Measuring the nausea-to-emesis continuum in non-human animals: refocusing on gastrointestinal vagal signaling

Abstract

Nausea and vomiting are ubiquitous as drug side effects and symptoms of disease; however, the systems that determine these responses are arguably designed for protection against food poisoning occurring at the level of the gastrointestinal (GI) tract. This basic biological pathway using GI vagal afferent communication to the brain is not well understood. Part of this lack of insight appears to be related to current experimental approaches, such as the use of experimental drugs, including systemic chemotherapy and brain penetrant agents, which activate parts of the nausea and vomiting system in potentially unnatural ways. Directly related to this issue is our ability to understand the link between nausea and vomiting, which are sometimes argued to be completely separate processes, with nausea as an unmeasurable response in animal models. An argument is made that nausea and emesis are the efferent limbs of a unified sensory input from the GI tract that is likely to be impossible to understand without more specific animal electrophysiological experimentation of vagal afferent signaling. The current paper provides a review on the use of animal models and approaches to defining the biological systems for nausea and emesis and presents a potentially testable theory on how these systems work in combination.

Fig. 1

Analysis of latency to the first emetic response. This data set is derived from a prior published report showing the effects of intragastric administration of 120 mg/kg CuSO₄, n = 8 sham-operated and n = 8 abdominal vagotomized animals (Horn et al. 2014). A) The mean and standard deviation of emesis latency for each group. Normality tests indicate that both distributions are non-normal (Shapiro-Wilk test, p < 0.05). B) Box and whisker plots of the same data showing the median, 1^st and 3^rd quartiles, and whiskers representing 1.5 times the inter-quartile range. A scatterplot of all latency values is overlayed. A Mann-Whitney U test between groups is statistically significant, * p = 0.003. C) Cumulative incidence plots of the same data. Cox regression indicates statistical significance, p = 0.003. D) Number of emetic episodes from these two groups plotted as mean ± standard error of the mean. A two-sample t-test or Mann-Whitney U test was not statistically significant (p > 0.05).

Fig. 2

Vagal afferent pathway for nausea and emesis. NTS = nucleus of the solitary tract. Brain areas potentially involved in nausea are included, such as the insular cortex and amygdala, but other regions potentially play role (Vandenberghe et al. 2007; Catenoix et al. 2008; Mulak et al. 2008; Wang et al. 2008; Napadow et al. 2012).

Fig. 3

Gastrointestinal (GI) vagal afferent projections to the hindbrain and the divergence of the pathways for nausea and vomiting. Neurotransmitters that play a role in signaling from vagal afferents to hindbrain sites are indicated; and, presynaptic 5-HT₃ receptors, located on vagal afferents potentially modulate these GI inputs.

Fig. 4

Proposed mechanism for CuSO₄-induced nausea and emesis signaling in gastrointestinal (GI) vagal afferent fibers. EC = enteroendocrine cells in the mucosal layer of the GI tract.

Fig. 5

In vivo electrophysiology of single afferent fibers in the musk shrews. A) An in vivo anesthetized preparation. B) Mechanical stimulation of the gastric antrum triggers two emetic episodes (esophageal shortening and closely spaced intratracheal pressure changes; retches). C) Activation of GI vagal afferents by gastric distension (1ml balloon). Signal-to-noise ratio of spikes; red marks show the single-unit with the red waveform from section B. D) Simultaneous recording of two (of 6) vagal fibers from one shrew that were sensitive to gastric distension. Unit waveforms are shown on the right.

Fig. 6

In vitro electrophysiology of single afferent fibers in the musk shrew. Mechosensitive vagal afferent activity from the musk shrew stomach. A) Recording chamber. B) Representive recording showing the signal-to-noise ratio. (C) Vagal afferent activity after gentle touch is applied to gastric antrum (spikes/10 ms).

Fig. 7

Proposed model of emetic stimulation of gastrointestinal (GI) vagal afferent fibers. A threshold is shown for the emetic reflex, for those animals with an emetic reflex (human, cat, dog, ferret, shrew, etc.) and pica in rodents (e.g., rat). This threshold triggers an immediate response to a potential threat (e.g., GI poison). Less immediate dangers (i.e., low concentraions of toxins) can trigger a delayed strategy that supports a conditioned taste aversion, which leads to avoidance of a toxin in the future.