Autonomic control of gut motility: A comparative view

Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

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Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u

Review

Autonomic control of gut motility: A comparative view Catharina Olsson ⁎, Susanne Holmgren Department of Zoology/Zoophysiology, University of Gothenburg, Sweden

a r t i c l e

i n f o

Article history: Received 12 February 2010 Received in revised form 24 June 2010 Accepted 6 July 2010 Keywords: Acetylcholine Adrenaline Enteric nervous system Gastrointestinal tract Intestine Motility Neuropeptides Nitric oxide Serotonin Stomach

a b s t r a c t Gut motility is regulated to optimize food transport and processing. The autonomic innervation of the gut generally includes extrinsic cranial and spinal autonomic nerves. It also comprises the nerves contained entirely within the gut wall, i.e. the enteric nervous system. The extrinsic and enteric nervous control follows a similar pattern throughout the vertebrate groups. However, differences are common and may occur between groups and families as well as between closely related species. In this review, we give an overview of the distribution and effects of common neurotransmitters in the vertebrate gut. While the focus is on birds, reptiles, amphibians and fish, mammalian data are included to form the background for comparisons. While some transmitters, like acetylcholine and nitric oxide, show similar distribution patterns and effects in most species investigated, the role of others is more varying. The significance for these differences is not yet fully understood, emphasizing the need for continued comparative studies of autonomic control. © 2010 Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . Gut motility . . . . . . . . . . . . . . . . . . . . . . . 2.1. Function. . . . . . . . . . . . . . . . . . . . . . 2.2. Cellular mechanisms behind gut motility . . . . . . 2.3. Different patterns — propagating vs. non-propagating Control of gut motility . . . . . . . . . . . . . . . . . . 3.1. Anatomy of the innervation of the gut . . . . . . . 3.2. Factors affecting the control of gut motility . . . . . Mammals as a model for the nervous control of gut motility 4.1. Reflexes . . . . . . . . . . . . . . . . . . . . . . 4.2. The enteric nervous system. . . . . . . . . . . . . 4.3. The peristaltic reflex . . . . . . . . . . . . . . . . 4.4. Extrinsic reflexes. . . . . . . . . . . . . . . . . . 4.5. Extrinsic vs. intrinsic innervation . . . . . . . . . . Birds . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Gastrointestinal innervation . . . . . . . . . . . . 5.2. Effects on gut motility . . . . . . . . . . . . . . . Reptiles . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Gastrointestinal innervation . . . . . . . . . . . . 6.2. Effects on gut motility . . . . . . . . . . . . . . . Amphibians . . . . . . . . . . . . . . . . . . . . . . . 7.1. Gastrointestinal innervation . . . . . . . . . . . . 7.2. Effects on gut motility . . . . . . . . . . . . . . . Fish . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. Department of Zoology/Zoophysiology, University of Gothenburg, Box 463, SE 405 30 Göteborg, Sweden. Tel.: +46 31 786 3677. E-mail address: [email protected] (C. Olsson).

1566-0702/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.07.002

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C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

Bony fish . . . . . . . . . . . . . 8.1.1. Gastrointestinal innervation 8.1.2. Effects on gut motility. . . 8.2. Cartilaginous fish . . . . . . . . . 8.2.1. Gastrointestinal innervation 8.2.2. Effects on gut motility. . . 8.3. Cyclostomes. . . . . . . . . . . . 9. Comparative aspects and conclusions . . . References . . . . . . . . . . . . . . . . . . 8.1.

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1. Introduction

2. Gut motility

Gut motility, that is the contractions and relaxation of the gastrointestinal smooth muscle necessary for transport and processing of the food we eat, is under strict control to optimize the performance. The autonomic nervous system, including the enteric nervous system, plays an important part in this control. The general features of the gastrointestinal tract and its control is similar in all vertebrate groups. However, there are also differences between species, families or classes. This is often a reflection of feeding habits. The type of food an animal ingests as well as the feeding frequency have a profound impact on the gastrointestinal physiology and consequently, also on the need for accurate control mechanisms. This review will start with a general overview of gut motility and different motility patterns followed by a detailed summary of the present knowledge of the influence of autonomic innervation. Data from mammalian studies will form the background and the other vertebrate groups will be discussed from this point of view. For a more comprehensive overview of the enteric innervation of mammals, see e.g. Furness (2006). Special emphasis will be put on the distribution and effects of individual neurotransmitters; the data are also summarised in Tables 1–17. In addition to effects on motility, most transmitters discussed are involved in the control of gut secretion (see Holmgren and Olsson, 2010–this volume).

2.1. Function

Table 1 Presence of neurotransmitters in the mammalian enteric nervous system and effect on gastrointestinal motility. + denotes excitatory effect, − inhibition. Summary of data from studies on different mammalian species (see Costa et al., 1996; Timmermans et al., 1997; Grundy and Schemann, 2002; Tonini et al., 2002; Hansen, 2003 for details). Substance

Distribution

Motility

Acetylcholine Adrenaline/noradrenaline Bombesin/GRP Dopamine CCK CGRP GABA Galanin Glutamate Neurokinin A Neuropeptide Y Neurotensin Nitric oxide Opioids PACAP Purines Serotonin Somatostatin Substance P VIP

nc nc? nc nc nc nc nc nc nc nc nc nc? nc nc nc

+ − +

nc nc nc nc

+ − − − + − − − +/− − +/− + − + −

GRP, gastrin-releasing peptide; CCK, cholecystokinin; CGRP, calcitonin gene-related peptide; GABA, γ-aminobutyric acid; PACAP, pituitary adenylate cyclase-activating polypeptide; VIP, vasoactive intestinal polypetide; nc, enteric nerve cell body.

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92 93 94 94 94 94 96 96 97

Different regions of the gastrointestinal tract play different roles in the breakdown of food and uptake of nutrients, and hence the food, or partly or fully broken down food particles, must be transported from the mouth to the anal region (see e.g. Hasler, 1999; Hansen, 2003; Wood, 2008). Motility can also be local, non-propagating, mixing food and gastric juices, thus facilitating breakdown, as well as putting nutrients in contact with enterocytes where uptake takes place. But motility is not restricted to when an animal has eaten and there is food in the gut. In most species there seems to be ongoing propagating contractions along the gastrointestinal tract also in fasted animals (migrating motor complexes, MMCs; see Section 2.3). The function of this interdigestive motility may for example be to keep the gut free from indigestible particles, dead enterocytes and unwanted bacteria, i.e. the motility functions as some sort of house keeper. 2.2. Cellular mechanisms behind gut motility Gut motility ultimately depends on depolarisation and repolarisation of gut smooth muscles, causing contractions and relaxations of the muscle. The smooth muscle cells generally display a continuous cyclic pattern of these depolarisations and repolarisations, called slow waves (Sanders, 1996; Sanders et al., 2006). The depolarisation must reach a threshold, triggering an action potential, for a contraction to take place and this usually needs some kind of additional external stimulus, like nervous or hormonal input. If the cell gets hyperpolarised it relaxes instead. The slow waves are not intrinsic to the muscle cells but originate in interstitial cells of Cajal (ICCs) that show spontaneous electrical rhythmicity (Sanders, 1996). The ICCs are electrically coupled via gap junctions, and slow waves propagate across the ICC network in a coordinated manner. In addition, the slow waves spread to smooth muscle cells. Hence the ICCs can function as pacemakers, setting the smooth muscle slow wave frequency. However, several pacemaker regions may exist along the gastrointestinal tract, leading to regional differences in slow wave frequency (Sanders et al., 2006). Slow waves have been recorded from the gut in amphibians and birds (Shonnard et al., 1988; Clench and Mathias, 1996; Prosser, 1995) but so far little is known about their presence and appearance in fish and reptiles. Similarly, little is known about the link between slow waves and ICCs in non-mammalian species. Nonetheless, ICCs (or at least ICC-like cells) have been reported from frog, lizard, birds and teleosts (Kirtisinghe, 1940; Lecoin et al., 1996; Reynhout and Duke, 1999; Martinez-Ciriano et al., 2000; Miyamoto-Kikuta and Komuro, 2007; Rich et al., 2007). 2.3. Different patterns — propagating vs. non-propagating contractions As already mentioned, the motility pattern differs between interdigestive and postprandial (after food intake) states. For example, both the frequency and the amplitude of contractions, and relaxation, can vary. The motility patterns also differ between different regions of the gut. Although gut motility has been described in all vertebrate groups,

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there are generally few systematic descriptions that characterize different motility patterns in non-mammalian species (see below). The gastrointestinal tract follows a similar plan in most vertebrates, however, there are several species and group differences (e.g., Stevens and Hume, 1995). For example, birds possess a crop and gizzard while many fish lack a stomach (e.g. cyprinids). There are also different specialisations to increase surface area, like the pyloric caeca in many teleosts and the spiral valves in elasmobranchs and holosteans. Consequently, what is known about motility in the mammalian gastrointestinal tract does not always translate to other groups of animals. Food intake induces propagating, propulsive contractile activity, often referred to as peristalsis. As will be described in more detail below, the stimulus may be chemical or mechanical properties of the food, acting via autonomic reflexes or release of hormones (Furness and Costa, 1987; Olsson and Holmgren, 2001; Hansen, 2003). Gut contents are pushed forward when the smooth muscle orally to the contents contracts; at the same time the muscles relax anally. The contractions may be initiated in any region of the gut and generally travel only a short distance before fading out. The stomach is separated from the intestine by the pyloric sphincter that is normally closed. Gastric emptying, that is the release of fluid and smaller particles into the proximal intestine, occurs when the gastric pressure exceeds the sphincter pressure, due to increased tension in the stomach wall and/or decreased tension in the pyloric sphincter. Migrating motor complexes (MMCs) are slowly propagating contractions that travel along most of the gastrointestinal tract in fasted animals (Szurszewski 1969; Husebye, 1999). MMCs are best characterised in mammals where they consist of three (sometimes four) distinct phases of which the most characteristic is phase III that contains rhythmic contractions. Phase I is almost silent while phase II contains irregular contractions. All three phases of MMCs have been demonstrated in several avian species including chicken, pheasant (Phasanius), quail and owl (Strix) (Clench et al., 1989). MMC-like activity seems to be present even in the fed state. In turkey (Meleagris), only phase III activity was shown (Mueller et al., 1990). Similarly, so far only phase III-like activity has been observed in teleosts (Karila and Holmgren, 1995; Holmberg et al., 2004). Non-propagating motility may also be of several kinds (Furness and Costa, 1987; Olsson and Holmgren, 2001; Furness, 2006). Local contractions and relaxations are often the predominant activity after food intake. They may be initiated at any location along the gut and help mix the gut content. Another type of motility is relaxation of the stomach to accommodate for the food as we eat. 3. Control of gut motility Presence of food in the gut is the most obvious stimulus for gut motility but even sight, smell or thought of food may affect motility (see e.g. Katschinski, 2000). In either case, the events are tightly regulated by hormonal and neuronal pathways, making sure the contractile activity is finely tuned to meet the demands. Autonomic reflexes play an essential part in both initiation and control of the motility (Furness and Costa, 1987; Bornstein et al., 2002; Furness, 2006; Grundy et al., 2006). The enteric nervous system is the part of the autonomic nervous system mainly responsible for the control of gastrointestinal functions like motility but also e.g. secretion. It is intrinsic to the gut, i.e. it comprises all neurons with their nerve cell bodies located within the gut wall. There is also extrinsic autonomic innervation of the gut (see Nilsson, 2010–this volume). Depending on the situation, the relative importance and involvement of a certain neuronal pathway vary. As will be discussed below, different motility patterns often require different control mechanisms. 3.1. Anatomy of the innervation of the gut The gut wall is similar in most vertebrates with two muscle layers oriented more or less perpendicular to each other, i.e. one (outer) runs in a longitudinal direction along the length of the gut and the other is

circular. In between the two muscle layers lies the myenteric plexus, containing most of the nerve cells involved in the control of motility (see e.g. Nilsson, 1983; Furness and Costa, 1987). Enteric nerve cells include the three main neuronal classes necessary to make up complex reflex pathways — sensory, inter- and motor neurons. In some vertebrate groups, the separate classes can be distinguished using size, morphology and/or transmitter (or other chemical markers) content (Furness, 2006; Olsson, 2009). In other groups of animals, the nerve cells seem to be phenotypically more uniform, or the right markers have not yet been discovered. Neuronal size and morphology also vary substantially between species and vertebrate classes (Olsson and Karila, 1995; Olsson, 2009). Most groups of vertebrates also have both cranial and spinal (extrinsic) innervation of the gut. In general, the anterior gut is innervated by the vagus nerve (cranial pathways) while the posterior parts are innervated by splanchnic nerves (spinal pathways). Sacral spinal innervation is less well documented in most non-mammalian groups. For a more detailed discussion on the comparative anatomy of the autonomic nervous system, see Nilsson (2010–this volume). Although not strictly part of the autonomic innervation, both the vagus and the splanchnic nerves also contain numerous sensory nerve fibres (Grundy and Schemann, 2002). These convey signals from the gut to the central nervous system, where they are perceived as e.g. pain or discomfort, or form part of extrinsic autonomic reflexes. In the following, these will be considered alongside the efferent innervation. 3.2. Factors affecting the control of gut motility The response to nerve signalling depends on the type of transmitters released by the nerve as well as the receptors present on the target. Although nerve cells can act directly on the smooth muscle cells, it has been shown in mammals that the signalling may be enhanced by ICCs situated close to the muscle cells (Ward et al., 2004; Sarna, 2008). The signalling may also be enhanced by local (or circulating) hormones. The type and amount of food present in the lumen also have profound effects on gut motility, by triggering different responses. These responses may be region-specific. For example, fat in the upper part of the intestine generally has an inhibitory effect on gastric emptying (Swan et al., 1966). Environmental factors like temperature (especially important for ectothermic animals like fish, amphibians and reptiles), pH and season may also have significant effects on motility (e.g. Gräns et al., 2010; Underhay and Burka, 1997). Many animals show clear seasonal changes in the type of food and frequency of feeding and this might also be accompanied by changes in the control mechanisms. So far, however, there are few studies considering these aspects. Furthermore, different disease states may severely affect the gut and its control mechanism. For example, infections may change the innervation patterns and cause upand/or down regulation of various signalling substances (Poli et al., 2001; Lomax et al., 2010). Other examples include congenital diseases like Hirshsprung's disease where there is a dramatic reduction in the number of enteric nerve cells, leading to reduced motility. The density of the enteric nervous system may also decrease in relation to e.g. diabetes or Parkinson's disease (Anderson et al., 2007; Du et al., 2009). 4. Mammals as a model for the nervous control of gut motility Dysfunction of the gut, including dysmotility, affects us all from time to time and may include a high degree of discomfort and pain. To find the reasons and hopefully a cure has attracted a lot of attention from scientists for decades. Consequently, the autonomic control of the mammalian gut has been a focus for research since the early discoveries by e.g., Bayliss and Starling (1899), Langley and Magnus (1905) and Cannon (1912).

