Conopeptides as Topical Local Anesthetics for Burn Pain

本提案的目标是开发芋螺毒素作为局部局部麻醉剂用于治疗烧伤疼痛。严重的烧伤通常会导致剧烈的疼痛，目前用阿片类药物治疗。最近，一些研究表明，局部麻醉剂的局部治疗，阻断钠通道，可能会提供一些疼痛缓解。Conopeptide mu-O-MrVIB是一种从海洋蜗牛Conus marmoreus中分离的肽类神经毒素，已被证明是一种非常有效和选择性的神经元钠通道阻断剂。我们的初步结果表明，合成MrVIB具有局部麻醉效果的持续时间长，可能代表一种新的治疗严重烧伤疼痛。在第一阶段的拟议研究中，我们计划优化生产mu-O-MrVIB和生产三个额外的同源conopeptides分离的Cognetix从不同的芋螺物种。我们将通过在大鼠皮肤退缩试验中测定其体内效力、起效时间和作用持续时间来评估这些芋头肽的功效。此外，我们还将确定它们对心血管和CNS系统的影响。我们还计划在烧伤动物模型中开始评估选定的μ-O-芋螺肽。建议的商业应用：在美国每年发生的200万起烧伤事故中，6万至20万人受伤严重，需要住院治疗。病人需要一种比鸦片类药物更有效、副作用更少的减轻严重和持续性烧伤疼痛的产品。我们建议mu-O-芋螺肽代表一类新的长效局部麻醉药，可能服务于这一适应症。据估计，全球局部麻醉剂的销售总额约为5亿美元。

The goal of this proposal is to develop conotoxins as topical local anesthetics for treatment of burn pain. Severe burn injuries often result in intense pain which is currently treated with opiates. Recently, a few studies have suggested that topical treatment with local anesthetics , which block sodium channels, may provide some pain relief. Conopeptide mu-O-MrVIB, a peptide neurotoxin isolated from marine snail Conus marmoreus, has been shown to be a very potent and selective neuronal sodium channel blocker. Our preliminary results indicate that synthetic MrVIB possesses a local anesthetic effect of long duration that may represent a novel therapy for severe burn pain. In phase I of the proposed research, we plan to optimize production of mu-O-MrVIB and to produce three additional homologous conopeptides isolated by Cognetix from different Conus species. We will evaluate the efficacy of these conopeptides by determining their in vivo potency, time of onset and duration of action in a rat skin flinch assay. In addition, we will determine their effects on cardiovascular and CNS systems. We also plan to initiate evaluation of selected mu-O- conopeptides in an animal model of bum injury. PROPOSED COMMERCIAL APPLICATIONS: Of the 2 million burn accidents each year in the U.S., 60,000 to 200,000 injuries are severe enough to require hospitalization. A product which relieved severe and persistent burn pain with greater efficacy and fewer side effects than opiates would be demanded by patients. We propose that mu-O-conopeptides represent a new class of long-acting local anesthetics which may serve this indication. Estimates are that worldwide sales of local anesthetics total about $500 million.