Department of Entomology and Nematology and University of California Davis Comprehensive Cancer Center, University of California Davis, One Shields Avenue, Davis, California, 95616, USA.
Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California, USA.
Neurotherapeutics. 2020 Jul;17(3):900-916. doi: 10.1007/s13311-020-00916-4.
The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene metabolites of cyclooxygenase and lipoxygenase metabolism, respectively. The analgesic properties of other lipid metabolites are more recently coming to light. Lipid metabolites have been observed to act directly at ion channels and G protein-coupled receptors on nociceptive neurons as well as act indirectly at cellular membranes. Cytochrome P450 metabolism of specifically long-chain fatty acids forms epoxide metabolites, the epoxy-fatty acids (EpFA). The biological role of these metabolites has been found to mediate analgesia in several types of pain pathology. EpFA act through a variety of direct and indirect mechanisms to limit pain and inflammation including nuclear receptor agonism, limiting endoplasmic reticulum stress and blocking mitochondrial dysfunction. Small molecule inhibitors of the soluble epoxide hydrolase can stabilize the EpFA in vivo, and this approach has demonstrated relief in preclinical modeled pain pathology. Moreover, the ability to block neuroinflammation extends the potential benefit of targeting soluble epoxide hydrolase to maintain EpFA for neuroprotection in neurodegenerative disease.
脂质在疼痛信号转导中的作用已经得到充分证实，这是基于数十年关于前列腺素和白三烯代谢物分别引起疼痛和炎症的知识。其他脂质代谢物的镇痛特性最近才被发现。脂质代谢物被观察到直接作用于伤害感受神经元上的离子通道和 G 蛋白偶联受体，以及间接作用于细胞膜上。细胞色素 P450 对特定长链脂肪酸的代谢形成环氧化物代谢物，即环氧脂肪酸 (EpFA)。这些代谢物的生物学作用已被发现可在多种类型的疼痛病理中介导镇痛作用。EpFA 通过多种直接和间接机制发挥作用，限制疼痛和炎症，包括核受体激动剂、限制内质网应激和阻断线粒体功能障碍。可溶性环氧化物水解酶的小分子抑制剂可以稳定体内的 EpFA，这种方法已在临床前模拟疼痛病理模型中证明了缓解作用。此外，阻断神经炎症的能力扩展了靶向可溶性环氧化物水解酶以维持 EpFA 用于神经退行性疾病神经保护的潜在益处。