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To find out more about the pathophysiology, studies should ultimately be performed on human subjects, however, the majority has involved other mammalian species. This includes a wide range of species with different feeding strategies and food choices, for example dog, rabbit, ferret, cat, pig and opossum. Nevertheless, the vast majority of the studies involve rodents and for a long time guinea-pig has been the number one animal model for studies of the enteric innervation (Furness, 1970; Costa and Furness, 1971; Costa and Furness, 1976; Furness and Costa, 1980; Costa et al., 1996). Today, due to the importance of molecular tools, mice and rats have challenged the guinea-pig, but still there are a substantial number of new publications each year involving the latter. 4.1. Reflexes Any gut movements are commonly achieved by the combined action of excitatory and inhibitory motor neurons, causing contraction and relaxation respectively of the smooth muscle. Reflexes are initiated by the stimulation of intrinsic or extrinsic sensory neurons, which in turn stimulate excitatory or inhibitory interneurons that subsequently send signals to the motor neurons (Fig. 1) (see e.g. Furness, 2006). The stimuli acting on the sensory neurons may be either mechanical or chemical (or both) arising from the presence of food in the gut. There may also be indirect stimulation of the nerves via the release of local hormones like serotonin from epithelial endocrine cells (Kirchgessner et al., 1992). 4.2. The enteric nervous system The enteric neurons are numerous in most mammals examined; where the cells have been counted they comprise similar numbers as the cells in the spinal cord (Furness and Costa, 1980; Furness and Costa, 1987; Gabella, 1987). The enteric nervous system is welldefined with cells clustered together in ganglia that may contain over 200 cells in e.g. guinea-pig (e.g. Furness, 2006). The ganglia are interconnected via bundles of nerve fibres making up a distinct

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network or plexus. The fibres make contact with other nerve cells within the plexus or run to the neighbouring layers innervating e.g. smooth muscle cells, blood vessels and endocrine cells. Occasionally, some cells send axons that reach outside the gut (see e.g. Dalsgaard and Elfvin, 1982). These cells are mainly sensory neurons (viscerofugal cells), making synapses with extrinsic autonomic nerves. The extent to which viscerofugal cells exist in non-mammalian species is little studied. In addition to the myenteric plexus, most mammals have numerous nerve cell bodies also in a submucous plexus. As the number of confirmed neurotransmitters in the central nervous system increases, almost all are also found in the enteric nervous system (Table 1). In 1996, Costa et al. published an extensive study of the distribution of putative transmitters in the guinea-pig small intestine. They described altogether 14 different classes of motor, sensory and inter-neurons based on the combination of transmitters and other chemical markers. Later another study expanded the number of classes to over 30 (Timmermans et al., 1997). The chemical coding has been translated into function for several of these nerve types (Costa et al., 1996; Furness, 2006). However, the scheme is yet far from complete. Furthermore, classes and functions vary between species and even between regions within one species. The most widespread transmitter in the mammalian enteric nervous system is acetylcholine and it is present in subpopulations of motor-, inter- and sensory neurons (see e.g. Costa et al., 1996; Furness, 2006). Together with tachykinins like substance P and neurokinin A (NKA), acetylcholine is regarded as the main excitatory transmitter, causing gut contractions upon release from motor neurons (Furness, 2006). 4.3. The peristaltic reflex The common picture of the peristaltic reflex is that of an ascending pathway leading to the contraction of the circular muscle orally to the site of stimulation and a descending nerve pathway involved in downstream relaxation (Costa and Furness, 1976). The reflex includes

Fig. 1. Schematic drawing of local (intrinsic) enteric and extrinsic autonomic reflexes in the gut. Sensory neurons respond to mechanical (e.g. stretch of the muscle wall) or chemical (e.g. acid in the lumen) stimuli. The stimulus may also be indirect with mucosal endocrine cells responding to luminal stimuli by release of hormones (e.g. serotonin) that in turn stimulate the sensory nerves. Enteric sensory fibres stimulate inter- and/or motor neurons, causing contraction and relaxation of gut smooth muscle. Similarly, extrinsic sensory neurons activate sympathetic and parasympathetic autonomic (simplified in figure) nerves that may stimulate or inhibit the enteric neurons.

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1926), the other parts of the autonomic nervous system play important roles in the control of motility as well. The extrinsic autonomic pathways often modify the enteric signals and coordinate different activities (Grundy et al., 2006; Lomax et al., 2010). There are several well-described extrinsic reflexes involved in the control of motility in the mammalian gut. Either they may act on the same or near-by regions where the stimulus occurs (e.g. vago-vagal reflexes)

Table 2 Distribution of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) and effects of acetylcholine/carbachol in different vertebrates. Fig. 2. The peristaltic reflex includes ascending (in green) and descending (in red) pathways stimulated by the same sensory neuron (in blue). The ascending pathway causes contraction of the circular muscle while the descending causes relaxation. Different neurotransmitters are released from the respective motorneurons.

the simultaneous activation of both these pathways by a common sensory neuron, stimulating ascending and descending excitatory interneurons that in turn stimulate excitatory and inhibitory motor neurons, respectively (Fig. 2). Generally, it is more complex. Most neurons receive input from several other neurons, both inhibitory and excitatory. The interneurons make up complex networks, each innervating other interneurons, both ascending and descending, as well as motorneurons to both muscle layers (Spencer et al., 2005). Ascending interneurons stimulate two sets of excitatory motor neurons, causing contraction of the circular and longitudinal muscles respectively (see e.g. Furness, 2006; Wood, 2008). In most mammals studied, ascending excitatory motor neurons contain acetylcholine and tachykinins while descending, inhibitory motor neurons contain nitric oxide and vasoactive intestinal peptide (VIP) and/or its close relative pituitary adenylate cyclase-activating polypeptide (PACAP) (Costa et al., 1996; Timmermans et al., 1997). Other inhibitory transmitters include adenosine triphosphate (ATP) and γ-amino butyric acid (GABA). Ascending excitatory interneurons also contain acetylcholine and tachykinins while descending interneurons in addition to acetylcholine may contain e.g. nitric oxide synthase (NOS), VIP or somatostatin (see e.g. Furness, 2006). The roles of other signalling substances may be more variable, depending on the region or species and the receptors expressed. For example, at least 14 different serotonin (5-hydroxytryptamine, 5-HT) receptors (including subtypes) exist that may be expressed in the gastrointestinal tract (Nichols and Nichols, 2008). While activation of some type of serotonin receptors leads to contractions others cause relaxation of the gut. In either case, the receptors may be located directly on the smooth muscle or on excitatory (cholinergic) or inhibitory enteric neurons respectively (Nichols and Nichols, 2008). It should be noted that neuronally released serotonin represents about 10% only of the total concentration in the mammalian gut, the rest originates from epithelial endocrine cells (Hansen, 2003). Other transmitters with varying effects include enkephalin, opioids, and neurotensin. Somatostatin and galanin have mainly an indirect inhibitory effect on motility, while bombesin and cholecystokinin are predominantly stimulatory. Calcitonin gene-related peptide (CGRP) is also mostly inhibitory but may play an additional role in sensory neurons. For a more comprehensive overview of the neurohumoral control of gut motility in mammals see e.g. Hansen (2003). 4.4. Extrinsic reflexes Although the enteric nervous system may function without central input as was suggested already by the early studies of Bayliss and Starling, Cannon and several others (see e.g. Thomas and Kuntz,

Species

Distribution Sto

Myxini Myxine glutinosa Cephalaspidomorphi Lampetra fluviatilis Chondrichthyes Elasmobranchii Amblyraja radiata Dipturus batis Leucoraja neavus Raja brachyura Raja clavata Raja microocellata Raja montagui Scyliorhinus canicula Squalus acanthias Actinopterygi Teleostei Ammotretis rostratus Anguilla anguilla Cyprinus carpio Danio rerio Gadus morhua Haemulon flavolineatum Labrus berggylta Lipophrys pholis Lophius piscatorius Myoxocephalus scorpius Oncorhynchus mykiss Pleuronectes platessa Rhombosolea tapirina Salmo salar Salmo trutta Tinca tinca Sarcopterygii Amphibia Anura Bufo marinus Xenopus laevis Reptilia Agama sp. Python molurus Cuora amboinensis Pelodiscus sinensis Aves Gallus sp.

Int

Motility Sto

References

Int +

11, 13, 29

(−)

+ + + + + +

nf, nc

+ + + +

+

+

+ + Sto no, Oes +

+ + SI (+), R SI (+), R SI (+), R SI (+), R SI (+), R (+) +

+ + + + +

13

+ + + + +

13 29 34, 35 34, 35 33, 34, 35 34, 35 34, 35 31, 33, 34 22, 29

+ + + + + + +

29 17 10 1 3, 13, 16, 18, 26, 30 4 29, 32 12, 14, 21, 26, 29 7 29 7 8 6 2 29

+

5, 28 25

+

19, 23

+ + +

9 27 15

+

22, 24

+ + + +

Sto, stomach; Int, intestine; Oes, oesophagus; SI, spiral intestine; R, rectum; nc, nerve cell body; nf nerve fibre; no, no effect. References: 1. Backman (1917); 2. Bernheim (1934); 3. Burka et al. (1989); 4. Burnstock (1958); 5. Campbell (1969); 6. Goddard (1973); 7. Grove and Campell (1979); 8. Gräns and Olsson (unpublished); 9. Holmberg et al. (2003); 10. Holmberg et al. (2004); 11. Holmgren and Fänge (1981); 12. Jensen and Holmgren (1985); 13. Jensen and Holmgren (1991); 14. Karila et al. (1998); 15. Kim et al. (1965); 16. Kitazawa (1989); 17. Kitazawa et al. (1986b); 18. Kitazawa et al. (1986c); 19. Knight and Burnstock (1999); 20. Nilsson and Fänge (1969); 21. Nilsson and Holmgren (1983); 22. Ojewole (1980); 23. Ojewole (1983a); 24. Seno et al. (1978); 25. Sundqvist and Holmgren (2006); 26. Thorndyke and Holmgren (1990); 27. Toh and Mohiuddin (1958); 28. Tsai and Ochillo (1983); 29. Wartman et al. (1999); 30. von Euler and Östlund (1957); 31. Young (1933); 32. Young (1980a); 33. Young (1980b); 34. Young (1983b); 35. Young (1988).

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

or they may coordinate movements over longer distances. Many of the above-mentioned transmitters are also found in the extrinsic autonomic nerves. The sensory (afferent) components may have specialised peripheral endings like the intraganglionic laminar endings (IGLEs) that respond to mechanical stimuli (Phillips and Powley, 2000; Zagorodnyuk et al., 2001; Olsson et al., 2004). These are most prominent on vagal and pelvic afferents. There are also chemosensitive afferents. The extrinsic visceral afferents often contain CGRP, substance P and glutamate (Grundy and Schemann, 2002).

