Brain Fos expression during 48 h after cisplatin treatment: Neural pathways for acute and delayed visceral sickness

Abstract

Cancer chemotherapy drugs, such as cisplatin, are extremely potent for producing nausea and vomiting. The acute effects of these treatments are partly controlled using anti-emetic drugs, but the delayed effects (>24 h), especially nausea, are much more difficult to treat. Furthermore, cisplatin induces a long-term (up to 48 h) increase in pica in rats. Pica is manifested as an increase in consumption of kaolin (clay) and is used as a measure of visceral sickness. It is unknown what brain pathways might be responsible for this sickness associated behavior. As a first attempt to define this neural system, rats were injected (i.p.) with 3, 6, or 10 mg/kg cisplatin (doses reported to produce pica) and sacrificed at 6, 24, or 48 h to determine brain Fos expression. The primary results indicate: 1) increasing the dose of cisplatin increased the magnitude and duration of brain Fos expression, 2) most excitatory effects on hindbrain nucleus of the solitary tract (NTS) and area postrema (AP) Fos expression occurred within 24 h after cisplatin injection, 3) 6 and 10 mg/kg cisplatin treatment produced large increases in Fos expression in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), including 48 h after injection, and 4) cisplatin treatment produced little effect on Fos expression in the paraventricular and supraoptic nuclei of the hypothalamus. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex (NTS and AP), CeA, and BNST.

A histologically derived stereotaxic atlas and substance P immunohistochemistry in the brain of the least shrew (Cryptotis parva) support its role as a model organism for behavioral and pharmacological research

“…Brainstem SP has been implicated in autonomic control [16,29] and in control of emetic reflexes [41,46,48]. Of greatest relevance to the current use of C. parva as a small-animal emesis model, SP was found in the brainstem areas held to be key mediators of the emetic reflex: The area postrema, solitary tract and nucleus, and dorsal motor nucleus of the vagus nerve [4,[24][25][26]31]. Interestingly, preliminary results using c-fos immunohistochemistry as a marker for neuronal activation suggest that following the delayedphase emetic response, fos is increased most strongly in areas associated with dense SPL-IR fiber plexi (Ray, unpublished observations).…”

“…While rodent pica behavior has been used as a substitute for vomiting [24], it is unclear whether the neural substrates of this behavior are truly the same or similar enough for use as an emetic model. For a more appropriate model of emesis, researchers have turned to the insectivorous Soricid shrews, the house musk shrew [Suncus murinus; [25]] and the least shrew [Cryptotis parva; [11]], and to the carnivorous ferret [Mustela sp.…”

Migraine and motion sickness: What is the link?

“…In a review of the literature, Boscan, Kasparov and Paton (2002) pain signals (Hunt, Pini and Evans, 1987 (Horn, 2008). The association between nausea and the various responses associated with vomiting is not well understood, but it seems reasonable to assume that nausea involves communication between the brainstem centres that coordinate these responses and forebrain areas such as the extended amygdala (Horn, Ciucci and Chaudhury, 2007), which regulates responses to stress, conditioned flavor aversion and, possibly, anticipatory nausea and vomiting during chemotherapy.…”

“…The physiological basis of nausea is uncertain, but may involve communication between afferent pathways involved in vomiting (e.g., the chemoreceptor trigger zone, gastrointestinal visceral afferents and/or the labyrinth) (Takeda et al, 1993) and forebrain regions that integrate this sensory input with past experiences and concurrent sensory-motor and emotional activity (Horn et al, 2007).…”

Why is the neurobiology of nausea and vomiting so important?

“…1). For example, it seems reasonable that the emetic central pattern generator or final common pathway should connect to forebrain areas involved in nausea (the amygdala is a possible candidate: Horn, Ciucci, & Chaudhury, 2007) and these putative pathways could be assessed with electrophysiological methods during the induction of emeticlike responses.…”