Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction

650

Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction Paul LR Andrews* and Gareth J Sanger† Vagal afferents are extensively distributed in the digestive tract from the oesophagus to the colon. They are involved in the reflex control of normal gastrointestinal (GI) tract function (e.g. secretion and motility) as well as reflexes more characteristic of diseases such as functional dyspepsia and gastroesophageal reflux disease (e.g. vomiting, disordered lower esophageal sphincter relaxation and gastric accommodation). They are also implicated in signalling nonpainful sensations (e.g. nausea and early satiety) associated with disease. A variety of receptors has been identified on vagal afferents, which can either enhance (e.g. 5-HT3, CCK1, VR1 and NK1 receptors) or reduce (e.g. ghrelin, leptin, k-opioid and GABAB receptors) activity, offering a range of potential therapeutic targets. Commonly used laboratory species (e.g. rat and mouse) lack an emetic reflex, and the implications of this for models of upper GI disorders have been explored in the light of expanding knowledge of the neuropharmacology of the emetic reflex implicating glutamate, prostanoids, cannabinoids and substance P. Additional pathophysiological roles for vagal afferents (e.g. in thermoregulation, arousal and fatigue) are being investigated, raising the intriguing possibility of the vagus as a target in non-GI disorders. Addresses *Department of Physiology, St George’s Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK; e-mail: [email protected] † Department of Gastrointestinal Research, Neurology and Gastroenterology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Essex, CM19 5AW, UK Current Opinion in Pharmacology 2002, 2:650–656 1471-4892/02/$ — see front matter © 2002 Elsevier Science Ltd. All rights reserved. Abbreviations 5-HT 5-hydroxytryptamine CCK cholecystokinin FD functional dyspepsia GERD gastroesophageal reflux disease GI gastrointestinal IGLE intra ganglionic laminar endings IMA intra muscular arrays NTS nucleus tractus solitarius SP substance P TLESP transient lower esophageal sphincter relaxations TRP transient receptor potential

Introduction Extrinsic afferent neurones are implicated in several major disorders of the gastrointestinal (GI) tract. Attention tends to focus on the splanchnic (‘sympathetic’) and pelvic afferents because of their involvement in pain (see review by Blackshaw and Gebhart, this issue). This review focuses on the relatively neglected area of vagal afferents, suggested to mediate a ‘sixth sense’ [1•] and subtly modulate a

general sense of wellbeing and behaviour. More specifically, the role of the vagus is discussed in terms of the potential application of new molecular targets in the treatment of functional dyspepsia (FD), gastroesophageal reflux disease (GERD) and other disorders, drawing upon some of the teachings provided by past and current research into the mechanisms of emesis.

The vagus as a therapeutic target The name ‘vagus’ (cranial nerve X) derives from the Latin for ‘wanderer’, and is indicative of its extensive distribution. The vagus and its branches innervate the GI tract from the upper oesophageal sphincter to the transverse colon, and supply other thoracic, abdominal and pelvic structures including the heart, thymus, airways and lungs, pancreas, liver, hepatic portal vein, bile ducts, adrenal glands and uterus [2,3,4•]. The vast majority (perhaps 99%) of the vagal axons supplying the abdomen are unmyelinated C-fibres. At the level of the diaphragm, the ratio of afferents to efferents is between 8:1 and 10:1 for most mammalian species studied. Estimates for the number of vagal afferents supplying the abdominal viscera range from 16 000 in the rat to 23 000 in the ferret [5]. Abdominal vagal afferents terminate predominantly in the nucleus tractus solitarius (NTS) of the dorsal brainstem. From here, information is disseminated to autonomic motor nuclei (e.g. the dorsal motor vagal nucleus) and ‘higher’ regions of the brain including the parabrachial nucleus, hypothalamus, amygdala and insular cortex. The extensive distribution of the vagus to the gut provides a key bi-directional link with the brain, which regulates GI behavioural responses (e.g. food intake), pathophysiological sensations (e.g. nausea and early satiety), GI reflexes (e.g. gastric accommodation and vomiting) and basic GI functions (e.g. secretion and motility). Consequently, the vagus, and particularly its afferents, is a rich and relatively unexplored target for the treatment of several ‘functional’ GI diseases [6–8]. In practical terms, vagal afferents are also an attractive target because their peripheral terminals are relatively accessible to orally administered agents that might be restricted to the mucosa (c.f. β-adrenoceptor agonist treatment in asthma). In addition, the neurones terminate in a region of the brain (the dorsal medulla) where the blood-brain barrier is relatively permeable to blood-borne agents. Three basic types of vagal afferent dysfunction are amenable to pharmacological manipulation Sensations arising from the gut

Sensations that are associated with disease and likely to be mediated by abdominal vagal afferent activation include nausea, early satiety, bloating and epigastric discomfort.