85

Vagal efferent neurons (i.e. mainly parasympathetic preganglionic fibres) contain acetylcholine. The postganglionic neurons in vagal pathways are predominantly the enteric neurons. Spinal preganglionic fibres are likewise cholinergic while postganglionic (sympathetic) nerves are mainly adrenergic (Grundy and Schemann, 2002). However, in the pelvic region, postganglionic spinal neurons (sympathetic or parasympathetic, as defined by their preganglionic input from the lumbar or sacral spinal cord, respectively) that innervate the distal intestine may be either adrenergic or cholinergic (Keast, 1995; Luckensmeyer and Keast, 1995). Several additional

Table 3 Distribution and effects of catecholaminergic innervation in different vertebrates. Distribution correlates to catecholamine fluorescense (CA) or tyrosine hydroxylas (TH)immunoreactivity. Species

Distribution

Motility

CA Sto Myxini Myxine glutinosa Cephalaspidomorphi Lampetra fluviatilis Chondrichthyes Elasmobranchii Dipturus batis Leucoraja erinacea Leucoraja neavus Pteroplatytrygon violacea Raja brachyura Raja clavata Raja eglanteria Raja microocellata Raja montagui Scyliorhinus canicula Squalus acanthias Actinopterygi Teleostei Aldrichetta forsteri Ammotretis rostratus Anguilla anguilla Anguilla australis Carassius auratus Cyprinus carpio Gadus morhua Haemulon flavolineatum Labrus berggylta Lophius piscatorius Myoxocephalus scorpius Oncorhynchus mykiss Platycephalus bassensis Pleuronectes platessa Rhombosolea tapirina Salmo trutta Tetractenos glaber Tinca tinca Sarcopterygii Amphibia Anura Bufo marinus Reptilia Crocodylus porosus Agama sp. Python regius Aves Gallus sp.

TH Int

Sto

References

Adrenaline Int

Sto

Dopamine Int

Sto

Int

+/−

15, 32

nf, nc

nf

nf

nf

nf

5

+ +/− + +/− +/− + +/− +/− +/− +

R−

+

SI no SI no

R− R−

SI no SI no SI no

nf nf nf

+

− − − − − − −

+

− − −

+

− nf nf, nc nf

nf

nf nf

nf nf nf

−/+

−

− nf, nca no nf nf

SI no

R− R−

− −

nf nf

+/− − SI +, + SI +, SI +, − SI +, SI +, + +/−

32 22 11, 37, 34 37, 38 34, 36, 22 37, 38 37, 38 34, 36, 16, 22,

38

37, 38

37 25, 32

13 1, 2 10, 23, 32 2 2 20 12, 18, 24, 32 7 32 32, 35 14, 31 19, 21, 29 2 32 2, 13 2, 8 2, 3 4

9, 30

−

28 27 17

–

6, 26, 33

nf

Sto, stomach; Int, intestine; SI, spiral intestine; R, rectum; nc, nerve cell body; nf nerve fibre; no, no effect. References: 1. Anderson (1983); 2. Anderson and Campbell (1988); 3. Anderson (1990); 4. Backman (1917); 5. Baumgarten et al. (1973); 6. Bennett et al. (1973); 7. Bernheim (1934); 8. Burnstock (1958); 9. Campbell (1969); 10. Domeneghini et al. (2000); 11. Goodrich et al. (1980); 12. Groisman and Shparkovskii (1989); 13. Grove and Campell (1979); 14. Gräns and Olsson (unpublished); 15. Holmgren (unpublished); 16. Holmgren and Fänge (1981); 17. Holmgren and Nilsson (1983a); 18. Jensen and Holmgren (1985); 19. Kitazawa et al. (1986b); 20. Kitazawa et al. (1986c); 21.Kitazawa et al. (1989); 22. Lutz (1931); 23. Nilsson and Fänge (1967); 24. Nilsson and Fänge (1969); 25. Nilsson and Holmgren (1983); 26. Ojewole (1980); 27. Ojewole (1983a); 28. Olsson and Holmgren (unpublished); 29. Santer and Holmgren (1983); 30. Tsai and Ochillo (1983); 31. Watson (1979); 32. von Euler and Östlund (1957); 33. Young (1983a); 34. Young (1933); 35. Young (1980a); 36. Young (1980b); 37. Young (1983b); 38. Young (1988). a Submucosal plexus.

86

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

transmitters are found in cranial and/or spinal extrinsic fibres, including e.g. nitric oxide, substance P, CGRP and VIP (Dockray and Sharkey, 1986; Domoto et al., 1992; Olsson et al., 2004). The efferent Table 4 Distribution and effects of γ-aminobutyric acid (GABA) in different vertebrates. Species

Distribution Sto

Sarcopterygii Amphibia Anura Rana esculenta Xenopus laevis Reptilia Python regius Aves Coturnix coturnix Gallus sp.

Motility Int

Sto

References Int

4.5. Extrinsic vs. intrinsic innervation nf, nc nf, nc

nf nf, nc

nf, nc

nf, nc

5

nfa nf, nc

nf (nc)

1 2, 3, 6

–

3 4

no

Sto, stomach; Int, intestine; nc, nerve cell body; nf nerve fibre; no, no effect. References: 1. Baetge and Gershon (1986); 2. Csoknya et al. (1990); 3. Gábriel et al. (1990); 4. Olsson (2002); 5. Olsson and Holmgren (unpublished); 6. Saffrey et al. (1983). a Regions not defined. Table 5 Distribution of nitrergic innervation in different vertebrates. Distribution correlates to nitric oxide synthase (NOS)-immunoreactivity or NADPH-diaphorase activity. Species

Chondrichthyes Elasmobranchii Squalus acanthias Actinopterygi Teleostei Anguilla anguilla Carassius auratus Danio rerio Dicentrarchus labrax Engraulis japonicus Gadus morhua Oncorhynchus mykiss Sarcopterygii Amphibia Anura Bufo marinus Rana catesbeiana Xenopus laevis Caudata Ambystoma tigrinum Reptilia Crocodylus porosus Agama sp. Podarcis hispanica Podarcis siculus Python molurus Python regius Thamnophis sirtalis Aves Anas platyrhynchos Coturnix coturnix Columba livia Gallus sp.

neurons exert their effect on motility by modulating the activity of the enteric nervous system. Typical vago-vagal reflexes are the relaxation of the stomach in anticipation of the arrival of food (via mechano-stimulation of afferents in the oesophagus) or in response to distension by food already in the stomach (accommodation). Spino-spinal reflexes include the inhibition of the stomach e.g. after noxious stimuli to the intestine (see Furness, 2006).

Distribution

Motility

Sto

Int

Sto

nf, nc

nf, nc

26

nf

nf nf, nc nf, nc nf, nc nf, nc nf, nc nf, nc

6 2 9, 27 28 4 10, 11, 24, 25, 26 7, 17, 25

nf, nf, nf, nf,

nc nc nc nc

References Int

–

– –

– –

Although the intrinsic enteric innervation is essential for the initiation of peristalsis, postprandial activity becomes less coordinated without extrinsic input. In contrast, interdigestive motility, like MMCs, relies predominantly on the enteric nervous system (see Husebye, 1999). Basal MMC patterns are often maintained after extrinsic denervation, such as vagotomy while the disruption of MMCs after food intake involves vagal pathways (Al-Saffar, 1984; Rodriguez-Membrilla and Vergara, 1997). There are also regional differences, with the intrinsic control less elaborated in the stomach compared with the intestine. Furthermore, gastric peristalsis generally relies less on both extrinsic and intrinsic innervation, and may persist after cutting the myenteric plexus or combined vagotomy/ splanchnic nerve section (see Furness, 2006). 5. Birds 5.1. Gastrointestinal innervation Both intrinsic and extrinsic innervation of the avian gastrointestinal tract is similar to the mammalian. The myenteric neurons are gathered in ganglia and immunohistochemical studies have demonstrated the presence of several enteric neuronal subclasses. The extrinsic innervation of the avian gut is primarily by cranial fibres in the vagus nerve and the nerve of Remak (a ganglionated nerve trunk running along the avian intestine) and by spinal fibres in the splanchnic and pelvic nerves (Nilsson, 2010). The extrinsic innervation is believed to be mainly Table 6 Effects of purines in different vertebrates.

nf, nc nf, nc nf, nc

nf, nc nf, nc nf, nc

nf

nf

nf, nc

nf, nc

–

no

14, 15, 25 25 22 18

nf, nc nf, nc

nf nf, nc nf, nc nf, nc nf, nc

23 12 3, 19 5, 13 8 25 13

nf, nf, nf, nf,

nf, nc nf,nc nf, nc nf, nc

21 16 20 1

Oes− nf, nc

nc nc nc nc

Sto, stomach; Int, intestine; Oes, oesophagus; nc, nerve cell body; nf, nerve fibre; no, no effect. References: 1. Balaskas et al. (1995); 2. Brüning et al. (1996); 3. Burrell et al. (1991); 4. Chusovitina and Varaksin (2003); 5. D'Este et al. (1994); 6. Domeneghini et al. (2000); 7. Green and Campbell (1994); 8. Holmberg et al. (2003); 9. Holmberg et al. (2006); 10. Karila and Holmgren (1995); 11. Karila and Holmgren (1997); 12. Knight and Burnstock (1999); 13. Lamanna et al. (1999b); 14. Li et al. (1992); 15. Li et al. (1993); 16. Li et al. (1994); 17. Li and Furness (1993); 18. Maake et al. (1999); 19. Martinez-Ciriano et al. (2000); 20. Mirabella et al. (2000); 21. Mirabella et al. (2002); 22. Olsson (2002); 23. Olsson and Gibbins (1999); 24. Olsson and Holmgren (2000); 25. Olsson and Holmgren (unpublished); 26. Olsson and Karila (1995); 27. Olsson et al. (2008); 28. Pederzoli et al. (2007).

Species

Chondrichthyes Elasmobranchii Leucoraja neavus Raja brachyura Raja clavata Raja microocellata Raja montagui Scyliorhinus canicula Actinopterygi Teleostei Gadus morhua Lophius piscatorius Oncorhynchus mykiss Platichthys flesus Sarcopterygii Amphibia Anura Xenopus laevis Reptilia Agama sp.

Motility

References

Sto

Int

+/− +/− +/− +/− +/− +/−

SI no, SI no, SI no, SI no, SI no, SI no

+/− + +/−a

− −

R R R R R

− − − − −

9, 9, 8, 9, 9, 9,

10 10 9, 10 10 10 10

+/−

2 7 1 4

+/−

+/−

6

Oes no

−

3, 5

Sto, stomach; Int, intestine; Oes, oesophagus; SI, spiral intestine; R, rectum; no, no effect. References: 1. Holmgren (1983); 2. Jensen and Holmgren (1985); 3. Knight and Burnstock (1999); 4. Lennard and Huddart (1989); 5. Ojewole (1983b); 6. Sundqvist (2007); 7. Young (1980a); 8. Young (1980b); 9. Young (1983b); 10. Young (1988). a Dose-dependent response.

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

excitatory, although vagal inhibitory pathways exist. Most studies have been performed on chicken (domestic fowl, Gallus gallus) or other fowls. A large proportion of the neurons in all regions of the chicken gut contains nitric oxide synthase, the enzyme involved in the production of nitric oxide in the cells (Balaskas et al., 1995). Nitrergic neurons are also found in pigeons and duck (Table 5). Many NOS-immunoreactive neurons co-express VIP and PACAP and at least in pigeon, some also

Table 7 Distribution and effects of serotonin (5-hydroxytryptamine, 5-HT) in different vertebrates. Species

Myxini Eptatretus cirrhatus Myxine glutinosa Cephalaspidomorphi Lampetra camtschatica Lampetra fluviatilis Lampetra planeri Petromyzon marinus Chondrichthyes Elasmobranchii Leucoraja neavus Raja brachyura Raja clavata Raja microocellata Raja montagui Scyliorhinus canicula Scyliorhinus stellaris Squalus acanthias Holocephalii Chimaera monstrosa Actinopterygi Polypterus senegalus Teleostei Aldrichetta forsteri Anguilla anguilla Anguilla australis Carassius auratus Cyprinus carpio Danio rerio Gadus morhua Labrus berggylta Leuciscus idus Lophius piscatorius Myoxocephalus scorpius Oncorhynchus mykiss Oreochromis mossambicus Platycephalus bassensis Pleuronectes platessa Poecilia reticulata Psetta maxima Salmo salar Salmo trutta Tetractenos glaber Sarcopterygii Dipnoi Lepidosiren paradoxa Amphibia Anura Bufo marinus Rana catesbeiana Xenopus laevis Caudata Ambystoma tigrinum Reptilia Lampropholis guichenoti Chelodina longicollis Cuora amboinensis Pelodiscus sinensis Aves Gallus sp. Melopsittacus undulatus

Distribution

Motility

Sto

Sto

Int nf nf, nc

SI no, SI no, SI no, SI no, SI no, SI no

nf

46, 47 46, 47 45, 46, 47 46, 47 46, 47 15, 45, 46 14 18, 32

nf

49

nf

12

nf, nc + nf, nc nf, nc + nf, nc nf, nc

+

+ +

nf, nc + nf, nc

nf nf, nc

nf, nca

nf, nf, nf nf, nf,

+

+

nc nc + nc nca

nf, nc nf, nc

+

+

nf

nf

48 6, 24, 34 39 34

+

+/− +/− +/− +/− +/− +/−

nf

nf

34 16, 34, 44

no

nf, nc nf, nc nf, nc nf

nf nf

References Int

R R R R R

+ + + + +

4, 5 44 3, 4 4, 16 28 36 21, 25, 44 44 11 44 43 7, 10, 17, 19, 22, 29 26 3, 4 9, 43, 44 11 8, 37 42 4, 13 3, 4

33

−

nf, nc nf −

no

nf

nf

31

− −

− −

1 1 40 27

+/−

?

