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

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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.

Introduction

Nausea and vomiting are commonly encountered in clinical practice as adverse effects of a wide range of drug treatments and diseases. Some cancer chemotherapy drugs, such as cisplatin, are extremely potent agents for inducing nausea and vomiting (e.g., Hesketh, 1996, Martin, 1996). The acute emetic effect of these treatments are partly controlled using anti-emetic drugs, however the delayed effects (> 24 h), particularly nausea, are much more difficult to treat (e.g., Rudd and Andrews, 2005). Additionally, there is little understanding of the neural systems that are involved in the long-term side effects of chemotherapy and the underlying neural systems that are responsible for nausea (for review see Andrews and Horn, 2006). This lack of information has hampered the development of treatments that might target these systems to more completely manage the distress produced by nausea and emesis.

Several animal models have been used to study the delayed (> 24 h) emesis and malaise occurring after treatment with chemotherapy agents. Ferrets, pigs, dogs, and the house musk shrew show delayed phases of emesis after injection with chemotherapy agents (Fukui and Yamamoto, 1999, Milano et al., 1995, Rudd and Naylor, 1994, Sam et al., 2003). The rat, a species without a vomiting reflex, shows a delayed pica response when injected with cisplatin (e.g., Rudd et al., 2002, Vera et al., 2006). Pica is the consumption of a non-nutritive material, such as clay, and is probably an adaptive response to toxicosis because clay can bind toxins and limit the systemic effects of a poison (Phillips et al., 1995, Phillips, 1999). Delayed emesis in animals possessing an emetic reflex, and pica in rats, is partially inhibited by drug treatments that suppress chemotherapy-induced emesis in humans, including dexamethasone, 5-HT3 (serotonin type 3) receptor antagonists, and NK1 (neurokinin type 1) receptor antagonists (Fukui and Yamamoto, 1999, Rudd et al., 2002, Sam et al., 2003).

Despite the use of animal models for studies of delayed emesis very little work has been conducted to determine the neural systems of the brain responsible for the delayed adverse effects of chemotherapy agents. One approach to define activation of neural systems is labeling Fos protein in neuronal cells (e.g., Sagar et al., 1988). The contribution of the caudal hindbrain to the emetic reflex was shown by Fos expression in the nucleus of the solitary tract (NTS) and area postrema (AP) of the ferret and cat after treatment with cisplatin (Ariumi et al., 2000, Miller and Ruggiero, 1994, Reynolds et al., 1991, Van Sickle et al., 2003). The rat also shows increased cFos mRNA in the NTS and AP for up to 6 h after an injection of 10 mg/kg cisplatin (Endo et al., 2004). In contrast to the focus on hindbrain Fos expression after treatment with cisplatin, forebrain Fos expression that might be induced by injection of chemotherapy agents has not been reported. Nausea is likely the result of activation of forebrain systems, and elucidating the neural systems of the forebrain activated by cisplatin might prove important for delineating the neural substrates for the perception of acute and delayed nausea. Furthermore, little is known about the neural systems responsible for delayed emesis or malaise (> 24 h) produced by chemotherapy treatments.

In the current investigation brain Fos-like immunoreactivity (Fos expression) was used to investigate the involvement of hindbrain and forebrain neural pathways in the short- (6 and 24 h) and long-term (48 h) responses to the highly emetic agent cisplatin. Rats were injected intraperitoneally (i.p.) with 3, 6, or 10 mg/kg cisplatin and sacrificed at 6, 24, or 48 h to determine caudal hindbrain and forebrain Fos expression. These doses of cisplatin and time points represent those used in studies of cisplatin-induced pica in the rat (Rudd et al., 2002, Saeki et al., 2001, Takeda et al., 1993, Takeda et al., 1995, Yamamoto et al., 2002).

Section snippets

Subjects

Ninety adult male Sprague–Dawley rats (Charles River, Kingston, NY, USA) were housed individually in a temperature-controlled (22 °C) vivarium maintained on a 12:12 h light–dark cycle (lights on at 0700 h). Rats were maintained in the animal facility for at least 2 weeks before testing and weighed 400–500 g at the time of sacrifice. Unless otherwise noted, standard rodent chow and tap water were available ad libitum throughout the experiment. Rats were weighed frequently to habituate them to

Hindbrain Fos expression

See Fig. 1 for representative images comparing hindbrain Fos expression in saline and cisplatin (10 mg/kg) treated animals at 48 h after injection. The mean cell counts in Fig. 2 show Fos expression in the hindbrain occurring primarily in the middle and rostral levels of the NTS and AP with little expression in the NTSc following cisplatin treatment. Most cisplatin-induced Fos expression appeared at 6 and 24 h, but injection with 10 mg/kg cisplatin produced a prolonged response at 48 h (Fig. 2

Discussion

The present study showed the pattern of Fos expression over 48 h in the hindbrain and forebrain in response to three doses of cisplatin (3, 6, and 10 mg/kg). The key findings were: 1) increasing the dose of cisplatin increased the magnitude and duration of brain Fos expression, 2) most excitatory effects on hindbrain Fos expression occurred within 24 h after cisplatin injection, 3) 6 and 10 mg/kg cisplatin increased Fos expression in the CeA and BNST by 316% and 557%, respectively, during 48 h,

Acknowledgement

This work was supported by NIH funding (DK065971).

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