The role of vagal neurocircuits in the regulation of nausea and vomiting

Abstract

Nausea and vomiting are among the most frequently occurring symptoms observed by clinicians. While advances have been made in understanding both the physiological as well as the neurophysiological pathways involved in nausea and vomiting, the final common pathway(s) for emesis have yet to be defined. Regardless of the difficulties in elucidating the precise neurocircuitry involved in nausea and vomiting, it has been accepted for over a century that the locus for these neurocircuits encompasses several structures within the medullary reticular formation of the hindbrain and that the role of vagal neurocircuits in particular are of critical importance. The afferent vagus nerve is responsible for relaying a vast amount of sensory information from thoracic and abdominal organs to the central nervous system. Neurons within the nucleus of the tractus solitarius not only receive these peripheral sensory inputs but have direct or indirect connections with several other hindbrain, midbrain and forebrain structures responsible for the co-ordination of the multiple organ systems. The efferent vagus nerve relays the integrated and co-ordinated output response to several peripheral organs responsible for emesis. The important role of both sensory and motor vagus nerves, and the available nature of peripheral vagal afferent and efferent nerve terminals, provides extensive and readily accessible targets for the development of drugs to combat nausea and vomiting.

1. Introduction

Given the wide range of conditions, diseases and treatments that often result in nausea and vomiting, (medication, infection, toxins, motion sickness, pregnancy, intestinal blockage or slow transit, migraine headaches, hormonal disorders, CNS disorders, kidney failure, radiation therapy, psychiatric disorders, physical or emotional pain, cardiovascular dysfunction, to name a few), it is unsurprising that these are among the most frequently occurring symptoms observed in the clinic. Nausea is often a prodromal symptom of emesis although both nausea and vomiting can occur separately and are considered, at least partially, as separate physiological processes that may engage distinct central nervous system neurocircuitry.

While advances have been made in understanding both the physiological and neurophysiological underpinnings of nausea and vomiting, research has been hampered by lack of suitable animal models that replicate human behavior accurately. Nausea, for example, cannot be studied in non-humans, and surrogate behavioral markers such as excessive salivation, swallowing, conditioned taste aversion and conditioned disgust/gaping have been used to provide some insights into its neural control (Andrews and Horn, 2006; Darmani and Ray, 2009; Parker et al., 2011). Additionally, several commonly used laboratory species (rats, mice, guinea-pigs, rabbits) lack a vomiting reflex requiring investigations into emetic reflexes to either measure alternative outcomes (retching, fictive coughing, conditioned taste aversion and pica, for example), or to study less commonly used laboratory species that have an intact vomiting reflex (cats, dogs, ferrets, shrews); (Andrews and Horn, 2006; Darmani and Ray, 2009; Horn, 2008; Horn et al., 2013). It must be noted, as pointed out in previous review articles (Andrews and Horn, 2006; Horn, 2008) that only a limited number of strains of these laboratory species lacking a vomiting reflex have been tested using a restricted set of stimuli and it is not clear whether all species members lack an emetic reflex.

Regardless of these difficulties in elucidating the precise neurocircuitry involved in nausea and vomiting, it has been accepted for over a century that the locus for these neurocircuits encompasses several structures within the medullary reticular formation of the hindbrain, including the area postrema, nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMV), the reticular formation and the ventrolateral medulla (Andrews and Horn, 2006; Hornby, 2001; Miller and Ruggiero, 1994). Thumas (1891) described a bilateral structure at the caudal tip of the calamus scriptorius as the site of the vomiting center, as described by Hatcher and Weiss (1923), noting that destruction of the ala cinerea (vagal trigone) prevented vomiting (Hatcher and Weiss, 1923). Further studies noted that destruction of the area postrema, but not the vagal trigone itself, eliminated the emetic response to cardiac glycosides and termed this area the “emetic chemoreceptor trigger zone” (Borison and Wang, 1949; Borison and Brizzee, 1951; Wang and Borison, 1950). The final common pathway for emesis has not been defined, however and the existence of a discrete ‘central pattern generator’ for emesis, rather than a series of localized and integrated nuclei, remains controversial (Miller et al., 1994; Miller and Wilson, 1983).

2. Pathophysiology of vomiting

Understanding the pathophysiological features of vomiting provides an important reminder of the multiple organ systems involved, particularly the multiple autonomic reflexes that must be co-ordinated precisely by the “vomiting center” within the hindbrain, including excessive salivation, inhibition of normal gastric motility, retroperistaltic activity in the duodenum and stomach, relaxation of the lower esophageal sphincter, tachycardia, sweating, breath holding and contraction of abdominal and thoracic muscles (see Fig. 1).

Fig. 1. Schematic diagram illustrating vagal neurocircuits involved in nausea and vomiting.