−(+) + + −

−

+

2, 41 16 20, 23, 38

30, 35 1

87

contain galanin (Balaskas et al., 1995; Mirabella et al., 2000; Mirabella et al., 2002). Furthermore, there is an almost complete overlap between VIP and PACAP (Mirabella et al., 2002) (Table 17). Tachykinin-immunoreactive enteric neurons have been detected in most regions of the gut in several avian species including chicken (Gallus), quail (Coturnix coturnix), duck (Anas platyrhynchos) and crested tit (Parus cristatus) (Table 16). While immunoreactive nerve cell bodies were seen in the intestine they were not detected in the rectum (Suzuki et al., 1996; Aisa et al., 1997). Substance Pimmunoreactive nerve cell bodies are also present in the nerve of Remak (Komori et al., 1986b; Suzuki et al., 1994; Aisa et al., 1998). GABA-immunoreactive nerves have been found in both chicken and quail (Table 4). Nerve cell bodies are most prominent in the intestine. Adrenergic nerve fibres are common in the gut, innervating the myenteric plexus (Ojewole, 1980; Young, 1983a). Aminergic nerve cell bodies have also been demonstrated by fluorescence histochemistry in the avian myenteric plexus, at least in the chicken gizzard (Bennett et al., 1973), but the exact nature of the transmitter has not been studied in more detail. In contrast, Aisa et al. (1997) did not find any catecholaminergic cell bodies in the chicken intestine. Other neuropeptides including opioid- and neurotensin-immunoreactive enteric nerves have been demonstrated (Tables 8–15). 5.2. Effects on gut motility Both acetylcholine and 5-HT cause contractions of isolated smooth muscle preparations of the chicken rectum (Ojewole, 1980; Kitazawa et al., 2006). The response to acetylcholine was atropine-sensitive, suggesting muscarinic receptors. Tachykinins likewise contract the gut (Table 16). In the chicken ileum, tetrodotoxin (TTX) reduced the contractile response, implying an indirect effect of the tachykinins via TTX-sensitive neurons. In contrast, no effect of TTX was seen in the crop (Denac and Scharrer, 1988; Liu and Burcher, 2001). Substance P and NKA may act via NK1-receptors on cholinergic neurons (Liu and Burcher, 2001). Adrenaline induces relaxation of the chicken rectum, acting via alpha-adrenoceptors (Ojewole, 1980). Although there is a lack of reports on the distribution of bombesin/ gastrin-releasing peptide (GRP) or cholecystokinin (CCK) in nerves in the avian gut, pharmacological studies have shown effects in vitro. In most cases, it cannot be deduced whether these effects mimic neuronal or hormonal signalling. In pigeon (Columba) proventriculus, bombesin has a mixed effect, causing relaxation of the longitudinal muscle and contraction of circular muscle while in the chicken crop and intestine, the effect is mainly excitatory (Table 8). TTX did not affect the response in the latter, suggesting an effect directly on the smooth muscle (Denac and Scharrer, 1988). The sulphated form of CCK8 contracts longitudinal muscle strips from the chicken ileum in a TTX-sensitive manner (Martin et al., 1994). It was proposed that the effect of CCK was mediated via substance P and serotonin release while not involving acetylcholine. Notes to Table 7: Sto, stomach; Int, intestine; SI, spiral intestine; R, rectum; nc, nerve cell body; nf nerve fibre; no, no effect. References: 1. Adamson and Campbell (1988); 2. Anderson (1983); 3. Anderson and Campbell (1988); 4. Anderson and Campbell (1989); 5. Anderson (1990); 6. Baumgarten et al. (1973); 7. Beorlegui et al. (1992); 8. Bermúdez et al. (2007); 9. Bjenning and Holmgren (1988); 10. Burka et al. (1989); 11. Burkhardt-Holm and Holmgren (1989); 12. Burkhardt-Holm and Holmgren (1992); 13. Burnstock (1958); 14. Cimini et al. (1985); 15. Faraldi et al. (1990); 16. Goodrich et al. (1980); 17. Holmgren (1983); 18. Holmgren (unpublished); 19. Holmgren et al. (1985a); 20. Holmgren and Nilsson (1983a); 21. Jensen and Holmgren (1985); 22. Jensen and Holmgren (1991); 23. Johansson (2003); 24. Johnels and Östlund (1958); 25. Karila et al. (1998); 26. Kiliaan et al. (1989); 27. Kim et al. (1965); 28. Kitazawa (1989); 29. Kitazawa et al. (1986c); 30. Kitazawa et al. (2006); 31. Maake et al. (1999); 32. Nilsson and Holmgren (1983); 33. Nilsson and Holmgren (1992); 34. Nilsson and Holmgren (1998); 35. Ojewole (1980); 36. Olsson et al. (2008); 37. Reinecke et al. (1997); 38. Sundqvist and Holmgren (2008); 39. Tagliafierro et al. (1989); 40. Toh and Mohiuddin (1958); 41. Tsai and Ochillo (1983); 42. Wartman et al. (1999); 43. Watson (1979); 44. von Euler and Östlund (1957); 45. Young (1980b); 46. Young (1983b); 47. Young (1988); 48. Yui et al. (1988); 49. Yui et al. (1990).aNot specified in what region nerve cells are found.

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Table 8 Distribution and effects of bombesin/gastrin-releasing peptide (GRP) in different vertebrates. Species

Cephalaspidomorphi Lampetra camtschatica Lampetra fluviatilis Petromyzon marinus Chondrichthyes Elasmobranchii Amblyraja radiata Leucoraja erinacea Leucoraja neavus Raja clavata Raja microocellata Raja montagui Raja rhina Scyliorhinus canicula Scyliorhinus stellaris Squalus acanthias Squatina aculeata Holocephalii Chimaera monstrosa Actinopterygi Polypterus senegalus Chondrostei Lepisosteus platyrhincus Teleostei Anguilla anguilla Centrolabrus exoletus Ciliata mustela Ctenolabrus rupestris Cyprinus carpio Gadus morhua Haplochromis spp. Labrus berggylta Labrus mixtus Leuciscus idus Myoxocephalus scorpius Oncorhynchus mykiss Perca fluviatilis Poecilia reticulata Pollachius pollachius Platichthys flesus Raniceps raninus Sarcopterygii Amphibia Anura Bufo calamita Xenopus laevis Caudata Ambystoma tigrinum Hydromates italicus Necturus maculosus Reptilia Alligator mississipiensis Caiman crocodylous sp Caiman latirostris Crocodylus niloticus Chalcides chalcides Pogona barbatus Varanus gouldi Zonosaurus madagascariensis Python molurus Python regius Vipera berus Pelodiscus sinensis Trachemys scripta elegans Aves Pigeon Gallus sp.

Distribution

Motility

Sto

Sto

Int

References

34 28 28

+

nf, nc

22 2 1, 2 1, 2 1, 2 1, 2 22 12, 30 6, 7 16 30 35

nf

5

nf

17

nf

nf nf

nf

nf

nf nf nf nf − − nf

nf, nc nf nf nf nf nf nf nf nf nf

nf

+

+ −

+ +

nf

nf nf

nf nf

9 1 1 1 1 1, 15, 31 25 1 1 4 1, 32 1, 31 1 4 1 1 1

20 23

+ nf nf nf

nf nf nf

30 30 cm−/lm + cm−/lm + 18

nf nf

+

nf nf nf nf nf

− nf

nf nf nf

nf

nf, nc

Species

Int

nf, nc nf nf

nf nf nf nf nf nf nf nf nf nf nf nf nf nf nf nf nf nf nf, nc nf, nc nf nf

Table 9 Distribution and effects of calcitonin gene-related peptide (CGRP) in different vertebrates.

+

cm−/lm + Crop + +

3 19 33 20 27 20 20 27 20 20 20 11 29 13 8, 10, 11

Cephalaspidomorphi Lampetra camtschatica Lampetra fluviatilis Petromyzon marinus Actinopterygi Teleostei Anguilla anguilla Carassius auratus Danio rerio Gadus morhua Oncorhynchus mykiss Oreochromis mossambicus Sarcopterygii Dipnoi Neoceratodus forsteri Amphibia Anura Bufo marinus Rana catesbeiana Xenopus laevis Caudata Ambystoma tigrinum Reptilia Crocodylus niloticus Crocodylus porosus Iguana iguana Pogona barbatus Varanus gouldi Python molurus Python regius Vipera berus Trachemys scripta elegans Aves Gallus sp.

Distribution

Motility

Sto

Sto

nf

Int

References Int

nf, nc nf nf

15 9 9

nf nf, nf, nf, nf nf,

1 6 11 14 10 6

nc nc nc

−

nc

nf

4

nf

nf, nc nf nf

8 10 2

nf

nf

7

nf nf

5 12 10 5 5 3 5 5 13

nf nf − nf nf

nf nf nf nf nf nf nf

no

10

Sto, stomach; Int, intestine; nc, nerve cell body; nf, nerve fibre; no, no effect. References: 1. Domeneghini et al. (2000); 2. Holmberg et al. (2001); 3. Holmberg et al. (2003); 4. Holmgren et al. (1994); 5. Holmgren (unpublished); 6.Kiliaan et al. (1993); 7. Maake et al. (1999); 8. Murphy and Campell (1993); 9. Nilsson and Holmgren (1998); 10. Ohtani et al. (1989); 11. Olsson et al. (2008); 12. Olsson and Holmgren (unpublished); 13. Scheuermann et al. (1991); 14. Shahbazi et al. (1998); 15. Yui et al. (1988).

In addition to the responses to individual signalling substances, there are some studies looking at complex motility patterns in intact birds in vivo. The involvement of extrinsic innervation in the control of MMCs (see Section 2.3) was shown by vagotomy, which reduced the electrical activity in parts of the stomach as well as in the duodenum (Martinez et al., 1993). Similarly, the ganglionic blocker hexamethonium reduced the MMC-like activity. In turkeys, denervation affected motility in fasted but not fed birds (Chaplin and Duke, 1988). Extrinsic innervation also coordinated gastric and intestinal activities.

Notes to Table 8: Sto, stomach; Int, intestine; cm, circular muscle; lm, longitudinal muscle; nc, nerve cell body; nf nerve fibre. References: 1. Bjenning and Holmgren (1988); 2. Bjenning et al. (1991); 3. Buchan et al. (1983); 4. Burkhardt-Holm and Holmgren (1989); 5. Burkhardt-Holm and Holmgren (1992); 6. Cimini et al. (1985); 7. Cimini et al. (1989); 8. Denac and Scharrer (1988); 9. Domeneghini et al. (2000); 10. Erspamer et al. (1972); 11. Falconieri Erspamer et al. (1988); 12. Faraldi et al. (1990); 13. Gascoigne et al. (1988); 14. Holmgren (1983); 15. Holmgren and Jönsson (1988); 16. Holmgren and Nilsson (1983a); 17. Holmgren and Nilsson (1983b); 18. Holmgren et al. (1985b); 19. Holmgren et al. (1989); 20. Holmgren (unpublished); 21. Jensen and Holmgren (1985); 22. Kaiya et al. (2006); 23. Kim et al. (1965); 24. Kitazawa et al. (1990); 25. Langer et al. (1979); 26. Lundin et al. (1984); 27. Morescalchi et al. (1997); 28. Nilsson and Holmgren (1998); 29. Scheuermann et al. (1991); 30. Tagliafierro et al. (1987); 31. Thorndyke and Holmgren (1990); 32. Thorndyke et al. (1984); 33. Yamada et al. (1987); 34. Yui et al. (1988); 35. Yui et al. (1990).

