Abstract
Nausea is a prominent symptom and major cause of complaint for patients receiving anticancer chemo- or radiation therapy. The arsenal of anti-nausea drugs is limited, and their efficacy is questionable. Currently, the development of new compounds with anti-nausea activity is hampered by the lack of physiological correlates of nausea. Physiological correlates are needed because common laboratory rodents lack the vomiting reflex. Furthermore, nausea does not always lead to vomiting. Here, we report the results of studies conducted in four research centers to investigate whether nausea is associated with any specific thermoregulatory symptoms. Two species were studied: the laboratory rat, which has no vomiting reflex, and the house musk shrew (Suncus murinus), which does have a vomiting reflex. In rats, motion sickness was induced by rotating them in their individual cages in the horizontal plane (0.75 Hz, 40 min) and confirmed by reduced food consumption at the onset of dark (active) phase. In 100% of rats tested at three centers, post-rotational sickness was associated with marked (~1.5°C) hypothermia, which was associated with a short-lasting tail-skin vasodilation (skin temperature increased by ~4°C). Pretreatment with ondansetron, a serotonin 5-HT3 receptor antagonist, which is used to treat nausea in patients in chemo- or radiation therapy, attenuated hypothermia by ~30%. In shrews, motion sickness was induced by a cyclical back-and-forth motion (4 cm, 1 Hz, 15 min) and confirmed by the presence of retching and vomiting. In this model, sickness was also accompanied by marked hypothermia (~2°C). Like in rats, the hypothermic response was preceded by transient tail-skin vasodilation. In conclusion, motion sickness is accompanied by hypothermia that involves both autonomic and thermoeffector mechanisms: tail-skin vasodilation and possibly reduction of the interscapular brown adipose tissue activity. These thermoregulatory symptoms may serve as physiological correlates of nausea.
Highlights
Half of cancer patients experience nausea and vomiting during the course of their disease, either due to cancer itself or secondary to chemotherapy [1]
Our major novel finding is that in rats, provocative motion causes anorexic effect indicative of nausea state associated with a rapid and robust fall in the core body temperature; and that this latter effect is mediated, at least in part, by vasodilatation in the thermoregulatory tail vascular bed. This finding was confirmed in the musk shrew, where tail vasodilation preceded the first vomiting episode, when animals likely experienced nausea
Our observations mirror thermoregulatory changes reported in humans during nausea [12,13,14,15]
Summary
Half of cancer patients experience nausea and vomiting during the course of their disease, either due to cancer itself or secondary to chemotherapy [1]. Nausea and vomiting produced www.impactjournals.com/oncotarget by these and other chemothrerapeutic drugs are among the most severe and feared collateral effects of chemotherapy [3, 4] These side effects dramatically worsen quality of life, but may affect the patients’ willingness to continue their anti-cancer treatment. Most recent pre-clinical studies of novel antiemetic substances are based on emetic responses, and it is assumed that drugs which suppress retching/vomiting in animals may be good in suppressing nausea in humans. A researcher’s choice for assessing nausea is limited to just a few biological indices with either poor temporal resolution (e.g. reduced locomotion or food intake) or questionable face validity (e.g. pica - kaolin consumption) and specificity (eg. conditioned food aversion) (reviewed in [8])
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