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Gastrointestinal pharmacology: gut–brain signalling
Gastrointestinal pharmacology: gut–brain signalling Editorial overview Graham J Dockray Current Opinion in Pharmacology 2007, 7:555–556 Available online 26th November 2007 1471-4892/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2007.10.001
Graham J Dockray Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, PO Box 147, Liverpool L69 3BX, UK e-mail: [email protected]
Graham Dockray is a deputy vice chancellor of the University of Liverpool and professor of Physiology in the School of Biomedical Sciences. His research interests are in transepithelial signalling in the gastrointestinal tract, and in particular the physiology of the gut hormones and of gut–brain signalling.
For much of the past century, it seemed that the central nervous system received information about the state of the gastrointestinal tract via vagal and spinal afferent neurons that functioned more or less independently of the hormonal mechanisms controlling digestion. In part, these ideas were grounded in work carried out in the early part of the century which proved the existence of various gut hormones by demonstrating their action when all afferent nervous pathways were sectioned. However, over the past decade or two it has become clear that the afferent neurons linking gut to brain are a site of integration of an impressive and somewhat daunting array of endocrine, paracrine and neurohumoral signals. The relevant integrative events now appear to be important in normal digestion and to be disrupted in a variety of different diseases. The contributors to this issue have focussed on recent progress in our understanding and exploitation of gut–brain-signalling mechanisms in conditions ranging from irritable bowel syndrome to obesity. The early events that underlie the sensing of nutrients and other chemicals in the lumen of the gut have proved elusive. What is now becoming clear is that there are remarkable similarities in the mechanisms of nutrient sensing by the enteroendocrine cells that release gut hormones and the mechanisms of taste in the tongue. Rozengurt and Sternini deal with these mechanisms: they review exciting recent work showing that G-protein-coupled receptors (GPCRs) that respond to sweet or bitter compounds on the tongue, are also expressed by enteroendocrine cells and are associated with production of gut hormones. Quite literally, enterocrine cells ‘taste’ the luminal contents of the gut and this determines their secretion of hormones and paracrine agents that in turn direct the appropriate responses from other parts of the gut or, via actions on afferent neurons, signal to the CNS. The chemistry required to develop GPCR ligands of therapeutic potential is, of course, well developed so that it becomes possible to see how it might be feasible to selectively modulate the function of different enteroendocrine cell types for instance in treatments of obesity and type II diabetes. In addition to the capacity for nutrient sensing, the epithelium of the gut is also exposed to noxious or damaging stimuli and the capacity to activate appropriate defence mechanisms is essential. Holzer deals with organisation of these defence mechanisms. In particular, he focusses on the interesting role of primary afferent neurons, the progress made in identifying their nociceptors and consequences of their activation. Cholecystokinin (CCK) was the first of the gut hormones to be shown to act on vagal afferent neurons and is by far the most intensively studied. These mechanisms underlie the action of CCK in inhibiting food intake, and so are of relevance to developing new approaches to the treatment of obesity. As Raybould shows in her review, recent work in this area indicates new ways in
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Current Opinion in Pharmacology 2007, 7:555–556
556 Gastrointestinal
which CCK controls vagal afferent signalling; specifically, the idea is now emerging of a gate-keeper function by which CCK controls the expression of a number of receptors by vagal afferent neurons thereby determining their capacity to respond to other gut endocrine signals. One of the receptors whose expression is regulated by CCK in vagal afferent neurons, is the cannabinoid (CB1) receptor. Storr and Sharkey review in detail the endocannabinoid system as it pertains to the gut–brain axis. This area is of topical interest in view of the development of a CB1 ligand, rimonabant, as a potential anti-obesity drug. Their review argues plausibly for serious consideration to be given to the role of peripheral endocannabinoids in the regulation of food intake through mechanisms involving the vagus nerve. The CCK receptors provide a case-book lesson in the difficulties in developing novel therapeutic agents that target gut–brain signalling. The two CCK receptors (CCK1 and CCK2) are amongst the best studied of the receptors for gut hormones, and it is now over 20 years since high affinity, highly selective antagonists first became available for experimental use. It is much longer since peptide agonists (e.g. pentagastrin) were first used in the clinic in diagnosis. There has been no shortage of potential applications identified for CCK1 or CCK2 receptor ligands including treatment of feeding disorders and obesity, cancer therapy, treatment of panic disorder, irritable bowel syndrome and potentiation of analgesia.
Current Opinion in Pharmacology 2007, 7:555–556
Even so, as Berna et al. discuss, the development of drugs that are useful in any of these conditions is still some way off. There are many reasons for this, at least one of which is the difficulty of working with systems where the same receptor is expressed by many different cells with quite different functions. The final two reviews are focussed directly on human disease states associated with dysfunction of gut–brain signalling. Hobson and Aziz review the mechanisms of pain perception arising from the gastrointestinal tract. It is clear that while many different classes of compound are being applied to disorders of visceral perception, at least in part the development of new effective therapies will depend on the capacity to discriminate within this heterogeneous set of conditions in order to match treatment to the appropriate patient subgroup. Changes in pain threshold are a feature of irritable bowel syndrome; this complex and common condition, and the therapeutic challenge it presents, is discussed by Bradesi and Mayer. In addition to reviewing drug targets associated with neurohumoral signalling, they draw attention to the need to take into account the possible role of gut microflora. I would like to thank all the authors who have contributed to this issue. They have expertly, and topically, reviewed complex fields and have collectively emphasised both the opportunities and difficulties in developing drugs targeting disorders involving gut–brain signalling.
www.sciencedirect.com
Graham J Dockray Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, PO Box 147, Liverpool L69 3BX, UK e-mail: [email protected]
Graham Dockray is a deputy vice chancellor of the University of Liverpool and professor of Physiology in the School of Biomedical Sciences. His research interests are in transepithelial signalling in the gastrointestinal tract, and in particular the physiology of the gut hormones and of gut–brain signalling.