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

The role of the intrinsic innervation was studied in extrinsically denervated chicken oesophagus (Neya et al., 1990). Electrical stimulation of the chicken oesophagus induced ascending and descending contractions as well as descending relaxation. The contractions were mimicked by substance P and an opioid agonist and reduced by atropine or hexamethonium, suggesting that substance P and opioids may act by release of acetylcholine. The relaxation involved VIP (Neya et al., 1990). The effect of CCK in vivo seems to vary between regions; the electrical activity in the chicken stomach is reduced by infusion of CCK while intestinal activity may be induced (Martinez et al., 1992; Martinez et al., 1993). However, the response also depends on the CCK isoform applied. The inhibitory effect of CCK on gastric activity is probably mediated via the vagus, stimulating release of inhibitory nitric oxide (Martinez et al., 1993). In contrast, vagotomy did not affect the effect of CCK on the intestine, suggesting a direct effect on the smooth muscle. See also Tables 2–17 for effects of different neurotransmitters. 6. Reptiles 6.1. Gastrointestinal innervation The reptiles comprise a diverse group and there are few systematic attempts to study the enteric innervation and its effect on gut motility. The species investigated are often random representatives of crocodiles,

89

lizards, snakes and turtles/tortoises. In general, the enteric nervous system is well-developed, and at least in some species and regions there is a submucous nerve plexus in addition to the myenteric plexus (Timmermans et al., 1991; Olsson and Gibbins, 1999). The myenteric nerve cell bodies often make up small ganglia, but may also be seen as single cells (e.g. Lamanna et al., 1999b) (Fig. 3). As for birds, one of the best studied transmitters regarding distribution in the gut is nitric oxide. NOS-immunoreactive and/or NADPH-diaphorase reactive nerve cell bodies have been demonstrated in all groups of reptiles except turtles (Table 5). In estuarine crocodile (Crocodylus porosus), NOS-immunoreactive cell bodies were present in most myenteric ganglia throughout the gastrointestinal tract (Olsson and Gibbins, 1999). Likewise in Italian wall lizard (Podarcis sicula) and common garter snake (Thamnophis sirtalis) NADPH-diaphorase reactive nerve cell bodies were present in all regions (Lamanna et al., 1999b). In all three species, a proportion of the nitrergic neurons display VIP immunoreactivity. Generally, the NOS population is larger than the VIP population. In snake and lizard, NADPH-diaphorase reactive neurons also contain galanin (Lamanna et al., 1999b). The NO/galanin population was larger than the NO/VIP population. While present in most reptiles investigated (Table 17), no VIPimmunoreactive nerve fibres or cell bodies were detected in the yellowbelly slider (Trachemys (Pseudemys) scripta elegans) or two species of Natrix (N. natrix and N. maura) (Masini, 1986; Scheuermann

Fig. 3. The enteric nervous system in different vertebrate species. A. Whole mount preparation of the myenteric plexus in the rat stomach, with VIP-immunoreactive nerve cell bodies (arrows) in a ganglion (asterisk). B. Cross-section of the estuarine crocodile (Crocodylus porosus) stomach, with NOS-immunoreactive nerve cell bodies in two ganglia (asterisk) in the myenteric plexus. C. Cross-section of the python (Python regius) intestine, with substance P-immunoreactive fibres innervating the muscle layers and nerve cell bodies (arrows) in the myenteric plexus. D. Whole mount preparation of the myenteric plexus in the African clawed frog (Xenopus laevis) intestine, showing NADPH-diaphorase reactive nerve cell bodies and nerve fibres. E. Whole mount preparation of the myenteric plexus in the rainbow trout (Oncorhynchus mykiss) stomach, showing GABA receptor immunoreactive nerve cell bodies and nerve fibres. F. Whole mount preparation of the myenteric plexus in the zebrafish (Danio rerio) intestine, with nerve cell bodies labelled with antisera against the panneuronal marker Hu C/D. cm, circular muscle; lm, longitudinal muscle; NOS, nitric oxide synthase; VIP, vasoactive intestinal polypeptide.

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C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

et al., 1991). No galanin-immunoreactive neurons were seen in the yellowbelly slider either (Scheuermann et al., 1991). In contrast, there was numerous neuropeptide Y (NPY)- as well as bombesin- and substance P-immunoreactive nerve cells and fibres (Scheuermann et al., 1991). In most other species, both bombesin and NPY are found mainly in nerve fibres only (Tables 8 and 12). Tachykinin immunoreactivity is widespread in all regions of the gut and groups of reptiles, although in most studies only fibres and no nerve cell bodies have been demonstrated. In yellowbelly slider, substance P colocalized with CGRP (Scheuermann et al., 1991). Other putative transmitters found in the enteric innervation are GABA, CCK, neurotensin, opioids and somatostatin, however, most of these have only been studied in few species (Tables 4, 11, 13–15). 6.2. Effects on gut motility Electrical field stimulation of the lizard Agama rectum induces mixed responses, including both relaxation and contraction (Ojewole, 1983b). The contractile response is reduced by noradrenaline while Table 10 Distribution and effects of galanin in different vertebrates. Species

Cephalaspidomorphi Lampetra fluviatilis Chondrichthyes Elasmobranchii Hemiscyllium ocellatum Heterodontus portusjacksoni Rhinobatos typus Actinopterygi Chondrostei Acipenser transmontanus Teleostei Carassius auratus Gadus morhua Oreochromis mossambicus Platichthys flesus Psetta maxima Solea solea Sarcopterygii Dipnoi Lepidosiren paradoxa Neoceratodus forsteri Amphibia Anura Bufo marinus Xenopus laevis Reptilia Caiman crocodylous sp Crocodylus niloticus Crocodylus porosus Podarcis siculus Pogona barbatus Varanus gouldi Python molurus Python regius Vipera berus Thamnophis sirtalis Trachemys scripta elegans Aves Columba livia Gallus sp.

Distribution

Motility

Sto

Sto

Int

References Int

nf, nc

nf nf nf

2

nf nf nf

18 18 19

nf, nc

nf, nc nf, nc nf, nc nf, nc

nf nf

nf, nc nf

nf nf nf, nc −

2 nf, nf nf, nf, nf nf,

nc

11 9, 10 11 1 1 1

+ nc nc nc

nf nf

7 16

nf, nc nf

15 8

nf nf nf nf, nc nf nf nf nf nf

6 8 17 12, 13 8 8 5 8 8 13 20

+

−

nf, nc nf, nc

no?

−/+

14 3, 21

Sto, stomach; Int, intestine; nc, nerve cell body; nf, nerve fibre; no, no effect. References: 1. Bosi et al. (2007); 2. Bosi et al. (2004); 3. D'Este et al. (1994); 4. DeGolier et al. (1999); 5. Holmberg et al. (2003); 6. Holmgren et al. (1989); 7. Holmgren et al. (1994); 8. Holmgren (unpublished); 9. Karila et al. (1993); 10. Karila and Holmgren (1997); 11. Kiliaan et al. (1993); 12. Lamanna et al. (1999a); 13. Lamanna et al. (1999b); 14. Mirabella et al. (2000); 15. Murphy and Campell (1993); 16. Nilsson and Holmgren (1992); 17. Olsson and Holmgren (unpublished); 18. Preston et al. (1995); 19. Rombout and Reinecke (1984); 20. Scheuermann et al. (1991); 21. Suzuki et al. (1996).

Table 11 Distribution and effects of gastrin/cholecystokinin (CCK) in different vertebrates. Species

Chondrichthyes Elasmobranchii Raja clavata Raja microocellata Raja montagui Scyliorhinus stellaris Squalus acanthias Holocephalii Chimaera monstrosa Actinopterygi Teleostei Carassius auratus Ciliata mustela Cyprinus carpio Gadus morhua Leuciscus idus Myoxocephalus scorpius Oncorhynchus mykiss Pollachius pollachius Raniceps raninus Sarcopterygii Dipnoi Lepidosiren paradoxa Neoceratodus forsteri Protopterus annectens Amphibia Anura Bufo calamita Caudata Necturus maculosus Reptilia Varanus gouldi Natrix natrix Natrix maura Aves Gallus gallus

Distribution

Motility

Sto

Sto

Int

+ + +

SI +, R no SI +, R no SI +, R no

nf nf

Int

nf, nc

+

2 2 2 6 1, 4

nf

19

nf

7, 12 3 3 3, 11 16 3 18 3 3

nf nf nf nf

References

+

+

nf, nc nf +/−

nf nf

nf nf nf

8 17 17

nf

10

nf

+

+

nf

9 10 16 16

− − −

−/+

13, 14, 15

Sto, stomach; Int, intestine; SI, spiral intestine; R, rectum; nc, nerve cell body; nf nerve fibre; no, no effect. References: 1. Aldman et al. (1989); 2. Andrews and Young (1988); 3. Bjenning and Holmgren (1988); 4. Burka et al. (1989); 5. Burkhardt-Holm and Holmgren (1989); 6. Chiba et al. (1995); 7. Himick and Peter (1994); 8. Holmgren et al. (1985a); 9. Holmgren et al. (1985b); 10. Holmgren (unpublished); 11. Jönsson et al. (1987); 12. Kiliaan et al. (1993); 13. Martin et al. (1994); 14. Martinez et al. (1992); 15. Martinez et al. (1993); 16. Masini (1986); 17. Nilsson and Holmgren (1992); 18. Olsson et al. (1999); 19. Yui et al. (1990).

ATP enhances the relaxation. In the oesophagus, neither ATP nor VIP had any effect (Knight and Burnstock, 1999). However, relaxation is reduced by the L-arginine analogue L-NAME, suggesting a nitrergic pathway. Furthermore, acetylcholine contracts all regions of the gut except the stomach while adrenaline causes relaxation (Ojewole, 1983a). The cholinergic response is most likely a direct effect on the smooth muscle (Knight and Burnstock, 1999). Acetylcholine also contracts muscle preparations from the land tortoise (Cuora amboinensis), the Chinese soft-shell turtle (Pelodiscus sinensis) and Burmese python (Python molurus) (Toh and Mohiuddin, 1958; Kim et al., 1965; Holmberg et al., 2003). One of the most extensive studies of the control of gut motility in any reptile was by Holmberg et al. (2003), studying the effect of several transmitters on isolated longitudinal smooth muscle preparations from the intestine of Burmese python. In addition to acetylcholine, galanin and substance P were excitatory while VIP, PACAP, CCK, CGRP and neurotensin were without effect (Holmberg et al., 2003). Few studies have looked specifically at the extrinsic control of the reptilian gut. Stimulation of the vagus may cause both contraction and relaxation while the splanchnic innervation seems to be excitatory (Burnstock, 1972; Sneddon et al., 1973).

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

7. Amphibians

Table 13 Distribution and effects of neurotensin in different vertebrates.

7.1. Gastrointestinal innervation

Species

The amphibian enteric nervous system contains numerous nerve cell bodies in the myenteric plexus, most of which are distributed along nerve bundles or gathered in loosely arranged clusters (e.g. Gunn, 1951). Few neurons are located in the submucous plexus. As in birds and reptiles, most transmitters known from mammalian studies have been detected in one or several amphibian species. NOS-, VIP-, 5-HT- and GABA-immunoreactive nerve cell bodies have been demonstrated. In addition there may be adrenergic as well as CGRP-, galanin-, CCK-, NPY-, opioid- and substance P-immunoreactive nerve fibres (Tables 3, 9–12, 14, 16). In addition to substance P and neurokinin A, the two most widespread tachykinins in the gastrointestinal tract of mammals, birds and reptiles, amphibians have several more or less unique, related peptides like bufokinin and ranakinin. Bufokinin, isolated from the cane toad (Bufo marinus), is present in the gut and exhibits excitatory effects on gut motility (Liu et al., 2002, 2005). Co-localization studies have been most extensively performed in the cane toad. A small proportion of the NOS-immunoreactive neurons in the myenteric plexus (ca 11%) were VIP-immunoreactive

Table 12 Distribution and effects of neuropeptide Y (NPY) in different vertebrates. Species

Chondrichthyes Elasmobranchii Leucoraja neavus Raja clavata Raja microocellata Raja montagui Scyliorhinus canicula Scyliorhinus stellaris Scyliorhinus torazame Actinopterygi Teleostei Anguilla anguilla Carassius auratus Ciliata mustela Cyprinus carpio Gadus morhua Myoxocephalus scorpius Oncorhynchus mykiss Perca fluviatilis Platichthys flesus Poecilia reticulata Pollachius pollachius Raniceps raninus Sarcopterygii Dipnoi Lepidosiren paradoxa Amphibia Anura Xenopus laevis Reptilia Crocodylus porosus Varanus gouldi Python molurus Vipera berus Trachemys scripta elegans

91

Distribution

Motility

Sto

Int

Sto

nf nf nf nf nf nf nf

nf nf nf

nf nf

nf nf nf nf

References Int

2 2 2 2 3, 6 6 5

nf nf

nf nf nf nf nf nf nf nf

nf nf

+

7 11 2 2 2, 10, 15 2, 8 1, 2 2 2 4 2 2

nf

12

nf

nf

9

nf − nf nf, nc

nf nf nf nf nf, nc

13 9 9 9 14

Sto, stomach; Int, intestine; nc, nerve cell body; nf nerve fibre. References:1. Barton et al. (1992); 2. Bjenning and Holmgren (1988); 3. Bjenning et al. (1993); 4. Burkhardt-Holm and Holmgren (1989); 5. Chiba et al. (1995); 6. Cimini et al. (1992); 7. Domeneghini et al. (2000); 8. El-Salhy (1984b); 9. Holmgren (unpublished); 10. Jensen and Conlon (1992); 11. Kiliaan et al. (1993); 12. Nilsson and Holmgren (1992); 13. Olsson and Holmgren (unpublished); 14. Scheuermann et al. (1991); 15. Shahbazi et al. (2002).

