FABPs: Novel Roles in Pain and Inflammation

慢性疼痛影响三分之一的成年人口，并带来巨大的社会和经济负担。 目前的治疗方法通常包括非类固醇抗炎药，这些药物患有有限的 药效和阿片类药物，它们具有显著的成瘾倾向。因此，迫切需要 确定新的药物靶点，以促进非成瘾性止痛药的开发，以治疗慢性疼痛。这个 内源性大麻素脱氧核糖核酸(AEA)激活大麻素受体，而相关脂质 棕榈酰乙醇胺是过氧化体增殖物激活受体α(PPARα)的激动剂。 AEA激活大麻素受体或PPARα受体可减轻疼痛，从而定位 调制AEA和PEA信号是开发止痛药的一个有吸引力的策略。我们的团队 最近发现脂肪酸结合蛋白5(FABP5)是AEA和PEA的细胞内载体，其 抑制可提高AEA和PEA水平，并产生止痛作用。除了在大脑中的表达外，FABP5 富含外周感觉神经元和巨噬细胞，定位于促进疼痛的细胞群。 瞬时受体电位香草样受体1(TRPV1)是一种外周感觉表达的离子通道 炎症性热痛觉过敏所必需的神经元，并与不同的疼痛条件有关 人类。在这里，我们将测试FABP5抑制增强AEA和PEA信号通路的新假设。 感觉神经元通过减弱TRPV1的敏化和上调抑制疼痛 发炎。特定目标1将检验这样一个假设，即感觉神经元中FABP5的基因缺失揭开了面纱 AEA和PEA介导的镇痛作用及其在巨噬细胞中的缺失通过减轻疼痛来抑制疼痛 巨噬细胞的促炎输出。要询问这些效应背后的机制，具体来说 目标2将验证TRPV1敏化被抑制的假设，TRPV1敏化是一种放大炎性疼痛的过程 在缺乏FABP5的小鼠中。我们将进一步确定这一效应是否由增强的AEA和PEA介导 感觉神经元中的信号。具体目标3将检验FABP5对TRPV1必不可少的假设 在慢性炎症期间表达上调。具体地说，我们将研究潜在的分子机制 FABP5对感觉神经元TRPV1上调的调控如果成功，这项工作的结果将是 促进我们对FABP5、AEA和PEA对疼痛调制的理解，并将为 针对FABP5的镇痛剂的研究进展。

Chronic pain affects one third of the adult population and presents a massive societal and economic burden. Current treatment approaches typically include non-steroidal anti-inflammatory drugs that suffer from limited efficacy and opioids, which possess significant addiction liability. Consequently, there is an urgent need to identify novel drug targets to facilitate the development of non-addictive analgesics to treat chronic pain. The endocannabinoid anandamide (AEA) activates cannabinoid receptors while the related lipid palmitoylethanolamide (PEA) serves as an agonist at peroxisome proliferator-activated receptor alpha (PPARα). Activation of cannabinoid receptors by AEA or PPARα receptors by PEA reduces pain, thus positioning modulation of AEA and PEA signaling as an attractive strategy for the development of analgesics. Our group recently identified fatty acid binding protein 5 (FABP5) as an intracellular carrier for AEA and PEA, whose inhibition elevates AEA and PEA levels and produces analgesia. In addition to its expression in the brain, FABP5 is enriched in peripheral sensory neurons and macrophages, positioning it in cell populations that promote pain. Transient receptor potential vanilloid receptor 1 (TRPV1) is an ion channel expressed in peripheral sensory neurons that is essential for inflammatory thermal hyperalgesia and is implicated in diverse pain conditions in humans. Here, we will test the novel hypothesis that FABP5 inhibition potentiates AEA and PEA signaling in sensory neurons to suppress pain by attenuating the sensitization and upregulation of TRPV1 during inflammation. Specific Aim 1 will test the hypothesis that genetic deletion of FABP5 in sensory neurons unmasks analgesic effects mediated by AEA and PEA while its deletion in macrophages suppresses pain by attenuating the pro-inflammatory output of macrophages. To interrogate the mechanisms underlying these effects, Specific Aim 2 will test the hypothesis that TRPV1 sensitization, a process that amplifies inflammatory pain, is suppressed in mice lacking FABP5. We will further determine whether this effect is mediated by augmented AEA and PEA signaling in sensory neurons. Specific Aim 3 will test the hypothesis that FABP5 is essential for TRPV1 upregulation during chronic inflammation. Specifically, we will investigate the molecular mechanisms underlying the control of TRPV1 upregulation by FABP5 in sensory neurons. If successful, the outcome of this work will advance our understanding of pain modulation by FABP5, AEA, and PEA, and will provide a foundation for the development of analgesics targeting FABP5.