Abdominal vagal afferent neurones Andrews and Sanger

Electrical stimulation of abdominal vagal afferents does not induce pain but vagal afferents can modulate nociception. Following chronic damaging challenge to the gut [9], vagal sodium channels show plastic changes; however, the impact (if any) of such chronic changes on the nucleus tractus solitarius and the processing of visceral afferent information has not been investigated. Nevertheless, in spite of these associations, we are relatively ignorant of exactly which sensations are evoked by vagal afferents arising from specific regions of the GI tract. Consequently, there is an urgent need for human studies using techniques such as functional magnetic resonance imaging [10] to identify brain regions involved in processing this type of non-painful sensation. A study in rats using c-fos mRNA to map the brain regions activated by a noxious concentration of acid instilled into the stomach, pre- and post-vagotomy, revealed extensive activation of sub-cortical structures (e.g. regions of the NTS, thalamus, hypothalamus, central amygdala and habenula) but, surprisingly, not the insular cortex [11••], which is the main cortical site of projection of vagal afferent information. Physiologically inappropriate activation of reflexes by abdominal vagal afferents

Several inappropriate reflexes are triggered by abdominal vagal afferents: firstly, retching and vomiting, triggered by stimuli other than food poisoning; secondly, prolonged, exaggerated or frequent TLESRs and exaggerated relaxation of the crural fibres of the diaphragm, both of which can facilitate gastroesophageal reflux and belching; and thirdly, inadequate or exaggerated relaxation of the proximal stomach, leading to disordered emptying and aberrant sensations associated with, for example, early satiety, nausea or discomfort. Each of these aberrant responses could arise from disordered vagal afferent input or central processing (including descending inhibition) of afferent information. Extra-gastrointestinal disorders

Abdominal vagal afferents can modulate febrile or thermoregulatory responses [12•], somatomotor reflexes, exploratory behaviour, arousal, taste perception, release of neurohypophysial hormones (e.g. anti-diuretic hormone) and cardio-respiratory functions [3]. Abdominal and other vagal afferents might also be involved in the genesis of fatigue associated with cancer and its treatment [13•]. Together, these dysfunctions can be associated with conditions such as FD and GERD, as well as those in which nausea, vomiting and/or changes in feeding behaviour are significant issues. More speculative is the possibility of drugs that control aberrant vagal behaviour being of clinical use in GI and non-GI conditions associated with chronic fatigue [13•].

Basic properties of abdominal vagal afferents Information conveyed by GI vagal afferents can be broadly categorised into two types: mechanosensory, which signals stretch and contraction of the smooth muscle; and chemosensory, which monitors the chemical environment of the lumen and is sensitive to brushing of the mucosa [2].

651

Muscle mechanoreceptors

In an extensive review of vagal mechanoreceptors, Phillips and Powley [14••] highlighted morphological studies in which two distinct types of terminal structure were identified: intra ganglionic laminar endings (IGLEs), terminating in close contact with myenteric ganglia; and intra muscular arrays (IMAs) located in the circular and longitudinal muscle, which are in close contact with interstitial cells of Cajal. Quoting ‘form follows function’, they argue for a reassessment of functional studies that have presented a case for a single class of mechanoreceptor (‘in series’ tension receptor), responding to both passive stretch and active contraction of the gut, particularly the stomach. They propose that IGLEs have morphological features consistent with a tension receptor (e.g. Golgi tendon organ) whereas the IMAs have features more consistent with function as a stretch or length receptor (e.g. skeletal muscle spindle).In the mouse and rat, the two types of ending are also differently distributed, with the order of density for IGLEs being corpus > antrum > forestomach, whereas IMAs are found in high densities in the lower oesophageal and pyloric sphincters, with the subsequent order of density being forestomach > corpus > antrum. This regionalisation suggests functional differences and, hence, the need for detailed studies of these endings before the design of therapeutic strategies. Thus, if there are two ‘types’ of mechanoreceptor, they might contribute in different ways to the genesis of non-painful visceral sensations associated with gastric distension, contraction or relaxation. In addition, these endings could be differentially affected by disease. Camilleri [15•] draws attention to the importance of understanding the basic physiology of the receptors for the correct design and interpretation of clinical studies investigating visceral sensitivity in functional bowel disorders. The need for a re-examination of this issue is exemplified by an increasing number of clinical studies in which, differences are emerging in the sensory responses to changes in gastric tone, depending upon whether these changes are brought about by artificial distension, ingested food or duodenal lipid infusion [16•,17,18]. Mucosal receptors

These are vagal afferents present in the oesophagus, stomach, small intestine and colon, with receptive fields in the mucosa [2,4•]. Their precise properties depend upon their location but, in general, they respond to light stroking of the mucosa and to luminally and arterially delivered chemicals. Recently, recordings from rat gastric vagal mucosal afferents provided evidence that a population (17%) of fibres have multiple receptive fields and can be activated from at least two to three sites within the stomach, sometimes in different regions [19]. In addition, subpopulations of the afferents responded to capsaicin (32%) or cholecystokinin (CCK) (8%). The authors proposed that these afferents act as broadly tuned ‘generalist receptors’ integrating information from an entire organ.

