries. Federal agencies should facilitate the translation of this new biology by funding clinical (patientbased, not just patient-oriented) motility-related investigation. Let’s hope that the patient-based investigator is not the strain that is finally knocked out! MICHAEL CAMILLERI, M.D. Associate Editor, GASTROENTEROLOGY GASTROENTEROLOGY 1997;112:1785
T
he last two decades of motility research were devoted to descriptive characterization of clinical syndromes in which a motor component had long been suspected.The ability to place soft multilumen extrusions into any region of the gastrointestinal tract enabled recordings to be made with perfusion tubes and a pneumohydraulic, low-compliance infusion system. New insights were gained, and derangements have been documented in disease processes: lowamplitude intestinal contractions with infiltrative processes, simultaneous prolonged contractions when the lumen is obstructed, and the more frequent giant contractions of the colon before defecation in patients with functional diarrhea or their absence in colonic inertia. Yet two facts of life continue to bedevil the lives of “motorologists.” First, motor disturbances do not account for the symptoms in many patients with functional disorders because correction of the disturbance did not always relieve symptoms. Second, the mechanisms responsible for the disturbed function are largely unknown. Recent advances suggest the field is at the threshold of a significant metamorphosis, projecting “motility” and gastroenterology into the field of neuroscience. In whole humans, study of the perception of visceral stimulation has been facilitated by the application of controlled distention. At the brain and gut ends of the brain-gut axis, the level of psychosensory arousal and visceral tone influence the perception of mechanosensory stimuli in humans.The pathways or centers of relay (e.g., dorsal horn neurons) are being extensively studied in animal models. More specific pharmacological agents that can “probe” the pathways and mechanisms controlling gut motor and sen-
sory function, e.g., NK1 antagonists, k-opiate agonists, and serotonergic antagonists. Positron emission tomography and other functional brain imaging are defining the anatomic regions involved during visceral stimulation. Thus, there may be unusual central projection of afferents during rectal stimulation in patients with irritable bowel syndrome. These data require confirmation, but they indicate the neuroanatomic basis of limbic activation and possibly explain the association of affective disorders with functional gastrointestinal diseases. The second series of advances accrue from the combination of morphological and molecular biology approaches,providing insights into the pathogenesis of motor disorders. Models of pyloric stenosis or megacolon in strains of rats deficient in interstitial cells of Cajal (the pacemaker cells of the intestinal tract) or a neurotrophic factor that results in a complete absence of the enteric nervous system show the importance of these control mechanisms. However, targeted gene description in experimental pathology is only useful if the deletions are not lethal,and the phenotype is an approximation of the human condition.The experimental models studied to date are not an adequate representation of human disease but, ultimately, may lead to a greater understanding of the suffering patients who are knocking on our office door everyday for help! Morphological and electrophysiological studies of human tissue from patients with motility disorders are needed to better characterize the role of enteric neuronal subpopulations in disease. Human conditions are characterized by more subtle disturbances than the experimental animal models. The potential roles of ion channel dysfunction or altered intracellular translation in enteric nerves and smooth muscles require elucidation in health and disease. The way forward must surely involve a wide range of approaches.
Knockouts of the genes controlling the expression of each transmitter or receptor will provide insights on the role of that transmitter; however, single deletions may be less relevant in view of the redundancy of transmitters in nature and the fact that a single transmitter may not have an impact on integrated organ functions. In contrast, the human model continues to be a powerful alternative: selective antagonists or agonists to peptide or amine transmitters are still the best therapies we have until gene therapy becomes safe, feasible, and effective. Epidemiological studies have documented the high prevalence and economic impact of functional gastrointestinal disorders, in which sensorimotor dysfunction is a key player. Given the importance of its clinical impact and the promise of imminent progress of gastrointestinal neuroscience, “motility” needs a higher priority in federal funding support, just as the discipline needs to attract the talents of the “best and the brightest.” The descriptive studies of the past two decades have provided investigators with the tools to investigate the mechanisms that control motor and sensory functions. Studying the whole human, warts and all, is a sine qua non if the new biology is to have a real impact on health. These efforts should not be to the exclusion of basic investigation. Patient-based investigators must continue to apply rigorous science and bridge the gap toward the basic scientists because patientbased investigators can best appreciate the potential of these exciting discoveries. Federal agencies should facilitate the translation of this new biology by funding clinical (patientbased, not just patient-oriented) motility-related investigation. Let’s hope that the patient-based investigator is not the strain that is finally knocked out! MICHAEL CAMILLERI, M.D. Associate Editor, GASTROENTEROLOGY GASTROENTEROLOGY 1997;112:1785