Abstract
Extrinsic sensory neurons play a key role in the function of the gastrointestinal tract. They are responsible for the sensations that arise in the gut and can initiate automatic reflexes. In some cases, disordered sensation is clinically problematic—pain, bloating, excessive urgency and nausea are well-known examples. Major advances have been made in understanding the function of somatic sensory neurons in the last 50 years. However, the sensory neurons that mediate sensations from the viscera remain less well understood. This is partly because viscera receive a dense autonomic innervation that can be difficult to separate from extrinsic sensory neurons. A key requirement to understand the genesis of sensation is to distinguish the different classes of sensory neurons and the types of stimuli which they encode. The aim of this short paper is to summarise what was known about these matters 30 years ago and highlight some of the major advances in the understanding of the types of extrinsic sensory neurons to the gut. Necessarily, the choice of papers is somewhat idiosyncratic, but they illustrate the range of advances that have been made in distinguishing the different classes of gastrointestinal afferent nerves.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Extrinsic Sensory Neurons
- Including Irritable Bowel Syndrome (IBS)
- Intraganglionic Laminar Endings
- Splanchnic Pathways
- Gastrointestinal tractGastrointestinal Tract
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Extrinsic Afferents 30 Years Ago
It was known since the early 1800s that the dorsal roots largely contain sensory fibres, whereas ventral roots are primarily motor. In fact, some visceral afferents had been shown to project in the ventral roots in the 1970s (Ryall and Piercey 1970; Clifton et al. 1976; Coggeshall and Ito 1977). The first recordings of visceral afferent neurons were from vagal afferents to the stomach by Iggo and Paintal in the early 1950s (Paintal 1954; Iggo 1955). Their recordings identified a class of low-threshold, tension-sensitive afferents to the upper gut. A few years later, a distinct class of mucosal , chemosensitive vagal afferent fibres to the stomach was identified (Clarke and Davison 1978). This indicated that multiple functional classes of extrinsic visceral sensory fibres might exist, each encoding different types of mechanical and chemical stimuli. Early recordings from mesenteric nerves indicated that the spinal afferent innervation of the gut contained sensory units with properties that differed from vagal afferents (Bessou and Perl 1966). Many of the high threshold spinal fibres had branches associated with mesenteric arteries (Morrison 1973; Floyd and Morrison 1974). Further studies showed that these same fibres were responsive to hypoxia (Longhurst and Dittman 1987) and to a wide range of mediators released during damage and inflammation (Blackshaw and Gebhart 2002). Vagal and spinal afferent neurons were directly compared in the opossum oesophagus (Sengupta et al. 1992), showing clear differences in mechanosensitive responses, with many vagal afferents being saturating mechanoreceptors, while splanchnic afferents tended to have higher thresholds and a wider dynamic range (Sengupta 2000). A range of similar studies led to a widespread acceptance that spinal afferent pathways contain more neurons with nociceptor-like responses than vagal pathways (Berthoud et al. 2004; Beyak et al. 2006; Grundy et al. 2006; Brierley et al. 2012).
Classes of Visceral Afferents: The Last Three Decades
Studies in the last 30 y ears have added considerably to our understanding of the structure-function relationship of extrinsic sensory nerves to the gut. Molecular biological techniques have driven a revolution in understanding of the ion channels, receptors, second messenger systems and genetics of sensory neurons. However, this review will be restricted to a few key papers that have improved our understanding of struct ure-function relationships, specifically.