Pharmacology of abdominal vagal afferents Abdominal vagal afferents have their cell bodies in the nodose ganglion. Transmitters and receptors synthesized

652

Gastrointestinal

within this ganglion and subsequently transported to the nerve terminals are still being identified. Recent examples include the identification of mRNA for both leptin and the vanilloid receptor VR1 in human nodose ganglion neurones [20••]. The former provides an example of a receptor originally thought to be involved in modulation of satiety through neurones within the hypothalamic nuclei. The presence of leptin within the gut, the discovery of the leptin receptor on the vagus nerve, the modulatory effects of leptin on intestinal vagal mechanoreceptors in the cat and the known involvement of the vagus and other afferent signals in transmitting signals of satiety [20••, 21••,22,23] all suggest a need to evaluate the potential of other satiety-modulating hormones located within the hypothalamus and/or gut on vagal nerve functions. This approach is further supported by the ability of the so-called gastric satiety hormone, ghrelin, to affect both gastric motility and feeding behaviours through a mechanism blocked by vagotomy [24••]. Methods

Characterisation of receptors on peripheral terminals of vagal afferents located in the wall of the gut is technically difficult, because it is potentially confounded by indirect effects of test substances on gut smooth muscle contraction, secretion and blood flow. Some of these difficulties can be overcome by using in vitro preparations of gastrointestinal tissue [25]. As a compromise, vagal receptors have often been studied using in vitro preparations of nodose ganglion and cervical vagal nerve trunks, drawing upon the assumption that the receptors at these locations are functionally coupled to a physiologically appropriate intracellular mechanism. Nemoto et al. [26••] have recently modified the classical grease-gap technique to record from the rat abdominal vagus nerve. This technique has also been used to study the greater splanchnic nerves and the abdominal vagus in the mouse and house musk shrew (M Nemoto and PLR Andrews, unpublished data), drawing upon the same assumption as the cervical vagus recordings, namely that the responses recorded are predominantly from receptors located on the afferents. However, because the afferents outnumber the efferents by ~10:1 in the abdominal vagus, there is a high probability that this is the case. Moreover, because recordings are made closer to the gut, there is a greater likelihood that the receptors studied are those present on the peripheral vagal afferent terminals within the gut, rather than those present on other vagal neurones projecting from the heart, lungs and oesophagus. This preparation could readily be applied to branches of human abdominal vagus (or mesenteric nerves) adherent to the stomach, oesophagus or colon following surgical removal of these organs (e.g. for carcinoma). Stimulation of afferent activity

Single-fibre recording studies continue to identify a diverse range of chemicals to which the vagal afferents respond either with increased discharge or increased sensitivity to another chemical or their natural physical stimulus. These include capsaicin, CCK, 5-hydroxytryptamine

(5-HT), histamine, substance P (SP), ATP, adenosine, platelet-activating-factor, certain prostaglandins, IL-1β and veratrum alkaloids [25,27•,28,29•]. Some jejunal afferents can respond to both histamine and 5-HT [29•]. Leptin [21••] has recently been shown to activate some intestinal vagal mechanoreceptors; this was blocked by a recombinant IL-1β receptor antagonist but enhanced, in some cases, by CCK. The transient receptor potential (TRP) family of ion channels, of which the VR1 receptor is a member [30•], is of particular interest in the gut because neonatal administration of capsaicin leads to destruction of a large percentage of abdominal vagal afferents. Furthermore, acute administration of capsaicin activates approximately 30% of GI vagal afferents, irrespective of afferent modality or location, and induces desensitisation to the natural stimulus of the afferent neurone, irrespective of whether that neurone responded to capsaicin [25]. Thus, modulation of VR1 and related receptors offers an attractive target with the potential for both stimulation and blockade of afferents. A preliminary indication of the potential of this approach comes from a clinical study of FD in which symptom scores were reduced compared with those in a placebo study following 2.5 g/day of red pepper for 5 weeks [31]. The VR1 channel is also heat-sensitive, being activated at > 43°C. Another member of the TRP family, which is responsive to < 26°C and menthol, has recently been identified, and designated CMR1 [32••]. Intriguingly, both cold(10–36°C) and warm- (39–50°C) sensitive vagal afferents were reported in the oesophagus and stomach 20 years ago [33]. In addition, cold- and menthol-sensitive C-fibre afferents have just been detected in the cat urinary bladder [34]. Pharmacology of mucosal afferents

Both endocrine and enterochromaffin cells lining the gut, especially those containing CCK or 5-HT, have long been implicated in mucosal transduction mechanisms, including the activation of vagal afferents and the genesis of visceral sensations. Cholecystokinin

The fatty acid constituents of a meal are important lipids that determine the reflex and sensory responses to the meal. Fatty acids having a carbon-chain length greater than 12 inhibit gastric antral contractions and evoke relaxation of the proximal stomach in humans [35•]. A chain length greater than 12 is also required for the release of CCK, and this effect was exploited to investigate the involvement of CCK in transducing the vagal afferent responses to luminal fatty acids using single-fibre recordings from the rat jejunum [35•]. Both oleic acid (chain length 18) and butyric acid (chain length 4) discharged the afferents but only the response to oleic acid was blocked by the CCK1 receptor antagonist devazepide. It was concluded that the afferent response to oleic acid was mediated by local release of CCK but that butyric acid probably had a direct effect on the afferent terminal. In healthy volunteers, long-chain

