TASK Potassium Channel Antagonists to Treat Opioid Depression of Breathing

描述（由申请人提供）：阿片类药物引起的通气抑制是常见的临床问题，也是围手术期发病率的重要原因。该建议的总体假设是，这种呼吸抑制可以通过药物干预来克服。具体来说，我们将验证抑制颈动脉体TASK-1和TASK-3串联孔钾通道功能刺激呼吸并防止吗啡诱导的通气抑制的假设。颈动脉体对缺氧和高碳呼吸的调节至关重要，而TASK-1和TASK-3异源二聚体钾通道在颈动脉体化学感应细胞中提供主要的缺氧敏感钾传导。药物doxapram通过颈动脉体激活刺激呼吸，是一种有效的TASK-1和TASK-3钾通道拮抗剂。我们已经确定了另外两种TASK-1和TASK-3拮抗剂化合物，它们刺激呼吸的功效、效力和持续时间明显超过doxapram。我们的初步数据还表明，这些药物可以预防吗啡引起的超致死剂量呼吸抑制。在目标1和目标2中，我们提出研究以确定颈动脉体，更具体地说，颈动脉内的TASK-1和TASK-3钾通道是否是TASK拮抗剂化合物刺激呼吸的作用部位。我们将使用体积描记仪和血气分析来量化给药TASK拮抗剂化合物前后的大鼠呼吸。我们将研究颈动脉体有和没有手术去神经的大鼠，我们将研究颈动脉体中表达拮抗剂耐药突变体TASK-3亚基的大鼠。这些抗拮抗剂的TASK-3突变体将在我们提出的研究中确定。在Aim 3中，我们将使用动态潮汐末强迫来表征每种TASK拮抗剂对缺氧和高碳呼吸调节的影响。最后，在Aim 4中，我们将证实TASK拮抗剂逆转和预防吗啡诱导的呼吸抑制的功效，并确定TASK拮抗剂对吗啡镇痛的作用。如果我们的假设是正确的，这些研究将验证TASK-1和TASK-3钾通道作为治疗呼吸障碍的治疗靶点，并将提供一种新的药理学策略来提高阿片类药物给药期间的患者安全性。

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.