TRPA1 and General Anesthetics

TRPA1 和全身麻醉剂

• 批准号: 8190901
• 负责人: GERARD P AHERN
• 金额: $ 23.25万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-17 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190901
• 关键词: Adverse effects; Amino Acids; Anesthetics; Binding; Chemicals; Complex; Data; Docking; Electronics; General Anesthesia; General anesthetic drugs; Genetic; Goals; Inflammation; Inhalant dose form; Irritants; Isoflurane; Modeling; Operative Surgical Procedures; Pain; Pharmaceutical Preparations; Postoperative Pain; Property; Role; Site; TRP channel; Testing; Transmembrane Domain; Unconscious State; afferent nerve; analog; chemical group; desflurane; design; enantiomer; irritation; mustard oil; pain receptor; receptor

DESCRIPTION (provided by applicant): General anesthetics (GAs) are a diverse group of chemicals with the shared ability to induce reversible unconsciousness. Although these drugs have revolutionized surgery they are still less than ideal. In particular, many of these drugs provoke pain/irritation upon administration. Inhalant GAs can provoke airway irritation and sympathetic activation. Moreover, there is emerging evidence that noxious anesthetics have the potential to exacerbate post-surgical pain and inflammation. Approximately 200 million surgeries are performed worldwide each year, and therefore, understanding how GAs interacts with TRP channels is highly desirable. Our previous data show that desflurane/isoflurane excites sensory nerves by selectively activating the "mustard-oil" receptor (TRPA1). A major goal of this proposal is to elucidate amino acids in TRPA1 that are critical for anesthetic agonism. We hypothesize that desflurane binds to a cavity between the 5th and 6th transmembrane domains of TRPA1. We will explore 2 specific aims. (1) Using a genetic approach we will determine the putative sites on TRPA1 necessary for activation by desflurane. Our preliminary data reveal a critical role for transmembrane 5 of TRPA1 in anesthetic sensing, and thus we will focus on amino acids in this region. Further, we will model docking of desflurane to TRPA1 to validate our genetic/functional data and verify that desflurane directly interacts with TRPA1. (2) We will test the ability of desflurane analogs (including enantiomers) to activate TRPA1. These analogs are designed to probe the steric and electronic properties of the methoxy group in desflurane predicted to specifically interact with TRPA1. PUBLIC HEALTH RELEVANCE: Each year more than 200 million surgeries are performed worldwide under general anesthesia. Understanding the complete side effects of anesthetics is therefore an important objective. Many anesthetics are chemical irritants, provoking airways irritation and pain upon administration. In this proposal, we aim to identify the mechanisms by which these anesthetics activate pain receptors.

描述（由申请人提供）：全身麻醉药（GA）是一组不同的化学品，具有诱导可逆性意识丧失的共同能力。虽然这些药物已经彻底改变了外科手术，但它们仍然不够理想。特别地，这些药物中的许多在施用时引起疼痛/刺激。吸入性GA可引起气道刺激和交感神经激活。此外，有新的证据表明，有毒麻醉剂有可能加剧术后疼痛和炎症。全球每年约有2亿例手术，因此，了解GAs如何与TRP通道相互作用是非常必要的。我们以前的数据表明，地氟烷/异氟烷通过选择性激活“芥子油”受体（TRPA 1）来兴奋感觉神经。该提案的一个主要目标是阐明TRPA 1中对麻醉激动作用至关重要的氨基酸。我们假设地氟烷与TRPA 1的第5和第6跨膜结构域之间的空腔结合。我们将探讨两个具体目标。(1)使用遗传学方法，我们将确定TRPA 1上被地氟烷激活所必需的推定位点。我们的初步数据揭示了TRPA 1的跨膜5在麻醉感知中的关键作用，因此我们将专注于该区域的氨基酸。此外，我们将模拟地氟烷与TRPA 1的对接，以验证我们的遗传/功能数据，并验证地氟烷与TRPA 1直接相互作用。(2)我们将测试地氟烷类似物（包括对映体）激活TRPA 1的能力。这些类似物旨在探测地氟烷中甲氧基的空间和电子性质，预计该甲氧基与TRPA 1特异性相互作用。 公共卫生相关性：每年全世界有超过2亿例手术在全身麻醉下进行。因此，了解麻醉剂的全部副作用是一个重要的目标。许多麻醉剂是化学刺激物，在施用时引起气道刺激和疼痛。在这个提议中，我们的目标是确定这些麻醉剂激活疼痛受体的机制。