Vagal and Sacral Sensory Pathways
Anatomical studies in the early to mid 1990s, using tracers injected into the nodose ganglion, revealed both the morphology and extent of vagal afferent nerve endings in the gut wall (Berthoud et al. 1995, 1997; Fox et al. 2000). Systematic recordings showed that vagal mechanoreceptors are not all low threshold saturating fibres: there are also wide dynamic range endings too, at least in the oesophagus (Yu et al. 2005). The chemosensory afferents in vagus nerve have been shown to be activated by release of mediators from entero-endocrine cells (Blackshaw and Grundy 1990; Eastwood et al. 1998). Different classes of spinal afferents can be distinguished by sensitivity to distension, mucosal stroking and strong compression (Lynn and Blackshaw 1999). During this period, it was shown that there are differences in the spinal afferents that innervate the rectum (via sacral/pelvic pathways) compared to the colon (via splanchnic pathways). For example, a large population of low threshold mechanoreceptors innervates the rectum: these are much sparser in the colon and splanchnic pathways (Lynn et al. 2003). Systematic studies extended these findings, showing that there were significant differences in both mechanosensitivity and chemosensitivity (Brierley et al. 2004, 2005) of spinal afferents in pelvic and splanchnic pathways to the mouse large intestine. The upper gut and the rectum both receive prominent parasympathetic efferent innervation—from vagal and sacral pathways respectively. Similarly, both upper and lower gut are innervated by specialised afferents (from vagal and sacral ganglia) which include many low-threshold mechanoreceptors. These are strongly activated during normal physiology and presumably are responsible for vago-vagal and sacral parasympathetic reflexes involved in gastric accommodation and defaecatory behaviours respectively.
Vascular Afferents
One specific class of spinal afferents is particularly significant: these are higher threshold sensory neurons that have endings closely associated with mesenteric blood vessels (Bessou and Perl 1966; Morrison 1973; Floyd and Morrison 1974). Immunohistochemical studies showed that these neurons (and many other nociceptor-like cells) have a distinct chemical coding, containing immunoreactivity for the neuropeptides CGRP and a tachykinin (Gibbins et al. 1985). This fitted nicely with long-established finding that sensory neurons can cause peripheral vasodilation (Bayliss 1901), via the release of CGRP (Kawasaki et al. 1988). Studies tracing the pathways of these “vascular afferents” showed that they are not restricted to mesenteric vessels—they also innervate intramural blood vessels, particularly in the submucosa (Song et al. 2009). Their endings on blood vessels are sensitive to distortion of the vessel (Humenick et al. 2015) and to distension of the gut wall; these neurons appear to function as medium-to-high threshold mechanonociceptors (Song et al. 2009). Furthermore, they often have multiple receptive fields, spread over several centimetres of bowel (Berthoud et al. 2001) with the same neuron innervating both intramural and extramural blood vessels (Song et al. 2009). This provides a firm anatomical foundation for the observation that large distensions of the bowel cause upstream vasodilation of mesenteric arteries via an axon reflex (Meehan and Kreulen 1992). These same vascular afferents are sensitive to a wide range of mediators released by inflammation and by cell damage , thus they function as sophisticated polymodal nociceptors, alerting the central nervous system about actual or potential damage to the gut wall, while simultaneously triggering a protective hyperaemia.
In many organs, including the gut, populations of sensory fibres exist that cannot be activated by conventional mechanical and/or chemical stimuli; these are so-called “silent afferents”. In the gastrointestinal tract , application of mediators associated with damage and inflammation acutely cause sensitisation of many visceral sensory neurons (Su and Gebhart 1998). In some cases “silent afferents ” then become mechanically sensitive (Feng and Gebhart 2011). Experimental colitis also induces chronic hypersensitivity of some classes of visceral afferents, which outlasts the period of inflammation. These include vascular afferents with “serosal or mesenteric ” endings (Hughes et al. 2009). Specialised low threshold rectal afferents are not sensitised to the same degree (Lynn et al. 2008). There is also evidence that experimental inflammation chronically activates “silent afferents” at least some of which are mechanically-insensitive vascular (“serosal”) afferents (Feng et al. 2012). Potentially, this may explain the hypersensitivity associated with inflammatory conditions of the bowel, since more nociceptors become capable of responding to mechanical stimuli and each nociceptor’s response is exaggerated. Low-level inflammatory mechanisms may occur in functional bowel disorders, including Irritable Bowel Syndrome (IBS) (Wahnschaffe et al. 2001; Tornblom et al. 2002; Barbara et al. 2004). Responses to inflammatory mediators are likely to be important in generating pain in these conditions.