While the exact neural pathways of the central pattern generator responsible for emesis are unknown, the NTS is the recipient of direct or indirect inputs from the abdominal and thoracic vagus, pharyngeal, glossopharyngeal and trigeminal nerves, the spinal tract, the area postrema, the hypothalamus, the cerebellum and vestibular/labyrinthine systems as well as the cerebral cortex and the critical role this nucleus plays in the integration, modulation and regulation of many autonomic reflexes involved in emesis cannot be overstated. Distinct neural outputs from the NTS co-ordinate several of the effector responses of emesis (swallowing, salivation, respiration, cardiovascular, gastrointestinal) in a precisely regulated temporal manner. For simplicity, not all neural pathways and regions are illustrated. AP, area postrema; NTS, nucleus tractus solitarius; Vestibular N., Vestibular Nucleus; Facial N., Facial Nucleus; DMV, dorsal motor nucleus of the vagus; N.Amb., Nucleus ambiguous; VRG, ventral respiratory group; Parabrachial N., Parabrachial nucleus.

3. Role of vagal neurocircuitry in nausea and vomiting

The involvement and importance of vagal neurocircuitry in the generation of nausea and vomiting has been well defined across several species including humans (see reviews by Andrews and Sanger, 2002; Andrews and Horn, 2006; Horn, 2008; Hornby, 2001). The NTS is the recipient of direct neural inputs from the afferent (sensory) vagus as well as direct or indirect inputs from the pharyngeal, glossopharyngeal and trigeminal nerves, the spinal tract, the area postrema, the hypothalamus, the cerebellum and vestibular/labyrinthine systems as well as the cerebral cortex, all of which play important roles in the regulation of medullary reflexes controlling nausea and vomiting, as discussed below (Kalia and Mesulam, 1980a, 1980b; Miller and Ruggiero, 1994; Travagli et al., 2006). Regardless of the means by which it is produced, emesis is accompanied by increased c-fos immunoreactivity in the NTS, suggesting that this region coordinates the emetic response (De Jonghe and Horn, 2009; Ito et al., 2003; Miller and Ruggiero, 1994; Ray et al., 2009; Reynolds et al., 1991). Increased c-fos immunoreactivity was also observed in NTS projection targets which control the motor aspects of vomiting, including the DMV, nucleus ambiguus and phrenic motor nucleus (Ito et al., 2003; Miller and Ruggiero, 1994).

Neurons of the NTS have connections, including reciprocal connections, with several brainstem and higher CNS centers, and the critical role this nucleus plays in the integration, modulation and regulation of many autonomic reflexes involved in nausea and vomiting cannot be overstated. The timing of outputs from the NTS to co-ordinate various output responses of vomiting (swallowing, salivation, respiration, cardiovascular, gastrointestinal etc.) is not random and will be discussed within the context of their inputs and outputs from the NTS.

3.1. Vagal neurocircuits controlling GI functions in nausea and vomiting

Gastrointestinal vagal afferent fibers carry the information about the physiological state of the GI tract to the dorsal vagal complex (DVC; i.e., NTS, DMV, and area postrema) in the caudal brainstem. Vago-vagal reflexes, i.e., reflexes involving vagal sensory as well as vagal motor fibers, are initiated by the activation of low threshold mechano-, osmo- and chemo-receptors in the gut, which convey the information on the movement and composition of nutrients (Blackshaw et al., 2007; Travagli et al., 2006). Gastrointestinal vagal afferent fibers play a critical role in the induction of nausea and the generation of vomiting (Andrews et al., 1990) and the integrity of the abdominal vagus is essential for the generation of emesis. In 1951, for example, Wang and Borison demonstrated that vagotomy prevents the emesis associated with intragastric copper sulfate administration (Wang and Borison, 1951) and electrical stimulation of the abdominal vagus is known to induce an emetic response that includes an increase in blood pressure, licking and retching, increased activity of the abdominal muscles and an increased intragastric pressure (Andrews et al., 1990). Furthermore, in ferrets, stimulation of mucosal chemoreceptors in the stomach or the duodenum results in a long latency but sudden increase in vagal efferent discharge associated with the prodrome of vomiting, suggesting that activation of vagal afferents is involved in the generation of vomiting (Andrews and Wood, 1988).