Abdominal vagal afferent neurones Andrews and Sanger

triglycerides are generally more potent than medium-chain triglycerides at inducing feelings of fullness, nausea and suppression of hunger, and can enhance sensations evoked by gastric distension [16•]. In view of this, there has been considerable interest in the possible role of CCK in the genesis of heightened gastric mechano-sensitivity reported in a subgroup of patients with FD. 5-Hydroxytryptamine

The vast majority (> 90%) of 5-HT in the body is located in the enterochromaffin cells lining the small intestine. The presence of such a high concentration in the epithelium suggests a defensive role, and locally released 5-HT has been implicated in the pathogenesis of diarrhoea and vomiting through activation of neuronal 5-HT3 receptors. Over the past decade, 5-HT3 receptor antagonists (e.g. granisetron and ondansetron) have been used to treat the acute phase of emesis associated with anti-cancer chemo- and radiotherapy and have also been used in the treatment of post-operative nausea and vomiting [36]. The abdominal vagal afferents are proposed to have a major role in emesis associated with anti-cancer therapies, with 5-HT being released by exocytosis from the enterochromaffin cells to act on 5-HT3 receptors located on vagal afferents terminating in close proximity. The peripheral vagal afferent terminals are considered to be the main site of action for the anti-emetic effect of 5-HT3 receptor antagonists but central sites in the brainstem have also been implicated [36]. Thus, 5-HT3 receptor antagonists provide a clinical example that abdominal vagal afferents are a valid therapeutic target. Vagal afferent recording studies in ferrets and rats provided early evidence for 5-HT3-receptor-mediated activation. Studies such as these have continued because of the finding that 5-HT3 receptor antagonists can reduce the sensation of nausea and gastric perception changes associated with duodenal lipid infusion [17], and can modulate several GI reflexes involving vagal afferent activation (e.g. intestinal inhibition of gastric emptying). An immunohistochemical study [37] has recently described the GI distribution of 5-HT3 receptors in the rat, and has identified a widespread distribution in myenteric and submucosal neurones, interstitial cells of Cajal, some endocrine cells and vagal afferent terminals in the duodenum. In addition to its role in the protective reflexes, studies recording intestinal (duodenum and jejunum) afferent activity have provided evidence that 5-HT acting on 5-HT3 receptors mediates responses to hypertonic luminal stimuli and carbohydrate digestion products [38]. Inhibition of vagal afferent activity

In the abdominal vagus grease-gap preparation (see above), a 5-HT1 receptor agonist (5-CT) induced a small hyperpolarisation (M Nemoto, personal communication). Such effects are difficult to detect using single-fibre recording unless a background of activity is present spontaneously, evoked by distension or mucosal stimulation. Thus, this preparation might provide a simple way of ‘screening’ for receptors activated by locally released

653

chemicals that reduce the probability of the afferent nerve firing. Recent vagal afferent recording studies have identified k-opioid [28], GABAB [39••] or ghrelin [24••] receptor activation capable of reducing vagal afferent activation, although there were differences in the type of afferent affected. Leptin is also capable of inhibiting a population of vagal intestinal mechanoreceptors [21••]. The recognition that peripheral terminals of afferents have receptors that reduce, as well as increase, activation suggests that these nerve terminals should be regarded more as ‘integrators’. Further, the presence of ‘inhibitory’ receptors raises the possibility that there are endogenous agents (e.g. in the mucosa, from mast cells in the muscle or from axon collaterals of afferents) that regulate afferent sensitivity and which, if absent, lead indirectly to afferent sensitisation. Agents with such potential are of particular interest because of the possibility that they could provide an approach to therapy of disorders such as GERD, FD and irritable bowel syndrome, in which visceral afferent hypersensitivity or inappropriate afferent activation is implicated. The potential to develop drugs that inhibit vagal afferent nerve activity can be partly illustrated by the ability of the GABAB receptor agonist baclofen to reduce episodes of post-prandial TLESR (implicated in the pathophysiology of GERD) in animals and healthy human volunteers [39••]. Although in terms of mechanisms, the effect of baclofen is complicated by actions at both peripheral and central vagal nerve terminals, an ‘agonist’ approach to reducing afferent hypersensitivity is attractive because compared with a drug designed to inhibit one particular aspect of hypersensitivity, an agonist approach must have a higher probability of therapeutic success given that it is unlikely that a single sensitising factor is responsible for the genesis of hypersensitivity in a particular tissue. In addition, receptors located on the peripheral terminal that evoke hyperpolarisation are probably the same as inhibitory autoreceptors on the central terminals of the afferents in the NTS and, hence, if the agonist is centrally penetrant, it should enhance the efficacy. Sustaining changes in afferent sensitivity

The focus of many afferent recording studies has been to investigate mechanisms causing acute changes in either discharge or sensitivity. However, sustained changes in sensitivity are probably important in the pathophysiology of chronic disease. In the rat, mild gastritis (> 7 days) induced an increase in sodium currents in gastric thoracic dorsal root ganglion neurones but not nodose ganglion neurones [40••]. However, induction of gastric ulcers produced changes in sodium currents with an increased contribution by the tetrodotoxin-resistant component [41••]. These changes might contribute to long-term changes in afferent excitability and, hence, symptom generation. It would be interesting to know if non-gastric nodose neurones exhibit similar changes when the stomach is inflamed. Further studies of this type will be essential in understanding functional bowel disorders and identifying therapeutic targets.

