FABPs: Novel Roles in Pain and Inflammation

描述（由申请人提供）：慢性疼痛每年造成数十亿美元的生产力损失和医疗费用。目前的治疗策略在人群中受到部分疗效的影响，导致疼痛缓解不足。此外，许多长期使用的镇痛药（如吗啡或奥施康定）虽然实际上有效，但会导致耐受性和成瘾。因此，为非成瘾性镇痛药的开发确定新的药物靶点是势在必行的。生物活性脂质，如内源性大麻素和n -酰基乙醇胺（NAEs）调节整个神经系统的伤害感觉。临床前研究表明，调节内源性大麻素和NAE分解代谢是治疗疼痛的一种有吸引力的策略，也没有精神药物作用。最近，我们发现脂肪酸结合蛋白（FABPs）是第一个调节

DESCRIPTION (provided by applicant): Chronic pain accounts for billions of dollars of lost productivity and medical expenses annually. Current treatment strategies suffer from partial efficacy across the population, resulting in inadequate pain relief. Furthermore, many chronically administered analgesics (e.g., morphine or oxycontin), while actually effective, lead to tolerance and addiction. Consequently, it is imperative to identify novel drug targets for the development of non-addictive analgesics. Bioactive lipids such as endocannabinoids and N-acylethanolamines (NAEs) regulate nociception throughout the nervous system. Preclinical studies suggest that modulation of endocannabinoid and NAE catabolism represents an attractive strategy for the treatment of pain that is also devoid of psychotropic effects. Recently we identified fatty acid binding proteins (FABPs) as the first intracellular carriers that regulate endocannabinoid and NAE transport and inactivation in vitro. To date, it is not known whether FABPs regulate the endocannabinoid and NAE tone in vivo. The central goals of this project are to determine whether FABPs regulate endocannabinoid and NAE signaling and inactivation in vivo and to ascertain whether inhibition of FABPs produces endocannabinoid- and NAE-mediated antinociception. We will accomplish this by first determining whether ablation of FABPs reduces nociception in models of inflammatory pain. We will then identify the FABP subtypes that modulate pain and inflammation through a combination of complementary approaches: pharmacological manipulation and transgenic FABP knockout mice lacking specific subsets of FABPs. In the second aim of this proposal, we will employ mass spectrometry-based lipidomics to determine whether FABPs regulate endocannabinoid and NAE levels in vivo at relevant anatomical sites and consequently whether FABP inhibition produces endocannabinoid- and NAE-mediated analgesia. Finally, in the last aim, we will examine changes in peripheral cytokine and prostaglandin levels that accompany FABP inhibition and determine whether FABP inhibition alters the sensitization of nociceptive neurons. In summary, this study will identify FABPs as novel proteins that regulate nociception and inflammation and will evaluate the roles for individual FABPs in endocannabinoid and NAE inactivation in vivo. By ascribing novel roles to FABPs in nociception, this work will provide a foundation for the development of future FABP targeting therapeutics that may lead to improved analgesics.