Why Can't Rodents Vomit? A Comparative Behavioral, Anatomical, and Physiological Study

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed. © 2013 Horn et al

Representative recordings of the mouth movement, esophagus movement, and phrenic nerve activity from the mouse (C57BL6), rat (Sprague-Dawley), and musk shrew in the <i>in situ</i> brainstem preparation.

<p>Vertical dashed lines indicate the start of the contraction of the esophagus after resiniferatoxin (RTX) was perfused through the brainstem (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone-0060537-g004" target="_blank">Fig. 4</a>). Plots show 15 s pre-event versus 15 s post-event (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone-0060537-g012" target="_blank">Fig. 12</a> for group averages). Mouth and esophageal recordings indicate force (g), with positive deflections showing opening of the mouth and shortening of the esophagus. Lines and event marks above each trace indicate events detected by computer software (DataView; <a href="http://www.st-andrews.ac.uk/~wjh/dataview/" target="_blank">http://www.st-andrews.ac.uk/~wjh/dataview/</a>).</p

Mammalian phylogenetic tree [12], [18], [19].

<p>Specific species listed in the tree branches are examples and may not include all those contained in each class; species included in the current study are marked with a yellow highlight. A “+” sign notes a species with a well established emetic response (demonstrated in laboratory studies) (e.g., <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Darmani1" target="_blank">[10]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Matsuki1" target="_blank">[11]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Knox1" target="_blank">[23]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Zhang1" target="_blank">[42]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Andrews6" target="_blank">[50]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Schwartzberg1" target="_blank">[76]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone.0060537-Foss1" target="_blank">[79]</a>).</p

Representative anatomical images of the diaphragm and stomach in test species of Rodentia and emetic species. Bar = 1 cm.

<p>Representative anatomical images of the diaphragm and stomach in test species of Rodentia and emetic species. Bar = 1 cm.</p

Behaviors scored after animals were injected with saline (sc or ig) or the emetic agents apomorphine (sc), veratrine (sc), or CuSO₄ (ig).

<p>Data represent the percentage of animals of each species that showed specific behaviors for the 40 min test. No emetic responses were detected in any of these rodent species.</p

Average effects of resiniferatoxin (RTX; 40 nM) treatment on mouth, esophagus, and phrenic nerve responses from the brainstems of mouse (C57BL6), rat (Sprague-Dawley), and musk shrew (Fig. 4).

<p><b>A)</b> Mouth, esophagus, phrenic nerve events during the 15 s before and after (pre- and post-event) alignment to the first large esophageal movement (an esophageal movement that was greater than baseline movements). <b>B)</b> Effects when data are aligned to the first large mouth movement. * = p<0.05, Wilcoxon Signed Rank test, number of pre-events versus number of post-events. δ = p<0.05, Kruskal-Wallis one-way ANOVA, species effect for difference between pre-and post-event values. Data represent mean ± SEM.</p

Anatomical measures of the esophagus, diaphragm, and stomach.

<p>Esophagus length measures were total (from gastroesophageal border to caudal extremity of larynx) and abdominal (below the diaphragm) components. Esophagus circumference was measured directly above the gastroesophageal border. The diaphragm was measured for muscular and non-muscular regions. Stomach shape was measured by placing a horizontal line on the gastroesophageal and gastroduodenal borders and creating a vertical division to determine left and right stomach surface areas. A measure of gastric shape included statistical analysis using 100 points, with 4 restricted landmark points (points 1, 75, 76, and 100) placed on the anatomical borders with the esophagus and duodenum (only a few of these points are shown in blue; starting at point 1 on the gastroesophageal border and moving clockwise).</p

Esophagus and stomach area measures.

<p><b>A)</b> Abdominal esophagus circumference/total esophagus length (cm). <b>B)</b> Abdominal esophagus length/total esophagus length. <b>C)</b> Percentage of stomach area to the left of vertical division. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060537#pone-0060537-g003" target="_blank">Figure 3</a> for a diagram showing location of these measures. * = p<0.05, planned contrast, a rodent species compared to all emetic species. Data represent mean ± SEM.</p