654

Gastrointestinal

Emesis: a model to understand vagal pathophysiology? Perhaps the most studied aspect of GI vagal nerve pathophysiology is the emetic reflex, with one of the first papers on the topic of vagal afferents as a pharmacological target being published in 1930 [42]. The selective anti-emetic effect of 5-HT3 receptor antagonists provides drugs with considerable clinical efficacy, acting predominantly on abdominal vagal afferents [36]. Consequently, there are several important models developed from this area of research that have more general relevance to the study of other conditions such as GERD or FD, where vagal pathophysiology has been implicated. The continued interest in understanding the role of the vagus in emesis arises from the involvement of this pathway in anti-cancer therapy, food poisoning, post-operative nausea and vomiting, functional bowel disorders and side effects of some drugs. One problem in studying this reflex is that rodents (rat and mouse) and lagomorphs (rabbit) are incapable of vomiting, which is in contrast to the cat, dog, ferret, pig and shrew. It is also unclear whether animals that lack an emetic reflex can belch, a reflex that shares some features with vomiting (e.g. relaxation of the lower esophageal sphincter, induced by activation of gastric vagal afferents). The absence of the emetic reflex in commonly studied laboratory species raises the issue of their suitability for the study of the pathophysiology of the brainstemvagus-stomach axis (see review by Sanger and Hicks, this issue). To study the central neuropharmacology of the emetic reflex and associated upper GI tract motor events, an artificially perfused decerebrate preparation has been developed using Suncus murinus (the house musk shrew), which is an insectivore about the size of a mouse, with a well-characterised emetic reflex [43••]. In this preparation, emetic-like episodes (characterised by a pattern of diaphragm and thoracic activity and longitudinal shortening of the oesophagus) were evoked by abdominal vagal afferent stimulation. This preparation also swallows spontaneously. Therefore, models such as this might provide an alternative to the use of larger species when studying the neurophysiology and pharmacology of emesis and swallowing, as well as the autonomic control of the gut in general. Conditioned food aversion, a surrogate marker of nausea, has recently been demonstrated in S. murinus, further enhancing the use of this species in the study of emetic mechanisms [44]. In addition to the extensively studied role of 5-HT in the emetic reflex, the effects of other neurotransmitters and neuronal sensitisers are becoming increasingly apparent: Glutamate

This excitatory amino acid might be involved in central transmission of vagal afferent signals [45]. The non-NMDA receptor antagonist NBQX, when administered into the fourth ventricle, abolished both fictive-emesis (recordings of the neural correlates of emesis in paralysed decerebrate

animals) and the neuronal activation of the NTS evoked by abdominal vagal afferent stimulation [46]. NBQX also abolished the reflex relaxation of the proximal stomach induced by oesophageal distension; an observation consistent with the earlier finding in the rat that CNQX (another nonNMDA receptor antagonist) reduced the activation of pre-ganglionic vagal afferent fibres induced by oesophageal or gastric distension [47]. Prostanoids

Using intraperitoneal injection of lipopolysaccharides as a surrogate for bacterial infection, Girod et al. [48••] demonstrated that the resultant emesis in the pig could be blocked by bilateral cervical vagotomy but not by the 5-HT3 receptor antagonist granisetron. This observation is of particular interest because it provides an example where, although the vagus is implicated, it appears that vagal 5-HT3 receptors are not involved. In addition, their studies demonstrated that a combination of cyclo-oxygenase inhibitors, meloxicam and indomethacin, could block this response, implicating prostanoids in the mechanism of action. Further studies by this group [49•] indicated a role for prostaglandins in mediating both the acute and delayed emetic response to cisplatin, a cytotoxic drug for which there is clear evidence of vagal involvement. Specific prostaglandins (e.g. PGE2) activate and possibly sensitize mucosal mesenteric afferents [27•], and have been shown in grease-gap recordings to depolarise preparations of cervical [50] and abdominal vagus nerve in the rat (M Nemoto and PLR Andrews, unpublished data). Substance P

Neurokinin receptor (NK1) antagonists that penetrate into the brain and act on receptors for which the preferred ligand is SP have broad spectrum anti-emetic effects against emetic stimuli acting on central (e.g. motion and opioids) and peripheral vagal afferent pathways (e.g. cytotoxic drugs, radiation and gastric irritants). A site of action in the brainstem, probably in the NTS, is proposed to account for these broad spectrum anti-emetic effects. In addition, recordings from abdominal vagal afferents have shown that the NK1 receptor antagonist CP-99,994 and the 5-HT3 receptor antagonist granisetron both reduced the afferent discharge induced by SP [51]. Additionally, the afferent response to 5-HT was reduced by CP-99,994. The authors speculate that because enterochromaffin cells contain both 5-HT and SP, one explanation for these results is that each transmitter can stimulate the release of the other to act on NK1 or 5-HT3 receptors. Cannabinoids

The selective CB1 receptor agonist WIN 55 212-2 reduced the emetic response to morphine and morphine6-glucuronide in the ferret [52,53]. Using immunohistochemistry, CB1 receptors have been detected in the dorsal motor nucleus of the vagus, the medial and subnucleus gelatinosus subnuclei of the NTS and the area postrema.