Chondrichthyes Elasmobranchii Raja clavata Raja microocellata Raja montagui Actinopterygi Chondrostei Lepisosteus platyrhincus Teleostei Carassius auratus Centrolabrus exoletus Ctenolabrus rupestris Gadus morhua Gillichthys mirabilis Haplochromis spp. Helostoma temminkii Labrus berggylta Labrus mixtus Leuciscus idus Myoxocephalus scorpius Oncorhynchus mykiss Oreochromis mossambicus Perca fluviatilis Poecilia reticulata Platichthys flesus Psetta maxima Puntius conchonius Xiphophorus variatus Sarcopterygii Dipnoi Lepidosiren paradoxa Neoceratodus forsteri Protopterus annectens Amphibia Caudata Ambystoma tigrinum Necturus maculosus Reptilia Caiman crocodylous sp Pogona barbatus Varanus gouldi Python molurus Python regius Vipera berus Aves Gallus gallus

Distribution

Motility

Sto

Sto

Int

no no no

no no no

Int

References

nf, nc nf, nc

8

nf nf nf +/− nf

nf nf

no

nf nf nf nf nf nf nf +/− nf

nf nf nf

nf nf, nc nf nf nf

nf nf nf

18 9 18

nf nf

nf nf nf

nf

nf

14 2 2 12 23 16 16 2 2 3 2 2, 15 14 2 3 2 20 21 16

nf nf

− nf

1 1 1

17 −cm/+ lm −cm/+ lm 7, 10 +

(nf) nf nf nf

+

11, 13 11 11 5 11 11, 13

+

4, 15, 19, 22

no

Crop +

Sto, stomach; Int, intestine; cm, circular muscle; lm, longitudinal muscle; nc, nerve cell body; nf nerve fibre; no, no effect. References: 1. Andrews and Young (1988); 2. Bjenning and Holmgren (1988); 3. Burkhardt-Holm and Holmgren (1989); 4. Denac and Scharrer (1987); 5. Holmberg et al. (2003); 6. Holmgren (1983); 7. Holmgren and Jönsson (1995); 8. Holmgren and Nilsson (1983b); 9. Holmgren et al. (1985a); 10. Holmgren et al. (1985b); 11. Holmgren (unpublished); 12. Jensen and Holmgren (1985); 13. Jensen (unpublished); 14. Kiliaan et al. (1993); 15. Komori et al. (1986a); 16. Langer et al. (1979); 17. Maake et al. (1999); 18. Nilsson and Holmgren (1992); 19. Rawson et al. (1990); 20. Reinecke et al. (1997); 21. Rombout and Reinecke (1984); 22. Saffrey et al. (1982); 23. Van Noorden and Patent (1980).

(Li et al., 1993). Of the VIP-immunoreactive population, just over one third was NOS-immunoreactive. Neither VIP- nor NOS-immunoreactive cells expressed substance P. In addition, VIP-immunoreactive cells in the large intestine may show galanin or CGRP immunoreactivity (Murphy and Campell, 1993). Only the latter population projects to the circular smooth muscle layer. 7.2. Effects on gut motility There are only a few pharmacological studies on the control of gastrointestinal motility in amphibians, encompassing to our knowledge three species. Generally, acetylcholine, bombesin and

92

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

Table 14 Distribution and effects of opioids in different vertebrates. Species

Actinopterygi Polypterus senegalus Teleostei Anguilla anguilla Carassius auratus Centrolabrus exoletus Corydoras aeneus Ctenolabrus rupestris Cyprinus carpio Gadus morhua Gillichthys mirabilis Helostoma temminkii Labrus berggylta Labrus mixtus Myoxocephalus scorpius Oncorhynchus mykiss Oreochromis mossambicus Pelvicachromis pulcher Perca fluviatilis Platichthys flesus Poecilia reticulata Puntius conchonius Sarcopterygii Dipnoi Lepidosiren paradoxa Protopterus annectens Amphibia Anura Bufo calamita Bufo marinus Rana temporaria Xenopus laevis Caudata Ambystoma mexicanum Necturus maculosus Reptilia Caiman crocodylous sp Trachemys scripta elegans Aves Gallus gallus Parus cristatus

Opioids

References

Distribution

Motility

Sto

Int

Sto

nf

nf

4

nf, nc

nf, nc nf nf, nc nf nf, nc

nf nf

5, 13 11 1 13 1 12 1, 9 20 13 1 1 1 6 11 13 1 1 3 16, 17

nf nf

14 14

+ nf

(+) + + nf

8 15 2 8

(nf)

+ (nf)

2 7

Int

+ +/−

nf nf nf nf, nc nf, nc nf

+ nf, nc nf nf, nc

nf nf, nc nf

+

nf, nc −

+

8 19

− +

+a

+

a

−

+

10, 18 8

Sto, stomach; Int, intestine; nc, nerve cell body; nf, nerve fibre; +, nerve fibre/cell body not defined. References: 1. Bjenning and Holmgren (1988); 2. Buchan (1986); 3. Burkhardt-Holm and Holmgren (1989); 4. Burkhardt-Holm and Holmgren (19920; 5. Domeneghini et al. (2000); 6. Holmgren (1983); 7. Holmgren et al. (1985b); 8. Holmgren (unpublished); 9. Jensen and Holmgren (1985); 10. Jimenez et al. (1993); 11. Kiliaan et al. (1993); 12. Kitazawa et al. (1986a); 13. Langer et al. (1979); 14. Nilsson and Holmgren (1992); 15. Osborne and Gibbins (1988); 16. Rombout and Reinecke (1984); 17. Rombout et al. (1986); 18. Saffrey et al. (1982); 19. Scheuermann et al. (1991); 20. Van Noorden and Patent (1980). a Regions not defined.

tachykinins are excitatory transmitters while nitric oxide, VIP and PACAP cause inhibition (Tsai and Ochillo, 1983, Olsson, 2002; Johansson, 2003; Sundqvist and Holmgren, 2008). However, nitric oxide, VIP, PACAP and GABA were without effect on intestinal ring preparations from African clawed frog (Xenopus laevis) (Olsson, 2002). In mudpuppy (Necturus maculosus), the effect of bombesin was mainly inhibitory, with a weak increase in tonus seen only on the longitudinal muscle from the stomach. In the cane toad, dopamine caused relaxation of circular muscle preparations from the stomach (Tsai and Ochillo, 1983). Serotonin had mixed effects in Xenopus gut but triggered no response in cane toad (Table 7). The effect in Xenopus was probably direct on the smooth muscle. Purines like adenosine and ATP may also have mixed effects, depending partly on the developmental stage (Sundqvist, 2007). Neurotensin had an indirect relaxing effect on gastric circular muscle but a direct contracting effect on

longitudinal muscle preparations in mudpuppy (Holmgren et al., 1985b; Holmgren and Jönsson, 1995). The amphibian vagus nerve carries both cranial and spinal nerve fibres. Stimulation of cranial fibres produces inhibition of the stomach, while the spinal fibres cause contraction, probably via a cholinergic mechanism (Campbell, 1969). The splanchnic innervation may be either purely inhibitory, via adrenergic fibres, or give a combination of excitatory and inhibitory responses (Semba and Hiraoka, 1957; Campbell, 1969). 8. Fish In general, the best studied group of non-mammalian vertebrates regarding control of gut motility is fish. Fish is a taxonomically heterogeneous group that comprises at least four (depending on classification) classes of vertebrates as well as Myxini (hagfish), that is strictly speaking not a vertebrate group. The bony fishes include lungfish (Dipnoi), sturgeons (Chondrostei) and teleosts. The latter group contains over 20,000 species. Cartilaginous fishes include elasmobranchs, i.e. sharks and rays. Although lampreys (Cephalaspidomorphi) and hagfish have different origins, they are still commonly referred to as cyclostomes. For recent reviews of the enteric control of gut motility in fish, see also Holmgren and Olsson (2009), Gräns and Olsson (in press) and Olsson (2010). 8.1. Bony fish Most of the work on fish is done on teleost species. While distribution of transmitters has been studied in quite a high number of Table 15 Distribution and effects of somatostatin in different vertebrates. Species

Chondrichthyes Elasmobranchii Scyliorhinus canicula Scyliorhinus stellaris Squalus acanthias Actinopterygi Teleostei Anguilla anguilla Gadus morhua Oncorhynchus mykiss Puntius conchonius Sarcopterygii Dipnoi Lepidosiren paradoxa Neoceratodus forsteri Protopterus annectens Amphibia Anura Bufo marinus Rana ridibunda Caudata Necturus maculosus Reptilia Alligator mississipiensis Crocodylus niloticus Crocodylus porosus Varanus gouldi Python molurus

Distribution

Motility

Sto

Sto

Int

References Int

nf nf nf

nf

nf

nf

+/−

nf

4 7, 14 6, 9 1, 22, 23

nf nf nf

19 12 19, 24

nf nf nf nf

21 15,16

nf nf nf nf nf

2 13 20 13 8

+/− +/−

nf nf nf

5 3 10, 18

+/−

11

Sto, stomach; Int, intestine; nf, nerve fibre. References: 1. Abad et al. (1987); 2. Buchan et al. (1983); 3. Cimini et al. (1985); 4. Domeneghini et al. (2000); 5. Faraldi et al. (1990); 6. Grove and Holmgren (1992a); 7. Grove and Holmgren (1992b); 8. Holmberg et al. (2003); 9. Holmgren (1983); 10. Holmgren and Nilsson (1983a); 11. Holmgren et al. (1985b); 12. Holmgren et al. (1994); 13. Holmgren (unpublished); 14. Jensen and Holmgren (1985); 15. Junquera et al. (1986); 16. Junquera et al. (1987); 17. Kitazawa et al. (1990); 18. Lundin et al. (1984); 19. Nilsson and Holmgren (1992); 20. Olsson and Holmgren (unpublished); 21. Osborne and Gibbins (1988); 22. Rombout and Reinecke (1984); 23. Rombout et al. (1986); 24. Tagliafierro et al. (1996).

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101 Table 16 (continued)

Table 16 Distribution and effects of tachykinins in different vertebrates. Species

Myxini Myxine glutinosa Cephalaspidomorphi Lampetra fluviatilis Chondrichthyes Elasmobranchii Amblyraja radiata Dipturus batis Raja clavata Raja microocellata Raja montagui Scyliorhinus stellaris Squalus acanthias Actinopterygi Polypterus senegalus Teleostei Anguilla anguilla Carassius auratus Centrolabrus exoletus Ciliata mustela Ctenolabrus rupestris Cyprinus carpio Danio rerio Gadus morhua Gillichthys mirabilis Labrus berggylta Labrus mixtus Leuciscus idus Myoxocephalus scorpius Oncorhynchus mykiss Perca fluviatilis Platichthys flesus Pleuronectes platessa Psetta maxima Poecilia reticulata Pollachius pollachius Puntius conchonius Raniceps raninus Sarcopterygii Dipnoi Lepidosiren paradoxa Neoceratodus forsteri Protopterus annectens Amphibia Anura Bombina bombina Bufo bufo Bufo calamita Bufo marinus Rana esculenta Rana ridibunda Rana temporaria Xenopus laevis Caudata Ambystoma mexicanum Necturus maculosus Salmandra salamandra Reptilia Alligator mississipiensis Caiman crocodylous sp Crocodylus niloticus Crocodylus porosus Podarcis hispanica Pogona barbatus Varanus gouldi Python molurus Python regius Vipera berus Trachemys scripta elegans

Distribution

Motility

Sto

Sto

Int

nf

+ + + nf nf, nc

nf, nc

nf

nf

nf

nf nf nf

Int no

29

no

29

+ SI (+), R + SI (+), R + SI (+), R +

+ +

nf

nf, nc

nf nf nf nf, nc nf nf − nf

nf nf

nf

nf nf

nf nf

nf

nf nf nf nf nf

+

+ +

+

+

+

nf nf

(nf) nf nf

+

nf

nf nf nf nf

nf nf nf nf nf nf nf

nf

nf

nf nf

nf nf

nf

nf

nf

nf nf nf, nc nf nf nf nf nf nf nf, nc

nf

nf nf nf nf nf nf, nc

+

+

Species References

+

+

29 65 2 2 2 13 15, 22, 44 11, 56 5, 14 37 5 5 5 5, 39, 40, 41, 42 20, 54 5, 28, 30, 31, 36 64 5, 65 5 10 5 3, 5, 21, 23, 24, 29, 38 5 5 65 4, 58 10 5 59 5

26 29 52

9 9 27 45, 46, 47, 51, 55 17 34, 35 9, 50 18, 33 3, 49

+/−

+

25 7 8

no

+ +

93

27, 32 27 53 12 27 27 19 27 27, 32 61 (continued on next page)

