Physiological changes associated with copper sulfate-induced nausea and retching in felines

Abstract

Nausea is a common disease symptom, yet there is no consensus regarding its physiological markers. In contrast, the process of vomiting is well documented as sequential muscular contractions of the diaphragm and abdominal muscles and esophageal shortening. Nausea, like other self-reported perceptions, is difficult to distinguish in preclinical models, but based on human experience emesis is usually preceded by nausea. Here we focused on measuring gastrointestinal and cardiorespiratory changes prior to emesis to provide additional insights into markers for nausea. Felines were instrumented to chronically record heart rate, respiration, and electromyographic (EMG) activity from the stomach and duodenum before and after intragastric delivery of saline or copper sulfate (CuSO₄, from 83 to 322 mg). CuSO₄ is a prototypical emetic test agent that triggers vomiting primarily by action on GI vagal afferent fibers when administered intragastrically. CuSO₄ infusion elicited a significant increase in heart rate, decrease in respiratory rate, and a disruption of gastric and intestinal EMG activity several minutes prior to emesis. The change in EMG activity was most consistent in the duodenum. Administration of the same volume of saline did not induce these effects. Increasing the dose of CuSO₄ did not alter the physiologic changes induced by the treatment. It is postulated that the intestinal EMG activity was related to the retrograde movement of chyme from the intestine to the stomach demonstrated to occur prior to emesis by other investigators. These findings suggest that monitoring of intestinal EMG activity, perhaps in combination with heart rate, may provide the best indicator of the onset of nausea following treatments and in disease conditions, including GI disease, associated with emesis.

Keywords: copper sulfate; gastric electromyogram; heart rate; nausea; respiratory activity detection; vomiting.

FIGURE 1

Placement of recording electrodes on the diaphragm (A), abdominal musculature (B), stomach antrum (C), and upper duodenum (D). A ruler with 1 mm hatch marks is placed next to the electrode in each panel.

FIGURE 2

Recordings from one animal (C2-21) during a baseline trial where neither saline nor CuSO₄ was administered. (A) raw EMG recordings from the abdominal musculature, diaphragm, intestine (duodenum), and stomach. (B) same recordings, smoothed with a 0.2 s time constant. (C) diaphragm and abdominal muscle activity for a shorter time period (first 10 s of traces in A) so that details of recordings are evident. The top two traces are raw EMG recordings, while the bottom two traces depict the same data smoothed with a 0.2 s time constant.

FIGURE 3

Recordings of diaphragm and abdominal muscle activity during a retching episode (continuous series of retches). The left traces are raw EMG activity, whereas the recordings are rectified and smoothed (time constant of 0.2 s) in the right panels.

FIGURE 4

Changes in heart rate (A), respiration rate (B), and the frequency of slow wave activity in the duodenum (C) and stomach (D) elicited by saline (left column) and CuSO₄ (right column) administration in one animal. Each data point indicates averaged data over a 1-s period. The vertical blue line in the left column denotes the time of saline administration, whereas the vertical red line in the right column shows when CuSO₄ was provided. The time period when retching occurred following CuSO₄ administration is designated by gold shading and black vertical lines.

FIGURE 5

Spectrograms of duodenal and stomach slow-wave activity following administration of saline (left column) and CuSO₄ (right column). Yellow represents the dominant frequency and blue the least dominant (scale of normalized signal power, 0–1). As in Figure 4, the blue vertical line indicates saline administration, the red vertical line designates CuSO4 administration, and the black vertical lines show when retching occurred.

FIGURE 6

Effects of CuSO₄ administration on physiologic parameters associated with the first retching episode. Each data point represents an average of data over 10 min during the baseline (prior to CuSO₄ administration) or retching periods. For the six animals that retched within 10 min of providing CuSO₄ (data indicated by green lines and symbols), the retching period was defined as the 10 min following CuSO₄ administration. For the four animals where retching occurred at longer latency (data indicated by red lines and symbols), the retching period was defined as the 10 min prior to the final retch of the initial episode. p values above each panel are for comparisons between each physiologic parameter during the baseline and retching periods (two-tailed paired t-test).