Detection of Nausea-Like Response in Rats by Monitoring Facial Expression

Abstract

Patients receiving cancer chemotherapy experience nausea and vomiting. They are not life-threatening symptoms, but their insufficient control reduces the patients’ quality of life. To identify methods for the management of nausea and vomiting in preclinical studies, the objective evaluation of these symptoms in laboratory animals is required. Unlike vomiting, nausea is defined as a subjective feeling described as recognition of the need to vomit; thus, determination of the severity of nausea in laboratory animals is considered to be difficult. However, since we observed that rats grimace after the administration of cisplatin, we hypothesized that changes in facial expression can be used as a method to detect nausea. In this study, we monitored the changes in the facial expression of rats after the administration of cisplatin and investigated the effect of anti-emetic drugs on the prevention of cisplatin-induced changes in facial expression. Rats were housed in individual cages with free access to food and tap water, and their facial expressions were continuously recorded by infrared video camera. On the day of the experiment, rats received cisplatin (0, 3, and 6 mg/kg, i.p.) with or without a daily injection of a 5-HT3 receptor antagonist (granisetron: 0.1 mg/kg, i.p.) or a neurokinin NK1 receptor antagonist (fosaprepitant: 2 mg/kg, i.p.), and their eye-opening index (the ratio between longitudinal and axial lengths of the eye) in the recorded video image was calculated. Cisplatin significantly and dose-dependently induced a decrease of the eye-opening index 6 h after the cisplatin injection, and the decrease continued for 2 days. The acute phase (day 1), but not the delayed phase (day 2), of the decreased eye-opening index was inhibited by treatment with granisetron; however, fosaprepitant abolished both phases of changes. The time-course of changes in facial expression are similar to clinical evidence of cisplatin-induced nausea in humans. These findings indicate that the monitoring of facial expression has the potential to be useful for the detection of a nausea-like response in laboratory animals.

Alterations of colonic sensitivity and gastric dysmotility after acute cisplatin and granisetron

“…7 In rodents, which are the most commonly used laboratory animals, indirect markers of nausea/vomiting need to be used because they lack the motor limb of the emetic reflex. In rats, these indirect markers include paired taste avoidance, 37 gaping, 38 changes in facial expression, 39 and pica. 13,23 Pica has been shown to be induced after both single 14,15 and repeated administration of cisplatin.…”

He-Wei granules inhibit chemotherapy-induced vomiting (CINV) in rats by reducing oxidative stress and regulating 5-HT, substance P, ghrelin and obestatin

“…However, 6 mg kg À1 cisplatin cannot induce delayed vomiting because of severe anorexia. 13 In our previous experiment, 3, 4, 5, and 6 mg kg À1 doses of cisplatin have been screened. According to the kaolin consumption, the general status of the animals, and the levels of biomarkers, a 5 mg kg À1 dose was considered to be more appropriate due to its stability and signicance.…”

“…12 However, although rats lack a motor reex of emesis, they display atypical feeding behavior, termed pica response. [13][14][15][16][17] Pica behavior is an aversive/ illness response that results in consumption of non-nutrient substances, such as kaolin, aer an emetic stimulus. 18,19 It has been conrmed that pica behavior can be used as a model of a nausea-like response or gastrointestinal malaise because it is induced by nausea stimuli and the amount of kaolin consumption is related to the severity of nausea in humans.…”

“…18,19 It has been conrmed that pica behavior can be used as a model of a nausea-like response or gastrointestinal malaise because it is induced by nausea stimuli and the amount of kaolin consumption is related to the severity of nausea in humans. 13 In addition, it has been shown by the Japanese group Yamamoto et al [13][14][15][16] that the magnitude of pica response in rats is directly related to the emetogenic potential in humans. The highly emetogenic anti-cancer drug (such as cisplatin)-induced kaolin ingestion behavior pica in rats is analogous to emesis.…”

“…As an antineoplastic agent with high risk of emetogenic level increase, cisplatin was used to simulate CINV in our study, 1,14 and cisplatin-induced pica behavior was regarded as an acceptable model to measure the antiemetic effect of drugs according to kaolin consumption and other indices. 1,13,16,18,20 As a classical formula that has been used for more than 1000 years, BXXXT is considered to be effective in controlling the emesis levels. In our previous study, HWKL has been found to reduce kaolin intake of rats in a pica model.…”