Morphological Studies of Afferent Nerve Endings
Some of the work in our laboratory in the last 15 years has characterised structure-function relationships of extrinsic visceral afferent neurons. Using a combination of rapid anterograde tracing (Tassicker et al. 1999) and in vitro afferent recording, we have identified the structure of some visceral afferent nerve endings and transduction sites in the gut wall. Using these techniques , the low threshold vagal mechanosensors in the stomach and oesophagus were shown to correspond to “intraganglionic laminar endings ” in the upper gut (Zagorodnyuk and Brookes 2000; Zagorodnyuk et al. 2001). Comparable low threshold mechanoreceptors were also described in the guinea pig rectum and shown to have similar flattened “intraganglionic laminar endings” in myenteric ganglia to those of vagal tension receptors (Lynn et al. 2003). Studies on the high threshold mechanonociceptors associated with mesenteric blood vessels characterised their endings as branching varicose axons on both extramural (mesenteric) arteries and on intramural arteries in the submucosa (Song et al. 2009). This study also showed that there are few sensory endings in either the serosal membrane or the mesenteric membranes (apart from those on blood vessels) indicating that the terms “serosal ” afferent and “mesenteric afferent ” are not anatomically accurate. We have also characterised the enteric viscerofugal neurons that project out the gut wall via the mesenteric nerves, where their action potentials can be recorded alongside extrinsic afferent fibres (Cervero and Sharkey 1988). They project to sympathetic ganglia (Kuramoto and Furness 1989; Messenger and Furness 1993) and, in the distal colorectum, to the spinal cord (Doerffler-Melly and Neuhuber 1988). Combining dye filling with recordings from mesenteric nerves, it was shown that action potentials of viscerofugal neurons can be recorded from mesenteric nerves (Hibberd et al. 2012b) and that the cell bodies of these neurons are mechanosensitive (Hibberd et al. 2012a). They also receive synaptic drive from other enteric neurons (Hibberd et al. 2014). Other classes of extrinsic afferents have also been characterised using these techniques, including mechanoreceptors innervating the internal anal sphincter (Lynn and Brookes 2011).
Overall, in the last 30 years, structural and functional studies of extrinsic sensory nerves that innervate the gastrointestinal tract have made considerable progress. Discrete classes of neurons that encode specific combinations of mechanical and chemical stimuli and transmit this information to the central nervous system. Whether these “labelled lines” of afferents synapse onto different classes of second order neurons in the spinal cord seems likely, but has not yet been systematically investigated. The presence of multiple classes of extrinsic sensory neurons undoubtedly complicates analysis of sensory signalling from the gut. However, it also raises the possibility that specific classes of afferents may be targeted by future therapeutics to modify common disorders of intestinal functions.
References
Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R (2004) Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126:693–702
Bayliss WM (1901) On the origin from the spinal cord of the vaso-dilator fibres of the hind-limb, and on the nature of these fibres. J Physiol 26:173–209
Berthoud HR, Kressel M, Raybould HE, Neuhuber WL (1995) Vagal sensors in the rat duodenal mucosa – distribution and structure as revealed by in vivo Dii-tracing. Anat Embryol (Berl) 191:203–212
Berthoud HR, Patterson LM, Neumann F, Neuhuber WL (1997) Distribution and structure of vagal afferent intraganglionic laminar endings (IGLEs) in the rat gastrointestinal tract. Anat Embryol (Berl) 195:183–191
Berthoud HR, Lynn PA, Blackshaw LA (2001) Vagal and spinal mechanosensors in the rat stomach and colon have multiple receptive fields. Am J Physiol Regul Integr Comp Physiol 280:R1371–R1381
Berthoud HR, Blackshaw LA, Brookes SJ, Grundy D (2004) Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol Motil 16(Suppl 1):28–33