Aves Anas platyrhynchos Coturnix coturnix Gallus sp. Parus cristatus

Distribution

Motility

Sto

Int

Sto

nf, nc nf nf

nf, nc nf nf, nc

nf

nf

References

Int

+

48 16 1, 6, 16, 43, 57, 60, 62, 63 27

Sto, stomach; Int, intestine; SI, spiral intestine; R, rectum; nc, nerve cell body; nf, nerve fibre; no, no effect. References: 1. Aisa et al. (1987); 2. Andrews and Young (1988); 3. Beorlegui et al. (1992); 4. Bermúdez et al. (2007); 5. Bjenning and Holmgren (1988); 6. Brodin et al. (1981); 7. Buchan et al. (1980); 8. Buchan et al. (1983); 9. Buchan (1986); 10. Burkhardt-Holm and Holmgren (1989); 11. Burkhardt-Holm and Holmgren (1992); 12. Burrell et al. (1991); 13. Cimini et al. (1985); 14. Domeneghini et al. (2000); 15. El-Salhy (1984a); 16. Fontaine-Perus et al. (1981); 17. Gábriel et al. (1990); 18. Holmberg et al. (2001); 19. Holmberg et al. (2003); 20. Holmberg et al. (2004); 21. Holmgren (1983); 22. Holmgren (1985); 23. Holmgren et al. (1982); 24. Holmgren et al. (1985a); 25. Holmgren et al. (1985b); 26. Holmgren et al. (1994); 27. Holmgren (unpublished); 28. Jensen and Holmgren (1985); 29. Jensen and Holmgren (1991); 30. Jensen et al. (1987); 31. Jensen et al. (1993); 32. Jensen (unpublished); 33. Johansson (2003); 34. Junquera et al. (1986); 35. Junquera et al. (1987); 36. Karila et al. (1998); 37. Kiliaan et al. (1993); 38. Kitazawa (1989); 39. Kitazawa et al. (1988a); 40. Kitazawa et al. (1988b); 41. Kitazawa et al. (1988c); 42 Kitazawa et al. (1990); 43. Komori et al. (1986b); 44. Kågström et al. (1996); 45. Li et al. (1993); 46. Liu et al. (2002); 47. Liu et al. (2005); 48. Lucini et al. (1993); 49. Maake et al. (1999); 50. McKay et al. (1990); 51. Murphy et al. (1993); 52. Nilsson and Holmgren (1992); 53. Olsson and Gibbins (1999); 54. Olsson et al. (2008); 55. Osborne and Campbell (1986); 56. Rajjo et al. (1989a); 57. Rawson et al. (1990); 58. Reinecke et al. (1997); 59. Rombout and Reinecke (1984); 60. Saffrey et al. (1982); 61. Scheuermann et al. (1991); 62. Suzuki et al. (1996); 63. Van Noorden and Patent (1980); 64. von Euler and Östlund (1957).

species, representing many orders and families, pharmacological studies have focussed mainly on Atlantic cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss). Similarly, while the distribution of neurotransmitters has been studied in sturgeons as well as three species of lungfish, virtually nothing is known of the physiology (Tables 2–17).

8.1.1. Gastrointestinal innervation The enteric nervous system of teleost fish contains similar densities of nerve cell bodies as in small mammals. The cells are spread over the myenteric plexus and only rarely make up ganglia that contain more than a few cells. Size and morphology may differ between species (see e.g. Olsson, 2009). In most species examined, there are few if any cell bodies in the submucous plexus. The vagus nerve innervates the oesophagus and stomach (if present), and the proximal part of the intestine. It contains fibres of both cranial (from the brainstem) and spinal origin (Nilsson, 1983, see Nilsson, 2010– this volume). Spinal nerves innervate the intestine as well as the stomach. The extent of sensory fibres running in the autonomic nerve trunks is little investigated in any fish group. A high percentage of the myenteric neurons expresses NOS, like in other vertebrates (Table 5). While pharmacological data suggest acetylcholine to be one of the most important transmitters in the teleost gut as in other vertebrates, there are to date few studies looking at the distribution of a cholinergic innervation. In cod, cholinergic fibres and some nerve cell bodies have been demonstrated (Karila et al., 1998). In contrast, serotonergic nerve fibres and cell bodies are common in many species (Table 7). The abundance is often inversely correlated to the number of serotonergic endocrine cells but may vary even between closely related species. Amongst eel (Anguilla sp.) for example, serotonin is found in enteric neurons and endocrine cells in A. australis while only in endocrine cells in A. anguilla (Anderson and Campbell, 1988; Domeneghini et al., 2000). In carpfish (cyprinids), the distribution seems to be restricted to nerve cells

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(Goodrich et al., 1980; Pan and Fang, 1993; Pederzoli et al., 1996; Olsson et al., 2008). The presence of peptidergic nerve cell bodies also varies between species, but this is most likely, at least in part, a reflection of the methods used for detection, including the affinity of antisera. CGRP-, galanin-, CCK-, neurotensin-, opioid-, tachykinin- and VIP- immunoreactive nerve cell bodies have been detected in one or several species (Tables 9–11, 13–14, 16–17). Generally, nerve fibres innervate the muscle layers, with the circular layer being more densely innervated. Catecholaminergic fibres and cell bodies have been demonstrated in a few species, mainly using fluorescence histochemistry (Table 3). 8.1.2. Effects on gut motility The effects of various neuropeptides and other signalling substances have been rather extensively studied in teleost species (for a comprehensive list of references see Gräns and Olsson, in press). Fewer studies, however, have looked at interactions between different transmitters and their relative importance during different circumstances. Similar to other vertebrates, acetylcholine and tachykinins cause contractions of the gut (Tables 2, 16). The exact response may depend on the experimental set-up and the physiological state of the gut, and may be seen as an increase in contraction amplitude, frequency or basal tone, or a combination of these effects. Serotonin also generally causes contractions (Table 7). Also similar to most other vertebrates, the effects of nitric oxide and VIP/PACAP are often inhibitory (Tables 5, 17). However, although VIP and PACAP share common receptors, the effect of VIP is less pronounced. For example, both mammalian and cod VIP were without effect on Atlantic cod intestine in vitro (Jensen and Holmgren, 1985; Olsson and Holmgren, 2000). In contrast, PACAP strongly reduced the rhythmic contractions. Furthermore, mammalian VIP inhibited cod gastric contractions in vivo (Jensen et al., 1991). In rainbow trout, the effect of VIP on the stomach varied depending on preparation (Holmgren, 1983). A nitrergic inhibitory tone has been shown in Atlantic cod and zebrafish (Karila and Holmgren, 1995; Olsson and Holmgren, 2000; Holmberg et al., 2006), while not in rainbow trout stomach (Olsson et al., 1999). Application of adrenaline/noradrenaline causes contraction of the stomach and relaxation of the intestine in several species including rainbow trout, brown trout (Salmo trutta) and European eel (Table 3). Other species show inhibitory (e.g. angler, Lophius piscatorius) or mixed (Atlantic cod) responses. The inhibitory effect may result from inhibition of acetylcholine release (Kitazawa et al., 1986a). The adrenergic effect is mostly mediated via extrinsic sympathetic nerves. Immunohistochemical as well as pharmacological evidence from cod suggest that cholinergic, excitatory pathways project orally while nitrergic, inhibitory pathways project anally (Karila and Holmgren, 1995; Karila and Holmgren, 1997; Karila et al., 1998). In addition, serotonin and tachykinins are involved in the excitatory pathway. The high degree of colocalisation between NOS and VIP/PACAP (Olsson and Karila, 1995) suggests that the two peptides are also involved in the inhibitory pathways. The exact mechanisms that trigger the ascending and descending pathways are, however, not clear. It has been suggested that serotonergic interneurons may stimulate cholinergic motorneurons (Holmgren et al., 1985a; Jensen and Holmgren, 1985; Jensen et al., 1987; Jensen and Holmgren, 1991) while tachykinins may have both direct (on the muscle) or indirect (via other neurons) effects (Holmgren, 1985; Holmgren et al., 1985a; Andrews and Young, 1988; Kitazawa et al., 1988b; Kitazawa et al., 1988c; Jensen and Holmgren, 1991; Jensen et al., 1993; Jensen, 1997). The interneurons stimulating release of nitric oxide and/or VIP/PACAP may release serotonin and/or acetylcholine (Karila, 1997). Spontaneous contractions in the Atlantic cod gut can be reduced by TTX showing that they are nerve-dependent. Both excitatory and inhibitory tones have been demonstrated, depending on release of

acetylcholine and/or serotonin and nitric oxide, respectively (Jensen and Holmgren, 1985; Karila and Holmgren, 1995; Olsson and Holmgren, 2000). The involvement of nerves has also been demonstrated for propagating contractions, whether initiated by distension of the gut as in brown trout (Salmo trutta) or spontaneously occurring as in non-fed zebrafish (Danio rerio) larvae (Burnstock, 1958; Holmberg et al., 2007). Stimulation of the vagus causes strong contractions of the brown trout stomach, while the anterior splanchnic nerve induces contraction mainly of the intestine (Burnstock, 1958). In European plaice (Pleuronectes platessa), vagally evoked contractions are reduced or abolished by atropine, indicating a dominating role for cholinergic fibres in the vagal extrinsic innervation (Edwards, 1972; Stevenson and Grove, 1977; Nilsson, 1983). Extrinsic reflexes demonstrated in fish are limited. Accommodation can be triggered by distension of the stomach but unlike in mammals, this takes place even if the extrinsic innervation is cut (Grove and Holmgren, 1992a; Grove and Holmgren, 1992b). The intestinal brake, i.e. signals from the proximal intestine that reduce gastric emptying, has also been studied in fish but again, the reflex pathways and exact mechanisms are not very well understood. CCK (most likely released from local endocrine cells) inhibits gastric emptying in rainbow trout (Olsson et al., 1999) and it could be suggested that this effect is at least partly mediated via stimulation of vagal afferent pathways like in mammals. 8.2. Cartilaginous fish 8.2.1. Gastrointestinal innervation Several species of rays and sharks have been investigated. The enteric nervous system is well developed, with a high density of nerve cell bodies (Kirtisinghe, 1940; Nicol, 1952; Olsson and Karila, 1995). The cells are often scattered along thick nerve fibre bundles. The extrinsic innervation includes in most species vagal fibres to the stomach and spinal fibres to the intestine (and part of the stomach) (Nilsson, 2010). In addition, the glossopharyngeal nerve (IX) may innervate the proximal part of the stomach. One of the species investigated in most detail is the spiny dogfish (Squalus acanthias). About two-thirds of the enteric nerve cell bodies contain NOS (Olsson and Karila, 1995). Immunoreactive nerve cell bodies are also found with antisera against bombesin/GRP, CCK, tachykinins and VIP (Tables 8, 11, 16–17). Serotonin and somatostatin have only been demonstrated in nerve fibres as have catecholamines (Table 7, 15). 8.2.2. Effects on gut motility Most studies looking at individual transmitter substances in elasmobranchs have revealed contractile responses. For example, both adrenaline and acetylcholine generally stimulate motility in the stomach and intestine, while adrenaline has an inhibitory effect on the rectum (Tables 2 and 3). The response to 5-HT is mainly excitatory, seen as an increase in contraction amplitude but, at the same time, frequency decreases in several species of rays (Table 7). Tachykinins also stimulate motility in isolated stomach and intestinal preparations while no effect of VIP is seen, except in the rectum where it causes relaxation (Tables 16 and 17). The effect of substance P is most likely direct on the smooth muscle since the response decreases in the presence of the neurotoxin TTX. Dopamine, ATP, bombesin and CCK are mainly excitatory (Tables 3, 6, 8, 11). Few if any studies have looked at enteric intrinsic reflexes, regarding either function or chemical content in the respective nerves. Studies by Campbell (1975) in the seventies showed that stimulation of the vagus in lesser spotted dogfish (Scyliorhinus canicula) inhibited contractile activity in the stomach. This suggested that the excitatory response to acetylcholine is mainly via intrinsic nerves. However, other similar studies did not see an inhibition (see

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95

Table 17 Distribution and effects of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in different vertebrates. Species

Distribution

Motility

VIP Sto Chondrichthyes Elasmobranchii Amblyraja radiata Raja clavata Raja microocellata Raja montagui Scyliorhinus canicula Scyliorhinus stellaris Squalus acanthias Holocephalii Chimaera monstrosa Actinopterygi Polypterus senegalus Chondrostei Lepisosteus platyrhincus Holostei Amia calva Teleostei Anguilla anguilla Carassius auratus Centrolabrus exoletus Ciliata mustela Corydoras aeneus Ctenolabrus rupestris Cyprinus carpio Danio rerio Gadus morhua Gillichthys mirabilis Gyrinocheilus aymonieri Haplochromis spp. Helostoma temminkii Hemigrammus ocellifer Hypophthalmichthus molitrix Labrus berggylta Labrus mixtus Lepomis gibbosus Lepomis macrochirus Leuciscus idus Myoxocephalus scorpius Oncorhynchus mykiss Oreochromis mossambicus Pantodon buchholzi Perca fluviatilis Platichthys flesus Pleuronectes platessa Poecilia reticulata Pollachius pollachius Psetta maxima Puntius conchonius Raniceps raninus Salmo trutta Uranoscopus japonicus Sarcopterygii Dipnoi Lepidosiren paradoxa Neoceratodus forsteri Protopterus annectens Amphibia Anura Acris crepitans Alytes obstericans Atelops oxyrhyncus Bombina bombina Bufo bufo Bufo calamita Bufo marinus Hyla arborea Rana catesbeiana Rana esculenta Rana ridibunda Rana temporaria