The cell bodies of vagal afferent fibers are located in the nodose ganglion and transmit afferent signals via glutamatergic synapses to the second-order neurons located in the NTS (Andresen and Yang, 1990; Andresen and Kunze, 1994; Baptista et al., 2005; Smith et al., 1998). The NTS consists of various subnuclei, which are organized in a viscerotopic manner (Altschuler et al., 1989, 1991; Barraco et al., 1992; Travagli et al., 2006). Activation of GI vagal afferents and administration of emetic agents activate neurons in the subnucleus gelatinosus of the NTS, which receives gastric afferent input, the subnucleus centralis, which controls the sensory aspect of swallowing, as well as the medial and ventrolateral NTS, which control cardiovascular and respiratory functions, respectively (Hornby, 2001; Miller and Ruggiero, 1994; Reynolds et al., 1991). Neurons of the NTS involved in GI regulation innervate the adjacent DMV, using predominately glutamate, norepinephrine and especially GABA as neurotransmitters. The DMV contains the preganglionic parasympathetic motoneurons that relay the appropriate integrated neuronal response back to the upper GI tract via the efferent vagus nerve (reviewed: Travagli et al., 2006). Rather than exhibiting a viscerotopic organization, DMV neurons are organized in neuronal “columns” that project to the viscera through each of the five subdiaphragmatic vagal branches (Jarvinen and Powley, 1999; Shapiro and Miselis, 1985; Travagli et al., 2006). DMV neurons within each “column”, however, are not identical but comprise heterogeneous neuronal populations that differ in their neurochemical, morphological and electrophysiological properties (Babic et al., 2011; Browning et al., 1999; Fox and Powley, 1992; Jarvinen and Powley, 1999; Travagli et al., 1991). Regardless of their heterogeneity, as preganglionic parasympathetic neurons, all DMV neurons are a priori cholinergic, and activate nicotinic acetylcholine receptors present on postganglionic neurons within the target organ of interest, in this case the stomach and upper gastrointestinal tract. Postganglionic neurons within the stomach and upper gastrointestinal tract form two distinct pathways; an excitatory cholinergic pathway that induces muscle contraction via activation of muscarinic cholinergic receptors on gastrointestinal smooth muscle, and a non-adrenergic, non-cholinergic inhibitory pathway that induces muscle relaxation via release of nitric oxide and/or vasoactive intestinal polypeptide. The excitatory cholinergic pathway appears to predominate under normal conditions thus gastric relaxation can be produced by either withdrawal/inhibition of the tonically active excitatory cholinergic pathway or activation of the inhibitory non-adrenergic, non-cholinergic pathway (reviewed in Travagli et al., 2006). Under normal conditions, the activity of DMV neurons that innervate the GI tract is controlled by a tonic GABAergic input from the NTS (Sivarao et al., 1998; Travagli et al., 1991, 2006). The activity of synaptic inputs impinging upon DMV neurons, hence the excitability and efferent output of DMV neurons, can be modulated by numerous neurotransmitters and neuromodulators, including those implicated in emetic reflexes such as, for example, opioid peptides (Browning et al., 2004, 2002), serotonin (Browning and Travagli, 1999; Mussa et al., 2008; Travagli and Gillis, 1995), endocannabinoids (Derbenev et al., 2004; Glatzer and Smith, 2005), tachykinins (Ladic and Buchan, 1996; Le et al., 2008; Lewis and Travagli, 2001) and dopamine (Cai et al., 2013; Zheng and Travagli, 2007). Activity within vagal efferent pathways during emetic reflexes results in a large retropulsive wave of intestinal motility accompanied by gastric contraction. Together with temporally co-ordinated relaxation of the antral/pyloric sphincter and the lower esophageal sphincter accompanied by contraction of the abdominal and intercostal muscles, this results in expulsion of gastric contents from the stomach and upper intestine (Lang et al., 1986, 1993; Miller, 1990).

The role of vagal afferent fibers in emesis has been most extensively studied in the context of chemotherapy induced nausea and vomiting (Hesketh, 2004; Andrews and Horn, 2006; Darmani and Ray, 2009). Under normal conditions, ingestion of nutrients, particularly glucose, leads to the release of 5-HT from entero-endocrine cells and subsequent activation of 5-HT₃ receptors on vagal afferents (Raybould, 2001, 2002; Raybould et al., 2003; Zhu et al., 2001). This excitatory signal is then relayed to the NTS (Raybould, 1998, 2001; Savastano et al., 2007; Travagli et al., 2006). It has also been shown that many chemotherapy agents, particularly cisplatin and related drugs, also cause the release of 5-HT from entero-endocrine cells and activate 5-HT₃ receptors on vagal afferents, while vagotomy decreases vomiting induced by cytotoxic drugs (Andrews et al., 1990; Andrews and Horn, 2006; Darmani and Johnson, 2004; Endo et al., 2000, 1990; Hawthorn et al., 1988). Perhaps the most convincing argument supporting the role of 5-HT in the induction of radio- and chemotherapy-induced nausea and vomiting is the efficacy of 5-HT₃ receptor antagonists, particularly in preventing acute-phase chemotherapy induced nausea and vomiting (reviewed in (Andrews and Horn, 2006; Darmani and Ray, 2009). The presumed site of action of these 5-HT₃ receptor antagonists is at peripheral vagal afferent terminals (Endo et al., 2000) although the presence of 5-HT₃ receptors within the brainstem, including area postrema, NTS and DMV and the ability of centrally applied 5-HT₃ receptor antagonists to attenuate chemotherapy induced nausea and vomiting suggests that the actions of 5-HT may not be restricted to peripheral sites (Darmani and Ray, 2009; Leslie et al., 1990; Liu et al., 2003; Reynolds et al., 1989, 1991). It is important to recognize that 5-HT released from enterochromaffin cells may also activate 5-HT receptors present on neurons within the enteric nervous system to modulate gastrointestinal motility (Endo et al., 2000; Glatzle et al., 2002; Tonini, 2005); disruption of normal gastrointestinal motility patterns also contributes to the genesis of nausea and vomiting (see below). A similar mechanism involving the activation of vagal afferents via 5-HT released from enterochromaffin cells has been proposed to be involved in the nausea and vomiting induced by several infectious agents including rotavirus (Hagbom et al., 2011), cholera toxin (Jensen et al., 1997), Salmonella typhimurium (Jensen et al., 1997) and campylobacter (Blakelock and Beasley, 2003). The use of 5-HT₃ receptor antagonists in treated gastroenteritis-related vomiting, particularly in infants and children, still requires evaluation, however (Cheng, 2011; Marchetti et al., 2011).

