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.
Breathing disorders affect millions of Americans and include sleep apnea, chronic obstructive pulmonary disease (COPD), neuromuscular disease, sudden infant death syndrome (SIDS), apnea in premature infants, and opioid- induced depression of breathing. Our studies will provide a foundation for development of new drug therapies to be used in the treatment breathing disorders.
|Boghosian, James D; Luethy, Anita; Cotten, Joseph F (2018) Intravenous and Intratracheal Thyrotropin Releasing Hormone and Its Analog Taltirelin Reverse Opioid-Induced Respiratory Depression in Isoflurane Anesthetized Rats. J Pharmacol Exp Ther 366:105-112|
|Jounaidi, Youssef; Cotten, Joseph F; Miller, Keith W et al. (2017) Tethering IL2 to Its Receptor IL2R? Enhances Antitumor Activity and Expansion of Natural Killer NK92 Cells. Cancer Res 77:5938-5951|
|Zhao, Haiting; Cotten, Joseph F; Long, Xiaoyan et al. (2017) The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP. Epilepsy Res 137:139-144|
|Luethy, Anita; Boghosian, James D; Srikantha, Rithu et al. (2017) Halogenated Ether, Alcohol, and Alkane Anesthetics Activate TASK-3 Tandem Pore Potassium Channels Likely through a Common Mechanism. Mol Pharmacol 91:620-629|
|Zhang, Honghai; Zhao, Haiting; Yang, Xiaoxuan et al. (2016) 5-Hydroxytryptophan, a precursor for serotonin synthesis, reduces seizure-induced respiratory arrest. Epilepsia 57:1228-35|
|Diaz-Gil, Daniel; Haerter, Friederike; Falcinelli, Shane et al. (2016) A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2. Anesthesiology 125:333-45|
|Kenny, Jonathan D; Chemali, Jessica J; Cotten, Joseph F et al. (2016) Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats. Anesth Analg 123:1210-1219|
|Chokshi, Rikki H; Larsen, Aaron T; Bhayana, Brijesh et al. (2015) Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore. Mol Pharmacol 88:926-34|
|Zeng, Chang; Long, Xiaoyan; Cotten, Joseph F et al. (2015) Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice. Epilepsy Behav 45:1-7|
|Cotten, Joseph F (2014) The latest pharmacologic ventilator. Anesthesiology 121:442-4|
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