PACAP Int

Sto

Int

nf nf

nf, nc nf, nc

References

VIP

PACAP

Sto

Int

no no no

no no no

nf, nc nf, nc nf, nc

Sto

Int

18, 20 5, 70 5 5 21 16, 17, 73, 74 19, 28, 46, 61, 65

R−

nf, nc

77

nf

nf

14

nf, nc

nf, nc

29

nf

nf

64

nf

nf nf, nc nf nf nf nf nf nf nf, nc

8, 18 4, 39 8 8 43 8 8, 40 26, 43, 62 8, 24, 34, 35, 38, 43, 58, 59, 60, 61 76 43 43 43 43 4 8 8 4 64 13, 43 8, 65 6, 8, 23, 27, 30, 58, 60 39 43 8 8 8 13 8 7, 66 1, 67, 68 8, 65 3 49

nf

nf, nc

nf nf nf

nf nf, nc nf, nc nf nf nf nf nf nf nf

nf nf nf nf nf nf nf nf nf nf nf, nf, nf, nf, nf nf nf

nc nc nc nc

nf, nc

nf nf, nc

−/ no

no

nf, nc

nf, nc

+/−

−

nf nf nf nf nf nf nf, nc

nf nf nf nf nf nf nf, nc nf nf, nc nf nf nf

−

−

−

nf nf nf

55 32 55

nf nf nf nf nf nf nf, nc nf nf, nc nf nf nf

10, 12 10 12 10 10 33 45, 53, 60, 63 10 60 10 36, 37 10

nf, nc

nf, nc

nf, nc

nf, nc

(continued on next page)

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Table 17 (continued) Species

Distribution

Motility

VIP

Xenopus laevis Caudata Ambystoma mexicanum Cynops hongkongensis Necturus maculosus Salmandra salamandra Reptilia Alligator mississipiensis Caiman crocodylous sp Crocodylus niloticus Crocodylus porosus Agama sp. Chalcides chalcides Lacerta viridis Pogona barbatus Podarcis hispanica Podarcis siculus Varanus gouldi Zonosaurus madagascariensis Natrix natrix Natrix maura Python molurus Python regius Vipera aspis Vipera berus Thamnophis sirtalis Trachemys scripta elegans Aves Anas platyrhynchos Columba livia Coturnix coturnix Gallus sp. Meleagris Parus cristatus

PACAP

References

VIP

PACAP

Sto

Int

Sto

Int

Sto

Int

Sto

Int

nf, nc

nf, nc

nf, nc

nf, nc

−

no

−

no

nf nf nf nf

nf nf nf nf

nf nf

nf nf nf nf, nc

nf, nc

−

12, 47 12 31 9

−

Oes no nf nf nf nf, nc nf

nf, nc nf nf, nc −

nf, nc nf nf nf nf

nf nf nf nf nf nf − − nf nf, nc nf nf

nf, nc

nf nf, nc

no

no

− nf, nc nf, nc

nf, nc

nf nf nf nf

56, 65

Oes−

11 33 33 57 41 52 65 33 15 42 33 52 48 48 25 60 48 33 42 71 51 50 22, 65 2, 22, 54, 65, 69, 72 75 33

Sto, stomach; Int, intestine; SI, spiral intestine; R, rectum; nc, nerve cell body; nf, nerve fibre; no, no effect. References: 1. Abad et al. (1987); 2. Aisa et al. (1987); 3. Anderson and Campbell (1988); 4. Andreozzi et al. (1997); 5. Andrews and Young (1988); 6. Beorlegui et al. (1992); 7. Bermúdez et al. (2007); 8. Bjenning and Holmgren (1988); 9. Buchan et al. (1980); 10. Buchan et al. (1981); 11. Buchan et al. (1983); 12. Buchan (1986); 13. Burkhardt-Holm and Holmgren (1989); 14. Burkhardt-Holm and Holmgren (1992); 15. Burrell et al. (1991); 16. Cimini et al. (1985); 17. Cimini et al. (1989); 18. Domeneghini et al. (2000); 19. El-Salhy (1984a); 20. Falkmer et al. (1980); 21. Faraldi et al. (1990); 22. Fontaine-Perus et al. (1981); 23. Grove and Holmgren (1992a); 24. Grove and Holmgren (1992b); 25. Holmberg et al. (2003); 26. Holmberg et al. (2004); 27. Holmgren (1983); 28. Holmgren and Nilsson (1983a); 29. Holmgren and Nilsson (1983b); 30. Holmgren et al. (1982); 31. Holmgren et al. (1985b); 32. Holmgren et al. (1994); 33. Holmgren (unpublished); 34. Jensen and Holmgren (1985); 35. Jensen and Holmgren (1991); 36. Junquera et al. (1986); 37. Junquera et al. (1987); 38. Karila and Holmgren (1997); 39. Kiliaan et al. (1993); 40. Kitazawa et al. (1990); 41. Knight and Burnstock (1999); 42. Lamanna et al. (1999b); 43. Langer et al. (1979); 44. Larsson et al. (1979); 45. Li et al. (1993); 46. Lundin et al. (1984); 47. Maake et al. (1999); 48. Masini (1986); 49. Matsuda et al. (2000); 50. Mirabella et al. (2000); 51. Mirabella et al. (2002); 52. Morescalchi et al. (1997); 53. Murphy and Campell (1993); 54. Neya et al. (1990); 55. Nilsson and Holmgren (1992); 56. Olsson (2002); 57. Olsson and Gibbins (1999); 58. Olsson and Holmgren (1994); 59. Olsson and Holmgren (2000); 60. Olsson and Holmgren (unpublished); 61. Olsson and Karila (1995); 62. Olsson et al. (2008); 63. Osborne and Gibbins (1988); 64.Rajjo et al. (1989b); 65. Reinecke et al. (1981); 66. Reinecke et al. (1997); 67. Rombout and Reinecke (1984); 68. Rombout et al. (1986); 69. Saffrey et al. (1982); 70. Sakharov and Salimova (1980); 71. Scheuermann et al. (1991); 72. Suzuki et al. (1996); 73. Tagliafierro et al. (1988); 74. Tagliafierro et al. (1989); 75. Vaillant et al. (1980); 76. Van Noorden and Patent (1980); 77. Yui et al. (1990).

Nilsson, 1983). Electrical stimulation of the splanchnic nerves instead increased the contractile activity in the stomach (Andrews and Young, 1993). Both anterograde and retrograde contractions were observed. 8.3. Cyclostomes Hagfish and lampreys have a simple, tube-like gut, lacking a proper stomach. The enteric nervous system is sparsely investigated in cyclostomes but intrinsic nerve cell bodies and nerve fibres are found throughout the gut (Kirtisinghe, 1940; Baumgarten et al., 1973; Goodrich et al., 1980; Gibbins, 1994). The vagal branches unite before they reach the intestine, and may contain cranial as well as spinal fibres (Nicol, 1952; Burnstock, 1969). In hagfish, few transmitters are found within the gut wall and pharmacological data is scarce. For example, while nitrergic enteric neurons are a common feature of almost any other species investigated, no NADPH-diaphorase reactive nerve cells were found in Atlantic hagfish (Myxine glutinosa) (Olsson and Karila, 1995). So far only serotonin containing enteric neurons have been identified (Goodrich et al., 1980; Nilsson and Holmgren, 1998).The enteric

innervation of lampreys seems more diversified. Bombesin, CGRP and galanin as well as catecholamines and serotonin have been demonstrated in enteric nerve fibres and cell bodies (Tables 3, 6, 7–9). While acetylcholine has a stimulatory effect on gut motility in hagfish, adrenaline gives rise to both contraction and relaxation (Holmgren and Fänge, 1981). Serotonin may cause contraction of the gut in both hagfish and lamprey, although in the former the effect is often weak (if present) (Table 7). There was no effect of substance P on Atlantic hagfish (Jensen and Holmgren, 1991). 9. Comparative aspects and conclusions As is obvious from the above summary, there are many similarities in the autonomic control of gut motility between the major vertebrate groups. As a general trait, the stomach and the proximal part of the intestine are innervated by vagal fibres, while splanchnic nerves innervate the intestine. There are, however, differences in the number and exact location of splanchnic innervation. Overall, very little is known about the exact origin of the extrinsic innervation of different regions of the gut in non-mammalian vertebrates. For example, with a

C. Olsson, S. Holmgren / Autonomic Neuroscience: Basic and Clinical 165 (2011) 80–101

few exceptions, there have been no tracing studies nor have there been many in vivo denervation studies in most species. Regarding the presence of neurotransmitters, most transmitters found in mammals are also found in the other vertebrate groups. The relative abundance and regional distribution may however vary, and these differences may be seen even between closely related species. Teleost fish is by far the best represented non-mammalian group when it comes to number of species investigated. The lack of comprehensive comparable studies from the other groups makes it difficult to draw definitive conclusions on whether to correlate differences to species or higher taxonomic levels. The species and/or class differences vary depending on transmitter. Some, like nitric oxide, show a very homogenous pattern in most species investigated. NOS are found in numerous nerve cell bodies and nerve fibres in the myenteric plexus throughout the gastrointestinal tract of elasmobranchs, teleosts, amphibians, reptiles and bird (Table 5). The only exception is hagfish, where no NOS-positive nerves were detected (Olsson and Karila, 1995). Another substance with marked species as well as class differences is serotonin. As discussed above, serotonergic intrinsic nerves are common in the gut (mainly the intestine) of many teleost species while in others, serotonin is predominantly found in endocrine cells (Anderson and Campbell, 1988). Intrinsic serotonergic nerves are also common in hagfish and lampreys, while rare in investigated elasmobranchs, amphibians, reptiles and birds (Table 7). For most signalling substances, there are only a handful of functional studies in birds, reptiles and amphibians (Tables 2–17). Some transmitters have very clear effects, e.g. nitric oxide inhibits/ relaxes gut smooth muscle in all species investigated (Table 5). Similarly, acetylcholine and tachykinins are excitatory in species representing all groups (Tables 2, 16). There are, however, other substances with less clear-cut effects. Adrenaline generally inhibits gut motility in the teleost intestine (Table 3) while the effect on the stomach varies between species. The effect in elasmobranchs also varies between regions but here interspecies differences are less pronounced. The scattered information from other groups indicates inhibitory actions. All in all, there is no substance where variations in effect can be solely attributed to the vertebrate class. Another other area where knowledge in non-mammalian species is clearly lagging behind is the involvement of autonomic and enteric innervation in the control of different motility patterns. This also includes the type of stimuli that induce autonomic reflexes and how other factors, like food status, temperature (in ectotherms) or season may affect the control systems. References Abad, M.E., Peeze Binkhorst, F.M., Elbal, M.T., Rombout, J.H.W.M., 1987. A comparative immunocytochemical study of the gastro-entero-pancreatic (GEP) endocrine system in a stomachless and a stomach-containing teleost. Gen. Comp. Endocrinol. 66, 123–136. Adamson, S., Campbell, G., 1988. The distribution of 5-hydroxytryptamine in the gastrointestinal tract of reptiles, birds and a prototherian mammal. An immunohistochemical study. Cell Tissue Res. 251, 633–639. Aisa, J., Azanza, M.J., Junquera, C., Peg, M.T., Garin, P., 1987. Intrinsic innervation in birds anterior gut. Front. Horm. Res. 16, 30–42. Aisa, J., Lahoz, M., Serrano, P.J., Junquera, C., Peg, M.T., Vera-Gil, A., 1997. Intrinsic innervation of the chicken lower digestive tract. Neurochem. Res. 22, 1425–1435. Aisa, J., Lahoz, M., Serrano, P.J., Castiella, T., Junquera, C., Azanza, M.J., Vera-Gil, A., 1998. Histochemical, immunohistochemical, and electron microscopy study of the caudal portion of the chicken intestinal nerve of Remak. Neurochem. Res. 23, 845–853. Al-Saffar, A., 1984. Analysis of the control of intestinal motility in fasted rats, with special reference to neurotensin. Scand. J. Gastroenterol. 19, 422–428. Aldman, G., Jönsson, A.C., Jensen, J., Holmgren, S., 1989. Gastrin/CCK-like peptides in the spiny dogfish, Squalus acanthias; concentrations and actions in the gut. Comp. Biochem. Physiol. 92C, 103–109. Anderson, C., 1983. Evidence for 5-HT-containing intrinsic neurons in the teleost intestine. Cell Tissue Res. 230, 377–386. Anderson, C., Campbell, G., 1988. Immunohistochemical study of 5-HT-containing neurons in the teleost intestine: relationship to the presence of enterochromaffin cells. Cell Tissue Res. 254, 553–559.

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Anderson, C., Campbell, G., 1989. Innervation of the gastrointestinal canal of the toad Bufo marinus by neurons containing 5-hydroxytryptamine-like immunoreactivity. Cell Tissue Res. 255, 601–609. Anderson, C.R., 1990. The ultrastructure and distribution of 5-HT-containing neurons in the intestine of a teleost fish, Aldrichetta forsteri. Cell Tissue Res. 259, 379–387. Anderson, G., Noorian, A.R., Taylor, G., Anitha, M., Bernhard, D., Srinivasan, S., Greene, J.G., 2007. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp. Neurol. 207, 4–12. Andreozzi, G., de Girolamo, P., Affatato, C., Antonucci, R., Russo, P., Gargiulo, G., 1997. VIP-like immunoreactivity in the intestinal tract of fish with different feeding habits. Eur. J. Histochem. 41, 57–64. Andrews, P.L., Young, J.Z., 1988. The effect of peptides on the motility of the stomach, intestine and rectum in the skate (Raja). Comp. Biochem. Physiol. 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