It is of interest to note, though, that tachykinin NK1 receptor antagonists are also efficacious in the treatment of chemotherapy induced nausea and vomiting suggesting that tachykinins may also be involved in this process (Darmani and Ray, 2009; Hesketh, 2004); tachykinins, including substance P, are also found within intestinal enterochromaffin cells and are released by cytotoxic drugs (Ray et al., 2009; Saito et al., 2003). As with serotonergic receptors, neurokinin receptors are also present within central vagal neurocircuits as well as the enteric nervous system hence tachykinins may modulate nausea and vomiting at multiple sites (Endo et al., 2000; Lewis and Travagli, 2001; Saito et al., 2003; Sanger, 2004).

The efficacy of 5-HT₃ and NK₁ receptor antagonists in the treatment of post-operative nausea, one of the most common post-operative complaints from patients, suggests that 5-HT and/or neurokinins also play a significant role in this form of nausea and vomiting (Diemunsch et al., 2009; Ho and Gan, 2006). Indeed, recent studies have demonstrated that, when administered together, 5-HT₃ and NK1 antagonists have synergistic interactions to counteract emesis (Darmani et al., 2011). While the pathophysiology of postoperative nausea and vomiting is incomplete, and the complexity of its multifactorial origins hampers elucidation/definition, it appears that, in addition to the use of inhalational anesthetics, the inherent physical manipulation, particularly in abdominal or gynecological surgical procedures, may cause the release of humoral substances, including 5-HT and neurokinins, which activates vagal afferent signaling to the brainstem and “vomiting center”. Postoperative nausea and vomiting is also particularly common following head and neck surgery; again physical manipulation of the sensory trigeminal nerve, hence activation of inputs terminating within the NTS, appears to be of importance (Becker, 2010).

Glucocorticoids, such as dexamethasone, are used commonly in combination with 5-HT₃ and NK-1 receptor antagonists in the treatment of both chemotherapy-induced and postoperative nausea and vomiting (Kris et al., 2011). The antiemetic mechanism of action of dexamethasone is still largely unknown described earlier, some of these effects may involve actions at glucocorticoid receptors within the DVC including the area postrema and NTS (Fukunaka et al., 1998; Ho et al., 2004; Morimoto et al., 1996) although it is important to note that dexamethasone has also been shown to modulate the actions of 5-HT receptors on vagal afferent nerves (Woods and Andrews, 1995).

Disruption of normal gastric motility patterns has also been correlated closely with the development of nausea, most likely via the abnormal activation of mechanosensitive gastrointestinal vagal afferents. The alterations in gastrointestinal motor activity observed during vomiting are regulated by the vagus nerve, since vagotomy and vagal block by anesthetics prevent this activity (Lang et al., 1986, 1993). Information regarding gastrointestinal motility/contractile activity is relayed via the afferent vagus nerve into the brainstem and thence to the paraventricular and supraoptic nuclei of the hypothalamus, the parabrachial nucleus and the limbic and cortical areas (Balaban and Porter, 1998; Karimnamazi et al., 2002; Suzuki et al., 2012; Yuan and Barber, 1991) where it is perceived as either normal or abnormal. Studies into pathophysiology of motion sickness have provided the majority of information regarding the interplay between gastric dysrhythmias and nausea & vomiting in humans. The shift from the normal 3 contractions per minute gastric slow wave rhythm to a faster 4–9 contractions per minute rhythm precedes the development of nausea and the intensity of the tachygastric response/motility pattern appears correlated with the severity of nausea (Xu et al., 1993). In addition to the well-described gastric dysrhythmia associated with motion sickness, gastric dysmotility has also been associated with nausea in patients with diabetic or idiopathic gastroparesis, functional dyspepsia, peptic ulcer disease and pregnancy, for example (Owyang and Hasler, 2002).

Nausea and vomiting are commonly experienced during pregnancy, affecting up to 80% of all pregnant women (review: Lee and Saha, 2011). While the precise etiology of nausea and vomiting during pregnancy is unknown, various metabolic and hormonal factors have been implicated. In particular, the ovarian hormones estrogen and progesterone, are known to alter esophageal, gastric and intestinal motility patterns, resulting in decreased smooth muscle contraction, decreased gastrointestinal motility and decreased gastric emptying (Depue et al., 1987; Koch et al., 1990; Walsh et al., 1996).

