TASK Potassium Channel Antagonists to Treat Opioid Depression of Breathing

TASK 钾通道拮抗剂治疗阿片类药物呼吸抑制

基本信息

批准号：
8843947
负责人：
Joseph F Cotten
金额：
$ 42.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843947
关键词：
Absence of pain sensation Acute Adverse event Affect American Amino Acids Anatomy Apnea Area Bilateral Binding Blood Gas Analysis Brain Stem Breathing Carbon Dioxide Carotid Body Cells Chimera organism Chronic Obstructive Airway Disease Clinical Data Denervation Development Disease Dose Doxapram Environmental air flow Foundations Health Hypercapnia Hypercapnic respiratory failure Hypoxia Intervention Intravenous Measures Mediating Molecular Morbidity - disease rate Morphine Neuromuscular Diseases Obesity Opioid Oxygen Patients Perioperative Pharmaceutical Preparations Pharmacotherapy Plethysmography Potassium Potassium Channel Premature Infant Rattus Regulation Resistance Respiratory physiology Role Site Sleep Apnea Syndromes Structure-Activity Relationship Sudden infant death syndrome Techniques Testing Therapeutic Agents Ventilatory Depression experience flopropione improved in vivo inhibitor/antagonist molecular site mutant novel patient safety premature pressure prevent response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Opioid drug-induced ventilatory depression is a common clinical problem and a significant cause of perioperative morbidity. The overall hypothesis of this proposal is that such respiratory depression may be overcome by pharmacological intervention. Specifically, we will test the hypothesis that inhibition of TASK-1 and TASK-3 tandem pore potassium channel function in the carotid body stimulates breathing and prevents morphine-induced ventilatory depression. The carotid body is essential for regulation of breathing by hypoxia and hypercarbia, and the TASK-1 and TASK-3 heterodimer potassium channel provides the predominant hypoxia-sensitive potassium conductance in carotid body chemosensing cells. The drug doxapram stimulates breathing through carotid body activation and is a potent TASK-1 and TASK-3 potassium channel antagonist. We have identified two additional TASK-1 and TASK-3 antagonist compounds that stimulate breathing with an efficacy, potency, and duration that markedly exceed that of doxapram. Our preliminary data also suggest these agents may prevent morphine-induced depression of breathing at supralethal doses. In Aims 1 and 2, we propose studies to determine if the carotid body and, more specifically, if TASK-1 and TASK-3 potassium channels within the carotid are the sites of action through which the TASK antagonist compounds stimulate breathing. We will quantify rat breathing before and after administration of the TASK antagonist compounds using plethysmography and blood gas analysis. We will study rats with and without surgically denervated carotid bodies, and we will study rats expressing antagonist-resistant mutant TASK-3 subunits in their carotid bodies. These antagonist-resistant TASK-3 mutants will be identified in our proposed studies. In Aim 3, we will use dynamic end-tidal forcing to characterize the effect of each TASK antagonist on breathing regulation by hypoxia and hypercarbia. Finally, in Aim 4, we will confirm the efficacy of TASK antagonists in reversing and preventing morphine-induced depression of breathing, and we will determine the effect of TASK antagonists on morphine analgesia. If our hypothesis is correct, these studies will validate TASK-1 and TASK-3 potassium channels as a therapeutic target for treatment of breathing disorders and will provide a novel pharmacologic strategy to improve patient safety during opioid administration.

描述（由申请人提供）：阿片类药物引起的通气抑郁症是常见的临床问题，也是围手术期发病率的重要原因。该提议的总体假设是，药理学干预可以克服这种呼吸抑郁症。具体而言，我们将检验以下假设：颈动脉体内抑制任务1和任务3串联孔钾通道功能可刺激呼吸并防止吗啡诱导的通气抑郁症。颈动脉体对于通过缺氧和高碳酸盐调节呼吸至关重要，而任务1和任务-3异二聚钾通道则提供了颈动脉化学效应细胞中主要缺氧的钾电导。 Doxapram药物通过颈动脉体激活刺激呼吸，是一种有效的任务1和Task-3钾通道拮抗剂。我们已经确定了另外的两种任务1和Task-3拮抗剂化合物，这些化合物的功效，效力和持续时间显着超过了doxapram。我们的初步数据还表明，这些药物可能会防止吗啡诱导的呼吸抑郁症。在目标1和2中，我们提出了研究，以确定颈动脉体，更具体地说，颈动脉内的任务1和任务3钾通道是否是任务拮抗剂刺激呼吸的作用部位。我们将使用多体积学和血液分析在给药前后对大鼠呼吸进行定量呼吸。我们将研究带有和没有手术颈动脉体的大鼠，我们将研究在其颈动脉体中表达抗拮抗剂突变的任务3亚基的大鼠。这些耐药的任务-3突变体将在我们提出的研究中确定。在AIM 3中，我们将使用动态末端攻击强迫来表征每个任务拮抗剂对缺氧和高碳酸盐呼吸调节的影响。最后，在AIM 4中，我们将确认任务拮抗剂在逆转和防止吗啡引起的呼吸抑制方面的功效，我们将确定任务拮抗剂对吗啡镇痛的影响。如果我们的假设是正确的，这些研究将验证任务1和Task-3钾通道作为治疗呼吸障碍的治疗靶点，并将提供一种新型的药理策略，以提高阿片类药物给药期间的患者安全。