Abdominal vagal afferent neurones Andrews and Sanger

Afferents. Edited by Ritter S, Ritter RC, Barnes CD. Boca Raton, FL, USA:CRC Press; 1992:279-302.

Conclusions The role of the vagus nerve in emetic mechanisms is well defined and research continues to identify improved ways of controlling this reflex and the associated sensation of nausea, as well as other pathophysiological responses with a proposed vagal involvement such as inappropriate TLESR, early satiety and perhaps fatigue. Two major additional areas of research are beginning to emerge. Firstly, new molecular targets are being identified both in the vagus nerve and its connecting brainstem sensory and motor nuclei. Several of these targets have previously been shown to modulate mechanisms of satiety through actions within brainstem and hypothalamic nuclei. Secondly, the role of the vagus nerve in non-gastrointestinal symptoms and sensations is becoming increasingly recognised, raising the exciting possibility of modulating conditions such as chronic fatigue through mechanisms at least partly dependent on vagal nerve function. Together, these areas of research point to the following outstanding issues and future directions. There is an urgent need to further develop behavioural models of gastro-oesophageal disease so that the mechanisms of, for example, TLESRs and gastric accommodation can be further dissected and related to whole-body behaviours such as those associated with reflux and/or feeding. The role of ‘satiety’ hormones and receptors on gastric pathophysiology needs to be re-examined in the light of recent evidence, which showed that at these hormones also exist within the gut and might directly influence vagal afferent nerve activity. Could this type of evidence lead to a new research direction in the understanding of functional dyspepsia? In the future, the relationship between the vagal-mediated mechanisms and sensations, and the symptoms of upper gut functional bowel disorders will become clearer, perhaps as new medicines are developed and targeted at vagal nerve function. Increased understanding of the influence of the vagus nerve on non-gastrointestinal sensations, such as arousal or fatigue, is likely to have an impact across several different therapeutic areas, including functional bowel disorders.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest •• of outstanding interest 1. Zagon A: Does the vagus nerve mediate the sixth sense? Trends • Neurosci 2001, 24:671-673. Raises some interesting ideas about visceral sensations. 2.

Grundy D, Scratcherd T: Sensory afferents from the gastrointestinal tract. In Handbook of Physiology, Section 6, Vol 1, Part 1. Edited by Wood JD. Bethesda, MD, USA: American Physiological Society; 1989:593-620.

3.

Andrews PLR, Lawes INC: A protective role for vagal afferents: an hypothesis. In Neuroanatomy and Physiology of Abdominal Vagal

655

4. •

Berthoud H-R, Neuhuber WL: Functional and chemical anatomy of the afferent vagal system. Auton Neurosci: Basic and Clinical 2000, 85:1-17. Useful current review of the vagal afferent system. 5.

Andrews PLR: Vagal afferent innervation of the gastrointestinal tract. In Progress in Brain Research, Vol 67. Edited by Cervero F, Morrison JFB. Amsterdam: Elsevier; 1986:65-86.

6.

Drossman DA, Corazziari E, Talley NJ, Grant Thompson W, Whitehead WE: The Functional Gastrointestinal Disorders. Edited by Drossman DA, Corazziari E, Talley NJ, Grant Thompson W, Whitehead WE. McClean, VA, USA: Degnon Associates; 2000.

7.

Thumshirn M: Pathophysiology of functional dyspepsia. Gut 2002, 51(Suppl 1):i63-i66.

8.

Farthing MJG, Ballinger AB: Drug Therapy for Gastrointestinal and Liver Disease. Edited by Farthing MJG, Ballinger AB. London: Martin Dunitz Ltd; 2001.

9.

Gebhart GF, Bielefeldt K, Ozaki N: Gastric hyperalgesia and changes in voltage gated sodium channel function in the rat. Gut 2002, 51(Suppl 1):i15-i18.

