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The first recordings of vagal afferent nerve fibre activity were performed by Paintal in the early 1950s. In these experiments, he showed that phenyldiguanide (later recognized as a 5-HT3 receptor agonist) stimulated the firing of C-fibres innervating the intestine. In the following years, ample physiological and psychological studies have demonstrated the importance of afferent information arising from the gut in the regulation of gastrointestinal function and behaviour. Many stimuli are capable of eliciting these functional effects and of stimulating afferent fibre discharge, including mechanical, chemical, nutrient- and immune-derived stimuli. Studies in the last 10 years have begun to focus on the precise sensory transduction mechanisms by which these visceral primary afferent nerve terminals are activated and, like the contribution by Zhu et al. in this issue of The Journal of Physiology, are revealing some novel and exciting findings.
In the gastrointestinal tract, some of the most robust physiological reflexes and behavioural responses come from stimuli that are generated within the lumen of the gastrointestinal tract. It is clear from morphological evidence that primary afferent nerve terminals lie below the epithelial cell layer in the lamina propria and are ideally situated to respond to both lumenal and internal stimuli. But this location also implies that responses to lumenal nutrients are indirect. Afferent neurons express a number of different receptors for neuroactive agents that are contained within enteroendocrine cells lining the wall of the gut, for example 5-HT, cholecystokinin (CCK) and histamine, and discharge in these afferents is directly stimulated by these substances. Eastwood et al. (1998) have shown that endogenous CCK acting at CCK-A receptors mediates the response of mesenteric afferents to protein digests. The present report by Zhu et al. (2001) provides compelling evidence for a role for 5-HT release from enterochromaffin cells, stimulation of 5-HT3 receptors on afferent nerve terminals and stimulation of afferent fibre activity in response to glucose, in addition to hyperosmotic stimulation.
The difficult question is whether these effects are nutrient specific or dependent on other factors, such as osmolarity. The observation that CCK and 5-HT3 agonists stimulate different populations of mucosal afferents (Hillesley & Grundy, 1998) supports the possibility of nutrient-specific pathways, since different nutrients stimulate a different repertoire of entero-endocrine cells. In the report by Zhu et al. (2001), the observation that a glucose solution of low osmolarity was able to stimulate mucosal afferents via release of 5-HT and 5-HT3 receptor activation suggests that this is a nutrient-specific response. That no response to glucose remained after administration of the 5-HT3 receptor antagonist suggests that there was no direct effect of glucose on the afferent nerve terminals.
How does carbohydrate in the lumen of the gastrointestinal tract release 5-HT from enterochromaffin cells? Data obtained by Raybould et al. (1998) have shown afferent-dependent feedback inhibition of gastric emptying is only induced by substrates of the sodium-glucose co-transporter SGLT-1. Ingested complex carbohydrates are digested in the lumen and by brush border enzymes to generate the monosaccharides glucose, galactose and fructose. Glucose and galactose enter the enterocyte via the sodium-glucose cotransporter SGLT-1 located on the apical surface of enterocytes. They exit the cell by facilitated diffusion via the basolaterally located GLUT-2. Fructose is absorbed by facilitated diffusion via GLUT-5. Raybould et al. (1998) have obtained preliminary evidence that SGLT-1 is critical for producing glucose-induced inhibition of gastric emptying. Perfusion of the intestine with 
-methyl glucose, a non-metabolizable substrate of SGLT-1, inhibits gastric emptying. In addition to direct effects of nutrients on endocrine cells, it is possible that there is an interaction between absorptive enterocytes, which express SGLT-1, and the endocrine cells to release 5-HT. Previous studies on release of 5-HT by glucose have used in vitro preparations including isolated loops of intestine, sheets of mucosa and impure preparations of EC cells. Since enterocytes express SGLT-1 it is not possible to discriminate between a direct effect of glucose on EC cells and an indirect effect via enterocytes.
The evidence presented in this report by Zhu et al. (2001) for a glucose-specific effect on vagal afferents mediated by 5-HT, together with that for CCK in mediating the response to products of protein digestion, is an important step in understanding sensory transduction of lumenal stimuli in the gastrointestinal tract. Further progress requires rigorous electrophysiological studies together with insights that can be gained from studies on the mechanisms of absorption of nutrients and their effects not only on entero-endocrine cells but also other epithelial cells.
| EASTWOOD C., MAUBACH, K., KIRKUP, A. J. & GRUNDY, D. (1998). Neuroscience Letters 254, 145-148. | [Medline] |
| HILLESLEY K. & GRUNDY, D. (1998). Neuroscience Letters 255, 63-66. | [Medline] |
| RAYBOULD H. E., BITTICACA, M., TABRIZI, Y., KO, J., WONG, H., WALSH, J. H., MEYER, J. H. & Sternini, C. (1998). Neurogastroenterology and Motility 10, 366. | |
| ZHU J. X., WU, X. Y. & LI, Y. (2001). Journal of Physiology 530, 431-442. | [Abstract/Full Text] |
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