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.
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