Chemotherapy agent cisplatin induces 48-h Fos expression in the brain of a vomiting species, the house musk shrew (Suncus murinus)

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2009-04, Vol.296 (4), p.R902-R911
• Main Authors: De Jonghe, Bart C, Horn, Charles C
• Format: Article
• Language: English
• Subjects: Amygdala - metabolism; Animals; Antiemetics - pharmacology; Antineoplastic Agents; Appetite, Obesity, and Digestion; Area Postrema - metabolism; Brain; Brain - drug effects; Brain - metabolism; Cancer; Chemotherapy; Cisplatin; Disease Models, Animal; Female; Isoquinolines - pharmacology; Mammals; Mesencephalon - metabolism; Nausea; Proto-Oncogene Proteins c-fos - metabolism; Quinuclidines - pharmacology; Receptors, Serotonin, 5-HT3 - metabolism; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists - pharmacology; Shrews; Solitary Nucleus - metabolism; Time Factors; Vomiting; Vomiting - chemically induced; Vomiting - metabolism; Vomiting - prevention & control
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.90952.2008

Monell Chemical Senses Center, Philadelphia, Pennsylvania Submitted 24 November 2008 ; accepted in final form 9 February 2009 Cancer chemotherapy drugs, such as cisplatin, potently produce nausea and vomiting. Acute effects of these treatments are partly controlled by antiemetic drugs, but the delayed effects (>24 h), especially nausea, are more difficult to treat. It is unknown what brain pathways produce this delayed sickness. Our prior data show that brain Fos expression is increased for at least 48 h after cisplatin treatment in the rat, a nonvomiting species. Here, we extend these observations by using house musk shrews ( Suncus murinus ), a species with an emetic response. Compared with saline injection, cisplatin treatment (30 mg/kg ip) induced Fos expression in hindbrain areas known to play a role in the generation of emesis, the dorsal motor nucleus (DMN), the area postrema, and the nucleus of the solitary tract (NTS), for up to 48 h. Cisplatin also stimulated Fos expression in the parabrachial nucleus (PBN) of the midbrain and the central nucleus of the amygdala (CeA) for at least 48 h after treatment. When animals were pretreated with the antiemetic palonosetron, a long-term serotonin type 3 (5-HT 3 ) receptor antagonist, cisplatin-induced Fos expression was significantly attenuated in the NTS, DMN, and CeA at 6 h but not at 48 h. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex and forebrain in the musk shrew, which is partially suppressed by a 5-HT 3 receptor antagonist. Our findings suggest the existence of an extensive neural system that could be targeted to reduce nausea, vomiting, and malaise in cancer patients receiving chemotherapy. emesis; palonosetron; serotonin type 3 receptor Address for reprint requests and other correspondence: C. C. Horn, Monell Chemical Senses Ctr., 3500 Market St., Philadelphia, PA 19104 (e-mail: horn{at}monell.org )