MECHANISM OF ACTION OF BUTORPHANOL

布托啡诺的作用机制

• 批准号: 6378428
• 负责人: Ing K. Ho
• 金额: $ 20.04万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378428
• 关键词: NMDA receptors; analgesics; autoradiography; drug withdrawal; excitatory aminoacid; glutamate receptor; laboratory rat; locus coeruleus; morphinans; narcotic antagonists; neural transmission; neuroanatomy; opioid receptor; psychopharmacology

DESCRIPTION: (Applicant's Abstract) The long term goal is to investigate butorphanol tartrate (Stadol)-induced physical dependence. A potent non-scheduled opioid analgesic agent, butorphanol, has substantial physical dependence and abuse liability as noted by case studies of butorphanol of abuse, literature reports, and our own data. In such cases, the normal therapeutic dose may be exceeded, leading to ingestion of larger doses for a longer periods of time than recommended. The objectives of the proposed studies are to focus on the mechanism of physical dependence upon butorphanol. Specifically, based on our research efforts conducted during the current support, the roles of k-opioid receptors, release of the excitatory neurotransmitter, glutamate, and NMDA receptors in the locus coeruleus of butorphanol dependent rats will be the targets of our investigation. Five specific aims will test the hypothesis that hyperexcitability of k-opioid receptors to opioid antagonists, induced by chronic exposure to butorphanol, results in exaggerated presynaptic release of glutamate and activation of postsynaptic glutamate receptors on noradrenergic neurons of the pontine locus coeruleus. These specific aims are: Aim 1: Characterization of k-opioid receptors in the development of physical dependence upon butorphanol. Aim 2: Investigation of glutamatergic neurotransmission within the locus coeruleus during the precipitation of withdrawal from dependence upon butorphanol by discrete locus coeruleus administration of selective-opioid receptor antagonists. Aim 3: Examination of the neuroanatomical link between the n. paragigantocellularis and the locus coeruleus as the putative substrate mediating the effects of k-opioid receptor stimulation on locus coeruleus glutamate levels during precipitated withdrawal from dependence upon butorphanol. Aim 4: Characterization of the involvement of locus coeruleus glutamate receptor subtypes in the development of dependence upon and withdrawal from butorphanol. Aim 5: Correlation tests of the degree of alteration in k-opioid receptors with the degree of glutamate release, change in NMDA receptors, and behavioral responses in butorphanol dependence.

描述：（申请人摘要） 长期目标是研究酒石酸布托啡诺 (Stadol) 诱导的 身体依赖性。 一种有效的非定期阿片类镇痛剂， 布托啡诺，具有严重的身体依赖性和滥用倾向， 布托啡诺滥用案例研究、文献报告和我们的研究表明 自己的数据。 在这种情况下，可能会超过正常的治疗剂量， 导致在更长的时间内摄入更大的剂量 受到推崇的。 拟议研究的目标是集中于 布托啡诺的身体依赖性机制。 具体来说，基于 我们在当前支持期间进行的研究工作， k-阿片受体，兴奋性神经递质谷氨酸的释放， 布托啡诺依赖性大鼠蓝斑中的 NMDA 受体 成为我们的调查对象。 五个具体目标将检验 假设 k-阿片受体对阿片类药物过度兴奋 由长期接触布托啡诺引起的拮抗剂，导致 突触前谷氨酸的过度释放和突触后的激活 脑桥蓝斑去甲肾上腺素能神经元上的谷氨酸受体。 这些具体目标是： 目标 1：k-阿片受体在开发中的表征 对布托啡诺的身体依赖性。 目标 2：研究基因座内的谷氨酸能神经传递 蓝斑在摆脱依赖的沉淀过程中 通过离散蓝斑给予选择性阿片类药物布托啡诺 受体拮抗剂。 目标 3：检查 n 之间的神经解剖学联系。 paragigantocellularis 和蓝斑作为假定底物 介导 k-阿片受体刺激对蓝斑的影响 快速戒除依赖期间的谷氨酸水平 布托啡诺。 目标 4：蓝斑谷氨酸参与的表征 依赖和戒断发展中的受体亚型 布托啡诺。 目标 5：k-阿片受体改变程度的相关性检验 随着谷氨酸释放的程度、NMDA 受体的变化，以及 布托啡诺依赖的行为反应。