For much of the past century, it seemed that the central nervous system received information about the state of the gastrointestinal tract via vagal and spinal afferent neurons that functioned more or less independently of the hormonal mechanisms controlling digestion. In part, these ideas were grounded in work carried out in the early part of the century which proved the existence of various gut hormones by demonstrating their action when all afferent nervous pathways were sectioned. However, over the past decade or two it has become clear that the afferent neurons linking gut to brain are a site of integration of an impressive and somewhat daunting array of endocrine, paracrine and neurohumoral signals. The relevant integrative events now appear to be important in normal digestion and to be disrupted in a variety of different diseases. The contributors to this issue have focussed on recent progress in our understanding and exploitation of gut–brain-signalling mechanisms in conditions ranging from irritable bowel syndrome to obesity. The early events that underlie the sensing of nutrients and other chemicals in the lumen of the gut have proved elusive. What is now becoming clear is that there are remarkable similarities in the mechanisms of nutrient sensing by the enteroendocrine cells that release gut hormones and the mechanisms of taste in the tongue. Rozengurt and Sternini deal with these mechanisms: they review exciting recent work showing that G-protein-coupled receptors (GPCRs) that respond to sweet or bitter compounds on the tongue, are also expressed by enteroendocrine cells and are associated with production of gut hormones. Quite literally, enterocrine cells ‘taste’ the luminal contents of the gut and this determines their secretion of hormones and paracrine agents that in turn direct the appropriate responses from other parts of the gut or, via actions on afferent neurons, signal to the CNS. The chemistry required to develop GPCR ligands of therapeutic potential is, of course, well developed so that it becomes possible to see how it might be feasible to selectively modulate the function of different enteroendocrine cell types for instance in treatments of obesity and type II diabetes. In addition to the capacity for nutrient sensing, the epithelium of the gut is also exposed to noxious or damaging stimuli and the capacity to activate appropriate defence mechanisms is essential. Holzer deals with organisation of these defence mechanisms. In particular, he focusses on the interesting role of primary afferent neurons, the progress made in identifying their nociceptors and consequences of their activation. Cholecystokinin (CCK) was the first of the gut hormones to be shown to act on vagal afferent neurons and is by far the most intensively studied. These mechanisms underlie the action of CCK in inhibiting food intake, and so are of relevance to developing new approaches to the treatment of obesity. As Raybould shows in her review, recent work in this area indicates new ways in
www.sciencedirect.com
Current Opinion in Pharmacology 2007, 7:555–556
556 Gastrointestinal
which CCK controls vagal afferent signalling; specifically, the idea is now emerging of a gate-keeper function by which CCK controls the expression of a number of receptors by vagal afferent neurons thereby determining their capacity to respond to other gut endocrine signals. One of the receptors whose expression is regulated by CCK in vagal afferent neurons, is the cannabinoid (CB1) receptor. Storr and Sharkey review in detail the endocannabinoid system as it pertains to the gut–brain axis. This area is of topical interest in view of the development of a CB1 ligand, rimonabant, as a potential anti-obesity drug. Their review argues plausibly for serious consideration to be given to the role of peripheral endocannabinoids in the regulation of food intake through mechanisms involving the vagus nerve. The CCK receptors provide a case-book lesson in the difficulties in developing novel therapeutic agents that target gut–brain signalling. The two CCK receptors (CCK1 and CCK2) are amongst the best studied of the receptors for gut hormones, and it is now over 20 years since high affinity, highly selective antagonists first became available for experimental use. It is much longer since peptide agonists (e.g. pentagastrin) were first used in the clinic in diagnosis. There has been no shortage of potential applications identified for CCK1 or CCK2 receptor ligands including treatment of feeding disorders and obesity, cancer therapy, treatment of panic disorder, irritable bowel syndrome and potentiation of analgesia.
Current Opinion in Pharmacology 2007, 7:555–556
Even so, as Berna et al. discuss, the development of drugs that are useful in any of these conditions is still some way off. There are many reasons for this, at least one of which is the difficulty of working with systems where the same receptor is expressed by many different cells with quite different functions. The final two reviews are focussed directly on human disease states associated with dysfunction of gut–brain signalling. Hobson and Aziz review the mechanisms of pain perception arising from the gastrointestinal tract. It is clear that while many different classes of compound are being applied to disorders of visceral perception, at least in part the development of new effective therapies will depend on the capacity to discriminate within this heterogeneous set of conditions in order to match treatment to the appropriate patient subgroup. Changes in pain threshold are a feature of irritable bowel syndrome; this complex and common condition, and the therapeutic challenge it presents, is discussed by Bradesi and Mayer. In addition to reviewing drug targets associated with neurohumoral signalling, they draw attention to the need to take into account the possible role of gut microflora. I would like to thank all the authors who have contributed to this issue. They have expertly, and topically, reviewed complex fields and have collectively emphasised both the opportunities and difficulties in developing drugs targeting disorders involving gut–brain signalling.
www.sciencedirect.com