10. Aziz Q, Thompson DG, Ng VWK, Hamdy S, Sarkar S, Brammer MJ, Bullmore ET, Hobson A, Tracey I, Gregory L et al.: Cortical processing of human somatic and visceral sensation. J Neurosci 2000, 20:2657-2663. 11. Michl T, Jocic M, Heinemann A, Schuligoi R, Holzer P: Vagal afferent •• signalling of a gastric mucosal acid insult to medullary, pontine, thalamic, hypothalamic and limbic but not cortical nuclei in the rat brain. Pain 2001, 92:19-27. An attempt to map the brain areas that react to a noxious gastric insult. 12. Romanovsky AA: Fever: the role of the vagus nerve. Auton • Neurosci: Basic and Clinical 2000, 85:1-154. Journal supplement reviewing the evidence for the role for the vagus nerve in the genesis of fever and related illness behaviour. 13. Andrews PLR, Morrow GR: Approaches to understanding the • mechanisms involved in fatigue associated with cancer and its treatments: a speculative review. In ESO Scientific Updates, 5, Fatigue and Cancer. Edited by Marty M, Recorelli S. Amsterdam: Elsevier Science BV; 2001:79-93. Potential novel pathophysiological role for the vagus nerve. 14. Phillips RJ, Powley TL: Tension and stretch receptors in •• gastrointestinal smooth muscle: re-evaluating vagal mechanoreceptor electrophysiology. Brain Res Rev 2000, 34:1-26. Timely re-evaluation of vagal mechanoreceptors with potential far-reaching therapeutic consequences. 15. Cammilleri M: Testing the sensitivity hypothesis in practice: tools • and methods, assumptions and pitfalls. Gut 2002, 51(Suppl 1):i34-i40. Useful guide to the methodology used in clinical studies, which suggests mechanisms for preclinical investigation. 16. Fried M, Feinle C: The role of fat and cholecystokinin in functional • dyspepsia. Gut 2002, 51(Suppl1):i54-i57. Useful summary of the links between fat, CCK and the symptoms of dyspepsia. 17.

Tack J, Demedts I, Meulemans A, Schuurkes J, Janssens J: Role of nitric oxide in the gastric accommodation reflex and in meal induced satiety in humans. Gut 2002, 51:219-224.

18. Kuiken SD, Vergeer M, Heisterkamp SH, Tytgat GNJ, Boeckxstaens GEE: Role of nitric oxide in gastric motor and sensory functions in healthy subjects. Gut 2002, 51:212-218. 19. Berthoud H-R, Lynn PA, Blackshaw A: Vagal and spinal mechanosensors in the rat stomach and colon have multiple receptive fields. Am J Physiol 2001, 280:R1371-R1381. 20. Burdyga G, Spiller D, Morris R, Lal S, Thompson DG, Saeed S, •• Dimaline R, Varro A, Dockray GJ: Expression of leptin receptors in rat and human nodose ganglion neurones. Neurosci 2002, 109:339-347. Suggests a new area of research into the mechanisms of action of leptin. 21. Gaige S, Abysique T, Bouvier M: Effects of leptin on cat intestinal •• vagal mechanoreceptors. J Physiol 2002, 543:679-689. Novel insights into multiple effects of leptin on vagal afferents.

656

Gastrointestinal

22. Bray GA: Afferent signals regulating food intake. Proc Nutri Soc 2000, 59:373-384. 23. Furness JB, Koopmans HS, Robbins HL, Clerc N, Tobin JM, Morris MJ: Effects of vagal and splanchnic section on food intake, weight, serum leptin and hypothalamic neuropeptide Y in rat. Auton Neurosci 2001, 92:28-36. 24. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, •• Fujimiya M, Niijima A, Fujino MA, Kasuga M: Ghrelin is an appetitestimulatory signal from stomach with structural resemblance to motilin. Gastroenterol 2001, 120:337-345. Suggests a role for the vagus in mediating the effects of ghrelin on both gastric motility and eating behaviour. 25. Blackshaw LA, Page AJ, Partosoedarso ER: Acute effects of capsaicin on gastrointestinal vagal afferents. Neurosci 2000, 96:407-416. 26. Nemoto M, Endo T, Minami M, Yoshioka M, Ito H, Saito H: 5 •• Hydroxytryptamine (5-HT)–induced depolarisation in isolated abdominal vagus nerves in the rat: involvement of 5-HT3 and 5-HT4 receptors. Res Com Mol Pathol Pharmacol 2001, 109:217-230. New method for investigating abdominal vagal pharmacology in vitro. 27. •

Kirkup AJ, Brunsden AM, Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies I. Receptors on visceral afferents. Am J Physiol 2001, 280:G787-G794. Thorough, insightful review of visceral afferent pharmacology. 28. Ozaki N, Sengupta JN, Gebhart GF: Differential effects of u-, d-, and k-opioid receptor agonists on mechanosensitive gastric vagal afferent fibres in the rat. J Neurophysiol 2000, 83:2209-2216. 29. Kreis ME, Jiang W, Kirkup AJ, Grundy D: Co-sensitivity of vagal • mucosal afferents to histamine ad 5-HT in the rat jejunum. Am J Physiol 2002, 283:G603-G611. Raises the possibility of multiple receptors on single afferents. 30. Gunthorpe MJ, Benham CD, Randall A, Davis JB: The diversity in the • vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 2002, 23:183-191. Useful review of this rapidly developing topic. 31. Bortolotti M, Coccia G, Grossi G, Miglioli M: The treatment of functional dyspepsia with red pepper. Aliment Pharmacol Ther 2002, 16:1075-1082. 32. McKemy DD, Neuhausser WM, Julius D: Identification of a cold •• receptor reveals a general role for TRP channels in thermosensation. Nature 2002, 416:52-58. Characterisation of a ‘cold’- and menthol-sensitive channel. 33. El Ouazzani T, Mei N: Electrophysiologic properties and role of the vagal thermoreceptors of lower esophagus and stomach of the cat. Gastroenterol 1982, 83:995-1001. 34. Jiang CH, Mazieres L, Lindstrom S: Cold- and menthol-sensitive C afferents of cat urinary bladder. J Physiol 2002, 543:211-220. 35. Lal S, Kirkup AJ, Brunsden AM, Thompson DG, Grundy D: Vagal • afferent responses to fatty acids of different chain length in the rat. Am J Physiol 2001, 281:G907-G915. Useful dissection of the ability of fatty acids with different chain lengths to affect vagal nerve function. 36. Sanger GJ, Andrews PLR: Emesis. In Drug Therapy for Gastrointestinal and Liver Disease. Edited by Farthing MJG, Ballinger AB. London: Martin Dunitz Ltd; 2001:45-61. 37.