Increased activation of mechanosensitive vagal afferents following either gastrointestinal dysrhythmia or dysmotility or following abnormal distention of the stomach, intestine or biliary tract also evokes nausea. While nociception is normally associated with the activation of spinal afferent pathways, some distention-evoked vagal afferents have been shown to encode information into a noxious range (Grundy, 2002; Randich and Gebhart, 1992; Renehan et al., 1995; Traub et al., 1996) hence may also be involved in the transmission of painful stimuli.

3.2. Vagal neurocircuits regulating cardiorespiratory functions in nausea and vomiting

Baro- and chemoreceptor reflexes are critical for blood pressure stabilization and regulation of tissue perfusion. At rest, in most species, there is a tonic level of cardiovascular-related parasympathetic nerve activity (Dergacheva et al., 2010). Activation of baroreceptor afferents by an increase in arterial pressure activates neurons in the NTS, primarily in the medial, commissural and ventral subnuclei. These NTS neurons send excitatory projections to cardiac vagal motoneurons in the nucleus ambiguus (Neff et al., 1998) as well as motoneurons innervating the airways (McAllen and Spyer, 1978). In addition, baroreceptor-responsive NTS neurons also affect sympathetic outflow to the vasculature via projections to the caudal ventrolateral medulla, which, in turn, sends inhibitory projections to the vasomotor center in the rostral ventrolateral medulla (reviewed in Guyenet, 2006; McAllen and Spyer, 1978). Baroreceptor activation, therefore, simultaneously activates the vagal outflow to the heart and inhibits sympathetic activity to the vasculature.

NTS neurons also receive afferent inputs from peripheral chemoreceptors. Although terminal fields of chemoreceptors display a certain degree of overlap with those of baroreceptors, their primary termination sites are in the commissural and medial subnuclei of the NTS. Stimulation of the carotid body chemoreceptors results in a reflex increase in the respiratory rate and volume, glandular secretions and vasoconstriction. These functions are mediated by the projections of NTS neurons to regions that regulate the autonomic functions of the airways as well as motor output to respiratory muscles. NTS neurons send direct projections to the vagal preganglionic neurons in the rostral nucleus ambiguus. These neurons, in turn, project to the intrinsic tracheobronchial ganglia, which provide the innervation to airway smooth muscle, submucosal glands and the vasculature (reviewed in Kc and Martin, 2010). Several tract tracing studies have demonstrated that NTS neurons also send monosynaptic projections to the ventral respiratory group (Alheid et al., 2011; Ellenberger and Feldman, 1990; Rosin et al., 2006). The ventral respiratory group includes several rostrocaudally arranged regions, namely the Bötzinger complex, the pre-Bötzinger complex, the rostral and the caudal VRG. Respiratory neurons in these regions display phases of activity relative to the breathing cycle (reviewed in Smith et al., 2009). A recent study has demonstrated that NTS subnuclei show a dichotomy in their projections to the ventral respiratory group. Specifically, medial and commissural subnuclei of the NTS project predominantly to the retrotrapezoid nucleus, rostral ventrolateral medulla and rostral portions of the ventral respiratory group, with only a small number of neurons projecting to the Bötzinger and pre-Bötzinger complex. In contrast, gelatinosus, dorsolateral and ventrolateral subnuclei were shown to have broader projection targets throughout the ventral respiratory group (Alheid et al., 2011).

Regulation of tissue perfusion is accomplished by adjustments of blood pressure, heart rate and respiration and requires integration of cardiovascular and respiratory functions. Both baro- and chemoreceptors are inhibited during inspiration and facilitated during post-inspiration and expiration. These effects persist following pulmonary denervation, suggesting that the integration of cardiovascular and respiratory functions occurs in the brainstem (Dergacheva et al., 2010). The interaction between these two systems can also be observed in respiratory sinus arrhythmia, a variation in heart rate observed during a respiratory cycle. Heart rate increases during inspiration and decreases during post-inspiration and expiration. Integration of cardiovascular and respiratory inputs has been shown to occur both at the level of the NTS as well as cardiac vagal preganglionic neurons in the nucleus ambiguus.

Changes in cardiovascular and respiratory functions are essential for the generation of vomiting. Vomiting is associated with an increase in blood pressure and a coordinated contraction of respiratory muscles. The co-ordinated activity of respiratory muscles (diaphragm, abdominal, intercostal) is essential to the production of increased thoracic and abdominal pressures required for vomiting. Unlike normal respiration, during emetic-like behavior the diaphragm and abdominal muscles co-contract accompanied by contraction of the external (inspiratory) intercostal muscles and relaxation of the internal (expiratory) intercostal muscles (Miller et al., 1987; Miller and Nonaka, 1990; Miller, 1990). Additionally, the area of the diaphragm surrounding the esophagus relaxes to assist in expulsion of gastric contents. The muscles of the upper airway undergo a temporally connected series of protective movements including raising the soft palate and closure of the glottis (Lang et al., 1993, 2002).

