TRPA1 and General Anesthetics

描述(申请人提供)：全麻药(GAS)是一组不同的化学物质，具有诱导可逆性意识丧失的共同能力。尽管这些药物给外科带来了革命性的变化，但它们仍然不够理想。特别是，这些药物中的许多在给药时会引起疼痛/刺激。吸入气体会引起呼吸道刺激和交感神经激活。此外，有新的证据表明，有毒麻醉药有可能加剧手术后的疼痛和炎症。全世界每年大约有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。我们先前的数据显示地氟烷/异氟醚通过选择性地激活“芥子油”受体(TRPA1)来兴奋感觉神经。这项建议的一个主要目标是阐明TRPA1中对麻醉兴奋至关重要的氨基酸。我们假设地氟烷结合在TRPA1的第5和第6跨膜结构域之间的一个空腔上。我们将探索两个具体目标。(1)利用遗传学方法，我们将确定地氟烷激活TRPA1所需的推测位点。我们的初步数据揭示了TRPA1的跨膜5在麻醉感觉中的关键作用，因此我们将重点关注这一区域的氨基酸。此外，我们将模拟地氟烷与TRPA1的对接，以验证我们的遗传/功能数据，并验证地氟烷与TRPA1直接相互作用。(2)检测地氟烷类似物(包括对映体)激活TRPA1的能力。这些类似物旨在探索地氟烷中甲氧基的空间和电子性质，预计地氟醚将与TRPA1特异地相互作用。 公共卫生相关性：全世界每年在全身麻醉下进行的手术超过2亿例。因此，了解麻醉药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，给药后会引起呼吸道刺激和疼痛。在这项提案中，我们的目标是确定这些麻醉剂激活疼痛受体的机制。

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.