Bessou P, Perl ER (1966) A movement receptor of the small intestine. J Physiol 182:404–426
Beyak MJ, Bulmer DCE, Jiang W, Keating C, Rong W, Grundy D (2006) Extrinsic afferent nerves innervating the gastrointestinal tract. In: Johnson LR (ed) Physiology of the gastrointestinal tract, 4th edn. Academic, San Diego
Blackshaw LA, Gebhart GF (2002) The pharmacology of gastrointestinal nociceptive pathways. Curr Opin Pharmacol 2:642–649
Blackshaw LA, Grundy D (1990) Effects of cholecystokinin (CCK-8) on two classes of gastroduodenal vagal afferent fibre. J Auton Nerv Syst 31:191–201
Brierley SM, Jones RC 3rd, Gebhart GF, Blackshaw LA (2004) Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice. Gastroenterology 127:166–178
Brierley SM, Carter R, Jones W 3rd, Xu L, Robinson DR, Hicks GA, Gebhart GF, Blackshaw LA (2005) Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice. J Physiol 567:267–281
Brierley SM, Hughes PA, Harrington A, Blackshaw LA (2012) Innervation of the gastrointestinal tract by spinal and vagal afferent nerves. In: Johnson LR (ed) Physiology of the gastrointestinal tract, 5th edn. Elsevier, Amsterdam, pp 703–731
Cervero F, Sharkey KA (1988) An electrophysiological and anatomical study of intestinal afferent fibres in the rat. J Physiol 401:381–397
Clarke GD, Davison JS (1978) Mucosal receptors in the gastric antrum and small intestine of the rat with afferent fibres in the cervical vagus. J Physiol 284:55–67
Clifton GL, Coggeshall RE, Vance WH, Willis WD (1976) Receptive fields of unmyelinated ventral root afferent fibres in the cat. J Physiol 256:573–600
Coggeshall RE, Ito H (1977) Sensory fibres in ventral roots L7 and Si in the cat. J Physiol 267:215–235
Doerffler-Melly J, Neuhuber WL (1988) Rectospinal neurons: evidence for a direct projection from the enteric to the central nervous system in the rat. Neurosci Lett 92:121–125
Eastwood C, Maubach K, Kirkup AJ, Grundy D (1998) The role of endogenous cholecystokinin in the sensory transduction of luminal nutrient signals in the rat jejunum. Neurosci Lett 254:145–148
Feng B, Gebhart GF (2011) Characterization of silent afferents in the pelvic and splanchnic innervations of the mouse colorectum. Am J Physiol 300:G170–G180
Feng B, La JH, Schwartz ES, Tanaka T, McMurray TP, Gebhart GF (2012) Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity. Am J Physiol 302:G676–G683
Floyd K, Morrison JF (1974) Splanchnic mechanoreceptors in the dog. Q J Exp Physiol Cogn Med Sci 59:361–366
Fox EA, Phillips RJ, Martinson FA, Baronowsky EA, Powley TL (2000) Vagal afferent innervation of smooth muscle in the stomach and duodenum of the mouse: morphology and topography. J Comp Neurol 428:558–576
Gibbins IL, Furness JB, Costa M, MacIntyre I, Hillyard CJ, Girgis S (1985) Co-localization of calcitonin gene-related peptide-like immunoreactivity with substance P in cutaneous, vascular and visceral sensory neurons of guinea pigs. Neurosci Lett 57:125–130
Grundy D, Al-Chaer ED, Aziz Q, Collins SM, Ke M, Tache Y, Wood JD (2006) Fundamentals of neurogastroenterology: basic science. Gastroenterology 130:1391–1411
Hibberd TJ, Zagorodnyuk VP, Spencer NJ, Brookes SJH (2012a) Identification and mechanosensitivity of viscerofugal neurons. Neuroscience 225:118–129
Hibberd TJ, Zagorodnyuk VP, Spencer NJ, Brookes SJH (2012b) Viscerofugal neurons recorded from guinea-pig colonic nerves after organ culture. Neurogastroenterol Motil 24:1041-e1548
Hibberd TJ, Spencer NJ, Zagorodnyuk VP, Chen BN, Brookes SJ (2014) Targeted electrophysiological analysis of viscerofugal neurons in the myenteric plexus of guinea-pig colon. Neuroscience 275:272–284
Hughes PA, Brierley SM, Blackshaw LA (2009) Post-inflammatory modification of colonic afferent mechanosensitivity. Clin Exp Pharmacol Physiol 36:1034–1040
Humenick A, Chen BN, Wiklendt L, Spencer NJ, Zagorodnyuk VP, Dinning PG, Costa M, Brookes SJ (2015) Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure. J Physiol 593:3693–3709
Iggo A (1955) Tension receptors in the stomach and the urinary bladder. J Physiol 128:593–607