Blocking either baro-or chemo-receptors by internal carotid artery ligation, or carotid body denervation, respectively, suppressed the emetic response (Uchino et al., 2006). In addition, during emesis, there is an activation of both baro- and chemo-receptors and the sensitivity of these reflexes is increased during retching and vomiting. It has been suggested that the predominance of the parasympathetic nervous system activity augments the emetic response, whereas predominance of sympathetic nervous system activity suppresses it. Studies in shrews and ferrets have demonstrated that arterial pressure increases during prodromal phase of retching, whereas heart rate decreases prior to retching, followed by a gradual increase (Andrews et al., 1990; Uchino et al., 2006). Interestingly, studies in mice, a species that does not vomit, have demonstrated that emesis was accompanied by tachycardia in contrast to bradycardia observed in shrews. However, the bradycardia observed in shrews was blocked by vagotomy, suggesting that it was due to baroreceptor activation. In contrast to the shrew, the baroreflex in mice and rats during emesis does not appear to be as sensitive (Uchino et al., 2006). These observations are consistent with findings on human subjects, which have demonstrated that during parabolic flight, subjects that vomited had an increased baroreflex responsiveness, whereas those that did not vomit displayed no changes (Schlegel et al., 2001). Moreover, recruitment of respiratory muscles during retching and vomiting elicit a change in the respiratory pattern (Cohen et al., 1992; Miller, 1990). Retching and vomiting are accompanied by a decrease in arterial oxygen tension and oxygen concentration in the trachea, conditions suggestive of chemoreceptor activation (Fukuda and Koga, 1993; Fukuda and Koga, 1995). The increased sensitivity of baro- and chemo-receptor afferents during emesis, as well as increased c-fos expression, as a marker of neuronal activation, suggest that NTS and area postrema coordinate the cardiovascular and respiratory components of the emetic response (Miller and Ruggiero, 1994; Reynolds et al., 1991).

3.3. Vagal neurocircuits regulating esophageal functions in nausea and vomiting

Neuronal tracing techniques (Broussard and Altschuler, 2000) have demonstrated that vagal motoneurons projecting to the pharynx and larynx are located within the compact as well as the external formation of the nucleus ambiguus. The location of esophageal motoneurons is dependent upon whether the esophagus is composed of smooth or striated muscle which appears to be species dependent (Broussard et al., 1998; Collman et al., 1992; Jean, 2001; Lawn, 1966). Thus, esophageal motoneurons are located within either the nucleus ambiguus (striated muscle; rat) or the dorsal motor nucleus of the vagus (smooth muscle; cat, rabbit, humans).

Regardless of their central location, however, esophageal moto-neurons receive inputs from NTS involved in the central integration of esophageal peristalsis and in the co-ordination of swallowing and airway-protective reflexes. During an emetic reflex, the lower esophageal sphincter relaxes in co-ordination with closure of the epiglottis and closure of the pharynx/larynx to protect the airways (Lang et al., 1993, 2002).

3.4. Area postrema inputs to vagal neurocircuits involved in nausea and vomiting

The area postrema is a chemosensitive organ adjacent to the NTS that was first identified as the emetic chemoreceptor trigger zone in the 1940s and 50s (Borison and Wang, 1949; Borison and Brizzee, 1951; Wang and Borison, 1950). As with other circumventricular organs, the area postrema is extensively vascularized with highly fenestrated capillaries and, by consequence, is not isolated from peripheral circulation by the blood brain barrier (Borison, 1989; Cottrell and Ferguson, 2004; Fry and Ferguson, 2007). The rodent area postrema is composed of three distinct regions, delineated on the basis of the neuronal locations and projections. The mantle zone comprises the dorsal aspect of the area postrema and, similarly to the central zone, is rich in neuronal cell bodies. The ventral zone contains primarily glial cells as well as a monolayer of tanycytes, joined together by tight junctions, which define the boundary with the adjacent NTS (Price et al., 2008). Apical dendrites of area postrema neurons extend toward the basal lamina side of endothelial cells, which allows these dendrites to receive blood-borne information from the vasculature (Price et al., 2008). The area postrema sends dense, excitatory (glutamatergic) projections to the NTS as well as less prominent projections to the nucleus ambiguus, dorsal motor nucleus of the vagus, parabrachial nucleus and the tegmental nuclei (Fry and Ferguson, 2007; Price et al., 2008). Approximately 60% of area postrema neurons exhibit pacemaking activity due to expression of a hyperpolarization-activated cation current (Shinpo et al., 2012); blockade of these channels has been demonstrated to suppress some forms of conditioned taste aversion, most likely by suppressing the area postrema neuronal excitability (Shinpo et al., 2012). The unique positioning of area postrema neurons allows them to receive both neural and humoral signals related to emesis and relay this information to the adjacent NTS, which, in turn, integrates these synaptic inputs and transmits them to motor centers associated with emesis. Area postrema neurons contain receptors for numerous neurotransmitters (dopamine, neurokinins, serotonin) as well as, neuropeptides and hormones involved in the regulation of gastrointestinal (cholecystokinin, glucagon-like peptide-1, ghrelin, peptide YY, amylin, adiponectin, oxynto-modulin), cardiovascular (angiotensin, vasopressin, endothelin, adrenomedullin) and immune (interleukin-1β interleukin-10; tumor necrosis factor-α prostaglandin) functions (review: Darmani and Ray, 2009; Price et al., 2008). Destruction of the area postrema either eliminates or delays the vomiting caused by systemic administration of several substances, including apomorphine, angiotensin II, cisplatin, interleukin-2, copper sulfate, nicotine and epinephrine (Borison, 1989).

