Some medications produce nausea and vomiting that may lead to loss of appetite and reduced food intake, which can negatively affect recovery from disease. Nausea and vomiting are frequently observed with use of cytotoxic chemotherapy agents. Little is known about the neural pathways and mechanism for detecting toxins. Gastrointestinal (GI) sensory nerve fibers play an important role in the initiation of vomiting, and may also be involved in the stimulation of nausea. The present proposal will focus on identifying the pathways and neurochemistry of GI vagal and spinal afferent fibers and brain nuclei that are activated by toxins. To address this issue experiments will be conducted to examine the effects of cisplatin (a chemotherapy agent) and lithium chloride (LiCI) (treatments that produce nausea in humans) on visceral afferent nerve activity and brain and spinal cord Fos expression. Studies will determine: (1) the properties (neurotransmitter receptors, stretch-sensitivity, site of innervation in the stomach and intestine) of vagal and spinal afferent fibers responsive to cisplatin and LiCI using a novel application of single-unit neurophysiology, (2) the brainstem and spinal cord sites that are activated by cisplatin and LiCI treatment using Fos expression, (3) the peripheral neural pathways involved in brain Fos expression produced by cisplatin and LiCI using lesions of the vagus and GI spinal nerves, and (4) the neurotransmitter receptors that play a role in the brain Fos response produced by cisplatin and LiCI treatment. An understanding of the physiology of toxin detection may contribute to nausea treatment in a large number of clinical situations, including cancer chemotherapy, diabetic gastroparesis, anorexia nervosa, ischemic gastropathy, chronic intestinal obstruction, abdominal malignancy, and functional dyspepsia. Effective treatment of nausea may substantially improve the quality of life for patients with chronic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065971-04
Application #
7239564
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Hamilton, Frank A
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$233,326
Indirect Cost
Name
Monell Chemical Senses Center
Department
Type
DUNS #
088812565
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Horn, Charles C; Meyers, Kelly; Lim, Audrey et al. (2014) Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews. Am J Physiol Regul Integr Comp Physiol 306:R341-51
Horn, Charles C; Kimball, Bruce A; Wang, Hong et al. (2013) Why can't rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS One 8:e60537
Huang, Dong; Meyers, Kelly; Henry, Severine et al. (2011) Computerized detection and analysis of cancer chemotherapy-induced emesis in a small animal model, musk shrew. J Neurosci Methods 197:249-58
Horn, Charles C; Henry, Severine; Meyers, Kelly et al. (2011) Behavioral patterns associated with chemotherapy-induced emesis: a potential signature for nausea in musk shrews. Front Neurosci 5:88
Horn, Charles C; Murat, Chloe; Rosazza, Matthew et al. (2011) Effects of gastric distension and infusion of umami and bitter taste stimuli on vagal afferent activity. Brain Res 1419:53-60
Horn, Charles C; Still, Liz; Fitzgerald, Christiana et al. (2010) Food restriction, refeeding, and gastric fill fail to affect emesis in musk shrews. Am J Physiol Gastrointest Liver Physiol 298:G25-30
Horn, Charles C (2009) Brain Fos expression induced by the chemotherapy agent cisplatin in the rat is partially dependent on an intact abdominal vagus. Auton Neurosci 148:76-82
Horn, Charles C (2009) Electrophysiology of vagal afferents: amino acid detection in the gut. Ann N Y Acad Sci 1170:69-76
Horn, Charles C; De Jonghe, Bart C; Matyas, Kathleen et al. (2009) Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat. Am J Physiol Regul Integr Comp Physiol 297:R1375-82
De Jonghe, Bart C; Lawler, Maureen P; Horn, Charles C et al. (2009) Pica as an adaptive response: Kaolin consumption helps rats recover from chemotherapy-induced illness. Physiol Behav 97:87-90

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