Kawasaki H, Takasaki K, Saito A, Goto K (1988) Calcitonin gene-related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessels of the rat. Nature 335:164–167
Kuramoto H, Furness JB (1989) Distribution of enteric nerve cells that project from the small intestine to the coeliac ganglion in the guinea-pig. J Auton Nerv Syst 27:241–248
Longhurst JC, Dittman LE (1987) Hypoxia, bradykinin, and prostaglandins stimulate ischemically sensitive visceral afferents. Am J Physiol 253:H556–H567
Lynn PA, Blackshaw LA (1999) In vitro recordings of afferent fibres with receptive fields in the serosa, muscle and mucosa of rat colon. J Physiol 518:271–282
Lynn PA, Brookes SJH (2011) Function and morphology correlates of rectal nerve mechanoreceptors innervating the guinea pig internal anal sphincter. Neurogastroenterol Motil 23:88–95
Lynn PA, Olsson C, Zagorodnyuk V, Costa M, Brookes SJ (2003) Rectal intraganglionic laminar endings are transduction sites of extrinsic mechanoreceptors in the guinea pig rectum. Gastroenterology 125:786–794
Lynn PA, Chen BN, Zagorodnyuk VP, Costa M, Brookes SJH (2008) TNBS-induced inflammation modulates the function of one class of low-threshold rectal mechanoreceptors in the guinea pig. Am J Physiol 295:G862–G871
Meehan AG, Kreulen DL (1992) A capsaicin-sensitive inhibitory reflex from the colon to mesenteric arteries in the guinea-pig. J Physiol 448:153–159
Messenger JP, Furness JB (1993) Distribution of enteric nerve cells projecting to the superior and inferior mesenteric ganglia of the guinea-pig. Cell Tissue Res 271:333–339
Morrison JF (1973) Splanchnic slowly adapting mechanoreceptors with punctate receptive fields in the mesentery and gastrointestinal tract of the cat. J Physiol 233:349–361
Paintal A (1954) A study of gastric stretch receptors; their role in the peripheral mechanism of satiation of hunger and thirst. J Physiol 126:255–270
Ryall RW, Piercey MF (1970) Visceral afferent and efferent fibers in sacral ventral roots in cats. Brain Res 23:57–65
Sengupta JN (2000) An overview of esophageal sensory receptors. Am J Med 108(Suppl 4a):87S–89S
Sengupta JN, Saha JK, Goyal RK (1992) Differential sensitivity to bradykinin of esophageal distension-sensitive mechanoreceptors in vagal and sympathetic afferents of the opossum. J Neurophysiol 68:1053–1067
Song X, Chen BN, Zagorodnyuk VP, Lynn PA, Blackshaw LA, Grundy D, Brunsden AM, Costa M, Brookes SJH (2009) Identification of medium/high-threshold extrinsic mechanosensitive afferent nerves to the gastrointestinal tract. Gastroenterology 137:274–284
Su X, Gebhart GF (1998) Mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat are polymodal in character. J Neurophysiol 80:2632–2644
Tassicker BC, Hennig GW, Costa M, Brookes SJH (1999) Rapid anterograde and retrograde tracing from mesenteric nerve trunks to the guinea-pig small intestine in vitro. Cell Tissue Res 295:437–452
Tornblom H, Lindberg G, Nyberg B, Veress B (2002) Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome [see comment]. Gastroenterology 123:1972–1979
Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD (2001) Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 121:1329–1338
Yu S, Undem BJ, Kollarik M (2005) Vagal afferent nerves with nociceptive properties in guinea-pig oesophagus. J Physiol 563:831–842
Zagorodnyuk VP, Brookes SJ (2000) Transduction sites of vagal mechanoreceptors in the guinea pig esophagus. J Neurosci 20:6249–6255
Zagorodnyuk VP, Chen BN, Brookes SJ (2001) Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach. J Physiol 534:255–268
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Brookes, S., Chen, N., Humenick, A., Spencer, N.J., Costa, M. (2016). Extrinsic Sensory Innervation of the Gut: Structure and Function. In: Brierley, S., Costa, M. (eds) The Enteric Nervous System. Advances in Experimental Medicine and Biology(), vol 891. Springer, Cham. https://doi.org/10.1007/978-3-319-27592-5_7
Download citation
DOI: https://doi.org/10.1007/978-3-319-27592-5_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-27590-1
Online ISBN: 978-3-319-27592-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)