From a clinical perspective, it is also important to recognize that the activity of neurons within several nuclei, including the area postrema, hence the ability of their synaptic outputs to influence vagal neurocircuits involved in the regulation of nausea and vomiting, may also be modulated by non-chemosensitive means. Compression of area postrema neurons following disruption of the brainstem blood supply as observed following a subarachnoid hemorrhage (Akpinar et al., 2005; Nozaki et al., 1992), for example, induces nausea and vomiting, as does cerebral artery dysregulation during migraine (Edvinsson and Uddman, 2005). Similarly, an increase in intracranial pressure from trauma, brain tumors or infections of the meninges (bacterial, fungal or viral) also may induce nausea and vomiting via alteration in the activity of area postrema neurons (Goehler et al., 2006; Wuchert et al., 2009). Conversely, modulating the activity of these neurons may present important, and readily available, therapeutic targets to disrupt chemoreceptor-mediated nausea and vomiting. Corti-costeroids such as dexamethasone and methylprednisolone, for example, may exert their anti-emetic effects via actions, at least in part, on glucocorticoid receptors within the dorsal vagal complex, including the area postrema (Morimoto et al., 1996; Sanger, 2004).

3.5. Vagal neurocircuits regulating nociception in nausea and vomiting

NTS neurons have dense reciprocal innervation with the trigeminal complex and facial motor nucleus (Zerari-Mailly et al., 2005); activation of trigeminal and facial nerves during intense headaches/migraine/dental pain activates parasympathetic reflexes that regulate cardiovascular, GI and respiratory functions, including emesis (Caous et al., 2001). As described earlier, NTS neurons can be activated following noxious stimulation of gastrointestinal vagal afferents (Randich and Gebhart, 1992; Renehan et al., 1995; Traub et al., 1996) although nociceptive inputs more often activate NTS neurons via spinal pathways (Boscan et al., 2002; Pickering et al., 2003a, 2003b).

3.6. Cerebellar and labyrinthine inputs to vagal neurocircuits involved in nausea and vomiting

The cerebellum does not appear to be essential for vomiting induced either by electrical stimulation of the vagus nerve or administration of emetic drugs, and while it certainly contributes to vestibular nucleus-induced vomiting associated with motion sickness, it appears to exert a modulatory, rather than principle, influence (Miller et al., 1994). Cerebellar neurons do send projections to the hindbrain vagal neurocircuits responsible for the coordination of emetic reflexes, however, via the vestibular nucleus (cerebellovestibular fibers) as well as via the hypothalamus (cerebellohypothalamic fibers) by way of the parabrachial and Kölliker-Fuse nucleus (see Section 4.7, (Balaban, 2004; Suzuki et al., 2012), hence the cerebellum is able to exert some influence over visceral functions such as nausea and vomiting. Electrical stimulation of the cerebellum can influence gastric and duodenal motility in both a vagally-dependent and vagally–independent manner (Lisander and Martner, 1975; Manchanda et al., 1972).

Activation of neurons within the vestibular system is critically important to the generation of nausea and vomiting associated with motion sickness. Similarly, nausea and vomiting are commonly associated with vestibular system diseases including vertigo, vestibular neuritis, labyrinthitis and benign paroxysmal positional vertigo (Cuomo-Granston and Drummond, 2010). Motion sickness induced by visual sensory inputs, however, does not appear to involve direct stimulation of the vestibular system but instead results from the mis-match of converging information from several sensory systems (vestibular, visual, visceral). Neuronal tracing studies have demonstrated that in species such as the rabbit, rat and cat, neurons of the medial and inferior vestibular system innervate vagal neurocircuits, including neurons within the NTS and reticular formation (Balaban and Beryozkin, 1994; Balaban, 1999; Ruggiero et al., 1996; Takeda et al., 2001) and neurophysiological experiments have demonstrated that some NTS neurons receive convergent inputs from the vestibular nuclei and the gastrointestinal tract (Suzuki et al., 2012). Such vestibulosolitarius and vestibuloreticular inputs may provide the anatomical basis for the integration of abnormal or mis-matched spatial and motion sensory inputs that result in emesis (Balaban and Porter, 1998; Balaban, 1999).

