Reversing anesthesia with Caffeine

用咖啡因逆转麻醉

• 批准号: 9145248
• 负责人: AARON P. FOX
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145248
• 关键词: Age; Amphetamines; Anesthesia procedures; Anesthetics; Animals; Arousal; Behavior; Blinded; Brain; Caffeine; Catecholamines; Chromaffin Cells; Coma; Cyclic AMP; Depressed mood; Dopamine; Dopamine Receptor; Ephedra; Forskolin; General anesthetic drugs; Genetic; Goals; Grant; Health; Hippocampus (Brain); Home environment; Hour; Human; Human Volunteers; Impaired cognition; In Vitro; Inpatients; Isoflurane; Knock-out; Learning; Literature; Mediating; Medicine; Membrane Lipids; Membrane Proteins; Methamphetamine; Methylphenidate; Mus; Neurobiology; Neurons; Neurotransmitters; Nociception; Outpatients; PC12 Cells; Patients; Pharmaceutical Preparations; Play; Property; Propofol; Purinergic P1 Receptors; Rattus; Receptor Activation; Recovery; Reporting; Research; Role; Secretory Cell; Series; Signal Transduction; Site; Synapses; Synaptic plasticity; Testing; Theophylline; Thinking; Time; United States; Work; behavioral study; clinically relevant; cognitive ability; drug testing; extracellular; fluidity; inhibitor/antagonist; neurotransmitter release; receptor; synaptic function; ward

 DESCRIPTION (provided by applicant): The objective of this research is to determine whether caffeine reverses anesthesia in humans. General anesthetics induce a coma-like state; recovery from anesthesia is passive and is due to the discontinuation of anesthetic. Problematically, recovery from anesthesia is somewhat random, dependent upon a variety of factors like age or genetics that are beyond the clinician's control. Although "waking" from anesthesia can be relatively rapid, cognitive abilities are depressed for hours. In addition, some patients "wake" very slowly. It would be extremely beneficial to be able to time recovery from anesthesia in a reproducible manner and to have that recovery be complete. Our preliminary results, carried out in cultured PC12 cells and hippocampal neurons, suggested that general anesthetics inhibit neurotransmitter release. We hypothesized that inhibition of neurotransmitter release plays a key role in how anesthetics produce anesthesia in animals and humans. Furthermore we hypothesized that drugs that reverse the inhibitory effects of anesthetics on the release machinery should reverse anesthesia. Historically, cAMP signaling has been shown to play a key role in synaptic function and plasticity. Elevating cAMP facilitates neurotransmitter release. We posited that elevating intracellular cAMP might alter anesthetic action by restoring neurotransmitter release. Three drugs that elevate [cAMP]i levels, were tested; these drugs were found to completely reverse the inhibitory effects of anesthetics on neurotransmitter release in in vitro studies. When tested, these same cAMP elevating drugs dramatically accelerated recovery from anesthesia in rats. The most effective drug tested was caffeine which dramatically accelerated recovery from anesthesia (isoflurane and propofol) at relatively modest concentrations. In addition to elevating [cAMP]i, caffeine also inhibits adenosine receptors. A2A receptors mediate caffeine's arousal effects since knocking out this receptor or blocking it pharmacologically suppresses caffeine mediated arousal. It is possible that caffeine's ability to inhibit adenosine receptors helps it to reverse anesthesia. The goals of this application are: 1) Blinded Behavioral Studies in Mice and Rats - a) Determine whether A2A receptors play a role in reversing anesthesia. b) Determine whether caffeine works for all anesthetics. c) Determine optimal caffeine timing for anesthesia reversal. 2) Blinded Studies in Human Volunteers - a) Determine whether caffeine accelerates recovery from anesthesia and whether it accelerates recovery of cognitive abilities. b) Determine the optimal caffeine concentration and timing for anesthesia reversal. c) Determine whether caffeine is effective for all anesthetics. If caffeine accelerates recovery from anesthesia and restore cognitive abilities, then it may have the potential to impact medicine in a positive manner and in a brief time frame.