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.

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 Sanger, 2002, 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 Sanger, 2002, Darmani and Ray, 2009, Horn, 2008, Horn et al., 2013). It must be noted, as pointed out in previous review articles (Andrews and Sanger, 2002, 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 Sanger, 2002, 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).