Mechanism of prostatic acid phosphatase-mediated analgesia

描述(由申请人提供)： 慢性疼痛在美国是一种常见的医疗投诉，超过25%的成年人报告了这一现象。它的治疗成本也非常高，并因失去工作时间和生产力而给社会带来额外的经济负担。目前治疗慢性疼痛的方法往往是无效的，而且有危险的副作用。需要进一步了解疼痛的传递，以便有新的治疗策略来治疗这种虚弱的疾病。我的长期目标是增加我们对神经系统内疼痛传递的了解，并提供一种潜在的治疗疼痛的新方法。我们最近发现一种名为前列腺酸性磷酸酶(PAP)的磷酸酶存在于痛觉神经元中。将该蛋白的一种可溶形式注射到脊髓中可导致持久的止痛，而该蛋白的遗传消除会导致增强的炎性疼痛反应。虽然PAP在生化检测中可以产生止痛化合物腺苷和大麻素，但PAP介导的镇痛机制尚不清楚。这一建议的具体目的是：第一，测试PAP是否通过产生止痛分子在体外减少细胞信号；第二，测试PAP是否通过产生止痛分子在体内抑制疼痛；第三，测试PAP介导的镇痛是否由于痛觉神经元神经元兴奋性降低所致。我将使用分子生物学和药理学相结合的方法来研究PAP在体外和活动物中的活性。 公共卫生相关性：了解PAP介导的止痛机制将为开发治疗慢性疼痛的新方法提供机会。

DESCRIPTION (provided by applicant): Chronic pain is a common medical complaint in the United States, reported by over 25% of adults. It is also very costly to treat, and results in additional economic burdens to society through lost work-time and productivity. Current treatments for chronic pain are often ineffective and have dangerous side-effects. Further understanding of pain transmission is needed to allow for new therapeutic strategies to treat this debilitating condition. My long term objectives are to increase our understanding of pain transmission within the nervous system and to provide a potentially novel therapeutic approach for treating pain. We have recently identified that a phosphatase called Prostatic Acid Phosphatase (PAP) is present in pain-sensing neurons. Injection of a soluble form of this protein into the spinal cord results in long-lasting analgesia, while genetic elimination of the protein results in enhanced inflammatory pain responses. The mechanisms of PAPmediated analgesia are unknown, although PAP can produce the analgesic compounds adenosine and cannabinoids in biochemical assays. The specific aims of this proposal are to: first, test if PAP reduces cell signaling in vitro by producing analgesic molecules; second, to test if PAP suppresses pain in vivo by producing analgesic molecules; and third, test if PAP-mediated analgesia is due to decreased neuronal excitability in pain-sensing neurons. I will use a combination of molecular biology and pharmacology to study the activity of PAP in vitro and in live animals. PUBLIC HEALTH RELEVANCE: Understanding the mechanism of PAP-mediated analgesia will provide opportunities to develop novel approaches to treat chronic pain.