Vestibular neurons have been shown to display functional receptors for several excitatory neurotransmitters, including acet-ylcholine muscarinic receptors, dopamine D2 receptors, serotonin 5-HT₂ receptors and histamine H1, and H2 receptors. Theoretically, antagonists of these receptors would decrease the activity of vestibular neurons, hence reduce the activity of their synaptic inputs into the dorsal vagal complex, and potentially be useful in the treatment of motion sickness. In practice, only antagonists of muscarinic cholinergic receptors and antihistamines have proved useful clinically (Horn et al., 2013; Yates et al., 1998).

3.7. Role of other central nervous system inputs to vagal neurocircuits involved in nausea and vomiting

Neurons within central vagal neurocircuits, particularly NTS neurons, have dense reciprocal connections with the hypothalamus which are critically important in the integration and regulation of several autonomic reflexes (Rinaman, 2007; Rinaman, 2010; Spyer et al., 1997; van der Kooy et al., 1984). The hypothalamus itself, however, does not appear to be essential to the genesis of nausea and vomiting (Miller et al., 1994). Hypothalamic subnuclei, particularly those adjacent to the third ventricle, may be activated by circulating neurohormones/neuropeptides resulting in the generation of emetic reflexes (Cottrell and Ferguson, 2004; Rodriguez et al., 2010). Actions of glucagon-like peptide-1, for example, to induce nausea and vomiting may be due, at least in part, to actions within the hypothalamus (Chan et al., 2013).

As described in Section 4.6, the parabrachial and associated Kölliker-Fuse nuclei relay inputs from vestibular nuclei to higher centers within the central nervous system including the hypothalamus, limbic system and forebrain, and are involved in the generation of nausea and vomiting induced by motion sickness. Studies have also demonstrated that parabrachial/Kölliker-Fuse neurons also receive reciprocal inputs from several of these ascending structures, including the cortex, basal forebrain and hypothalamus (Moga et al., 1990) as well as receiving inputs from vagal neurocircuits, particular neurons within the area postrema and NTS (Herbert et al., 1990). Parabrachial/Kölliker-Fuse neurons are activated by a variety of visceral sensations including baroreceptor (Jhamandas et al., 1991; Jhamandas and Harris, 1992), chemoreceptor (Hayward and Felder, 1995; Song et al., 2011), respiratory (Ezure, 2004; Kubin et al., 2006), gastrointestinal (Suzuki et al., 2012) and gustatory/taste (Karimnamazi et al., 2002; Rosen et al., 2011) inputs. Recent studies have also shown that parabrachial/Kölliker-Fuse neurons receive converging inputs from vestibular and visceral vagal afferents (Suzuki et al., 2012), and from orosensory and visceral vagal afferents (Karimnamazi et al., 2002) suggesting that GI irritation may amplify or reduce the sensitivity of parabrachial/Kölliker-Fuse neurons to body motion or taste. While the sensation of nausea is assumed to involve the cerebral cortex, the emetic reflex can be elicited in decerebrate animals demonstrating it can occur independently of forebrain involvement (Miller et al., 1994). Nevertheless, the dorsal vagal complex, particularly the NTS, has reciprocal direct or indirect projections to several higher CNS centers, including the parabrachial nucleus, hypothalamus, limbic system and forebrain (Moga et al., 1990; Terreberry and Neafsey,1987, 1983; van der Kooy et al., 1984) providing a neuroanatomical substrate for the involvement and integration of various sensory, affective and emotional responses to nausea and vomiting.

4. Conclusions

Nausea and vomiting are among the most common symptoms observed in the clinic and can result for a wide variety of conditions (medication, infection, toxins, motion sickness, pregnancy, gastrointestinal motility disorders, migraine headaches, hormonal disorders, CNS disorders, kidney failure, radiation therapy, psychiatric disorders, physical or emotional pain, cardiovascular dysfunction, to name a few). The emetic reflex is arguably the most complicated autonomic reflex involving the precise temporal co-ordination of multiple physiological systems including gastrointestinal, cardiovascular and respiratory. While a final common pathway for emesis has not been defined, and there is clearly much work still to be to describe the “central pattern generator” involved in emesis, the involvement and critical importance of vagal neurocircuitry in the generation of nausea and vomiting has been well defined across several species including humans.

The afferent vagus nerve is responsible for relaying a vast volume of sensory information from the thorax and abdominal viscera to the central nervous system. Neurons within the NTS not only receive these peripheral sensory inputs, but also have direct or indirect inputs with several other hindbrain, midbrain and forebrain nuclei responsible for co-ordinating and regulating the medullary reflexes controlling emesis but also the emotional and affective responses to nausea and vomiting. The efferent vagus nerve is responsible for relaying the integrated and co-ordinated output response to several peripheral organs (including the pharynx, larynx, esophagus, stomach and upper intestine) which results, ultimately, in the expulsion of gastric contents. The important role of both sensory and motor vagus nerves, and the available nature of peripheral vagal afferent and efferent nerve terminals, provides extensive and readily accessible targets for the development of drugs to combat nausea and vomiting.