Glatzle J, Sternini C, Robin C, Zittel TT, Wong H, Reeve JR, Raybold HE: Expression of 5-HT3 receptors in the rat gastrointestinal tract. Gastroenterol 2002, 123:217-226.

38. Zhu JX, Wu XY, Owyang C, Li Y: Intestinal serotonin acts as a paracrine substance to mediate vagal signal transmission evoked by luminal factors in the rat. J Physiol 2001, 530:431-442.

39. Blackshaw LA: Receptors and transmission in the brain-gut axis: •• Potential for novel therapies IV. GABAB receptors in the braingatsroesophageal axis. Am J Physiol 2001, 281:G311-G315. A complicated area, nicely reviewed, dealing with an ‘agonist’ approach to GERD. 40. Bielefeldt K, Ozaki N, Gebhart GF: Mild gastritis alters voltage •• sensitive sodium currents in gastric sensory neurons in rats. Gastroenterol 2002, 122:752-761. Association between inflammation and changes in the dorsal root ganglion but not nodose ganglion sodium channel function. 41. Bielefeldt K, Ozaki N, Gebhart GF: Experimental ulcers alter •• voltage-sensitive sodium currents in rat gastric sensory neurons. Gastroenterol 2002, 122:394-405. Association between gastric pathology and changes in nodose and dorsal root gangion sodium current. 42. Koppanyi T: Studies on the pharmacology of the afferent autonomic nervous system. Arch Int Pharmacodyn Therap 1930, 39:275-284. 43. Smith JE, Paton JFR, Andrews PLR: An arterially perfused •• decerebrate preparation of Suncus murinus (house musk shrew) for the study of emesis and swallowing. Exp Physiol 2002, 87:563-574. New method for the study of emesis and related vagal activity in a small laboratory animal. 44. Smith JE, Friedman MI, Andrews PLR: Conditioned food aversion in Suncus murinus (house musk shrew)-a new model for the study if nausea in a species with an emetic reflex. Physiol Behav 2001, 73:593-598. 45. Hornby PJ: Receptors and transmission in the brain-gut axis: potential for novel therapies II. Excitatory amino acid receptors in the brain gut axis. Am J Physiol 2001, 281:G1055-G1060. 46. Furukawa N, Hatano M, Fukuda H: Glutamatergic vagal afferents may mediate both retching and gastric adaptive relaxation in dogs. Auton Neurosci: Basic and Clinical 2001, 93:21-30. 47.

Partosoedarso ER, Blackshaw LA: Roles of central glutamate, acetylcholine and CGRP recepors in gastrointestinal afferent inputs to vagal preganglionic neurones. Auton Neurosci: Basic and Clinical 2000, 83:37-48.

48. Girod V, Bouvier M, Grelot L: Characterization of •• lipopolysaccharide-induced emesis in conscious piglets: effects of cervical vagotomy, cyclooxygenase inhibitors and a 5-HT3 receptor antagonist. Neuropharmacol 2000, 39:2329-2335. Indicates the existence of a vagal-nerve-mediated mechanism of emesis, insensitive to prevention by 5-HT3 receptor antagonism. 49. Girod V, Dapzol J, Bouvier M, Grelot L: The COX inhibitors • indomethacin and meloxicam exhibit anti-emetic activity against cisplatin-induced emesis in piglets. Neuropharmacol 2002, 42:428-436. Additional evidence for the involvement of prostaglandins in cytotoxicdrug-induced emesis. 50. Smith JAM, Amagasu SM, Eglen RM, Hunter JC, Bley KR: Characterisation of prostanoid receptor-evoked responses in rat sensory neurones. Br J Pharmacol 1998, 124:513-523. 51. Minami M, Endo T, Yokota H, Ogawa T, Nemoto M, Hamaue N, Hirafuji M, Yoshioka M, Nagahisa A, Andrews PLR: Effects of CP-99, 994,a tachykinin receptor antagonist, on abdominal afferent vagal activity in ferrets: evidence for involvement of NK1 and 5-HT3 receptors. Eur J Pharmacol 2001, 428:215-220. 52. Van Sickle MD, Oland LD, Ho W, Hillard CJ, Mackie K, Davison JS, Sharkey KA: Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 2001, 121:767-774. 53. Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, Makriyannis A, Malan TP: The cannabinoid agonist WIN55, 212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology 2001, 94:882-887.