Brain Fos expression during 48 h after cisplatin treatment: Neural pathways for acute and delayed visceral sickness
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).
References (45)
- et al.
Signals for nausea and emesis: implications for models of upper gastrointestinal diseases
Auton. Neurosci.
(2006) - et al.
The role of tachykinin NK-1 receptors in the area postrema of ferrets in emesis
Neurosci. Lett.
(2000) - et al.
Hypothalamic neuropeptide Y regulation of feeding and energy metabolism
Curr. Opin. Neurobiol.
(1992) - et al.
Methotrexate produces delayed emesis in dogs: a potential model of delayed emesis induced by chemotherapy
Eur. J. Pharmacol.
(1999) - et al.
The limbic lobe and its output channels: implications for emotional functions and adaptive behavior
Neurosci. Biobehav. Rev.
(2006) - et al.
Amygdala circuitry in attentional and representational processes
Trends Cogn. Sci.
(1999) - et al.
Role of vagal afferent innervation in feeding and brain Fos expression produced by metabolic inhibitors
Brain Res.
(2001) - et al.
Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin
Auton. Neurosci.
(2004) - et al.
The primate amygdala: neuronal representations of the viscosity, fat texture, temperature, grittiness and taste of foods
Neuroscience
(2005) - et al.
Behavioural and hypothalamic molecular effects of the anti-cancer agent cisplatin in the rat: a model of chemotherapy-related malaise?
Pharmacol. Biochem. Behav.
(2006)
Cholecystokinin induces c-fos expression in hypothalamic oxytocinergic neurons projecting to the dorsal vagal complex
Brain Res.
Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression
Curr. Opin. Pharmacol.
Cisplatin-evoked induction of c-fos protein in the brainstem of the ferret: the effect of cervical vagotomy and the anti-emetic 5-HT3 receptor antagonist granisetron (BRL 43694)
Brain Res.
Effects of 5-HT3 receptor antagonists on models of acute and delayed emesis induced by cisplatin in the ferret
Neuropharmacology
Differential action of ondansetron and dexamethasone to modify cisplatin-induced acute and delayed kaolin consumption (“pica”) in rats
Eur. J. Pharmacol.
Effects of HSP-117, a novel tachykinin NK1-receptor antagonist, on cisplatin-induced pica as a new evaluation of delayed emesis in rats
Jpn. J. Pharmacol.
Action of 5-HT3 receptor antagonists and dexamethasone to modify cisplatin-induced emesis in Suncus murinus (house musk shrew)
Eur. J. Pharmacol.
Pica in rats is analogous to emesis: an animal model in emesis research
Pharmacol. Biochem. Behav.
Synergistic interaction between CCK and leptin to regulate food intake
Regul. Pept.
Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology
Peptides
Agouti-related protein in the hypothalamic paraventricular nucleus: effect on feeding
Peptides
The bed nucleus is a neuroanatomical substrate for the anorectic effect of corticotropin-releasing factor and for its reversal by nociceptin/orphanin FQ
J. Neurosci.
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