Neural basis of learned food aversion and nausea

描述(由申请人提供)：一些药物会引起恶心和呕吐，可能会导致食欲不振和食物摄入量减少，这可能会对疾病的康复造成负面影响。使用细胞毒性化疗药物时，经常会出现恶心和呕吐。人们对检测毒素的神经通路和机制知之甚少。胃肠(GI)感觉神经纤维在呕吐的起始过程中起重要作用，也可能参与恶心的刺激。目前的建议将集中于确定由毒素激活的胃肠道迷走神经和脊髓传入纤维和脑核的通路和神经化学。为了解决这个问题，将进行实验，以检测顺铂(一种化疗药物)和氯化锂(LiCI)(导致人类恶心的治疗方法)对内脏传入神经活动以及脑和脊髓Fos表达的影响。研究将确定：(1)利用单位神经生理学的新应用，对顺铂和LICI作出反应的迷走神经和脊髓传入纤维的特性(神经递质受体，牵张敏感性，在胃和肠道的支配部位)，(2)通过Fos表达激活脑干和脊髓部位的顺铂和LICI治疗，(3)通过损害迷走神经和胃肠神经，参与顺铂和LICI产生脑Fos表达的外周神经通路，以及(4)在顺铂和LICI治疗产生的脑Fos反应中发挥作用的神经递质受体。了解毒素检测的生理学可能有助于在大量临床情况下治疗恶心，包括癌症化疗、糖尿病胃轻瘫、神经性厌食症、缺血性胃病、慢性肠梗阻、腹部恶性肿瘤和功能性消化不良。有效的恶心治疗可以显著提高慢性病患者的生活质量。

DESCRIPTION (provided by applicant): 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.