Mechanisms for Omega-6 Modulation of Primary Afferent Nociceptors

Omega-6 调节初级传入伤害感受器的机制

• 批准号: 10242063
• 负责人: Kenneth M Hargreaves
• 金额: $ 33.91万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242063
• 关键词: Ablation; Afferent Neurons; Amyloid beta-Protein; Analgesics; Animals; Arachidonic Acids; Autoimmune Diseases; Behavioral; Biological; Cardiovascular Diseases; Cell membrane; Cellular Membrane; Chemicals; Cutaneous; Data; Dependence; Diabetes Mellitus; Diet; Dietary intake; Electrophysiology (science); Exhibits; Exposure to; Fiber; Gene Expression; Goals; Healthcare; High Fat Diet; Image; Isoenzymes; Knowledge; Lead; Lipids; Measures; Mechanics; Mechanoreceptors; Mediating; Medical; Membrane Lipids; Methodology; Mus; Nerve; Neurons; Nociception; Nociceptors; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Oxides; Pain; Pain Disorder; Patients; Persistent pain; Phospholipase A2; Phospholipids; Play; Polyunsaturated Fatty Acids; Property; Public Health; Randomized; Recommendation; Reporting; Research; Risk Factors; Role; Sensory; Sex Differences; Skin; System; TRP channel; Tamoxifen; base; chronic painful condition; clinical development; dietary; drug development; experimental study; inhibitor/antagonist; ketogenic diet; knock-down; lipidomics; non-opioid analgesic; novel; novel strategies; pain relief; peripheral pain; programs; receptor; response; secondary analysis; side effect; small hairpin RNA; transcriptome sequencing

Although medical recommendations about diet are made for cardiovascular disease and diabetes, this is not the case for most pain disorders. However, diet could be a risk factor for chronic pain conditions as linoleic (LA) and arachidonic (AA) acid are essential omega-6 polyunsaturated fatty acids (ω-6 PUFA), where their cell membrane levels are regulated by dietary intake. Importantly, the oxidized metabolites of LA or AA have potent biological actions in activating targets such as transient receptor potential (TRP) channels, which are expressed on primary afferent nociceptors. Thus, the incorporation and release of omega-6 PUFAs from cellular membranes plays a key role in regulating nociceptor activities, including pain. Our central hypothesis is that dietary omega-6 PUFA-induced increase in nociceptor activities is mediated by the activity of PLA2 subtypes, resulting in activation of neuronal receptors/channels. This is supported by mulitple lines of preliminary data using a robust set of behavioral, electrophysiologic, imaging, and RNAseq methodologies. Aim 1. Determine which subclasses of DRG afferents mediate HFD-induced nociception. We will use six Cre+/--DTA+/- mouse lines generated for the conditional ablation of neurons expressing Nav1.8 (all nociceptors), TrpV1 (nociceptors), CGRP (peptidergic nociceptors), Mrgprd (non-peptidergic nociceptors), TrkC (Aβ low threshold mechanoreceptors (LTMR)) and TrkB (Aδ LTMR fibers) (Table 1). Mice will be fed a High omega-6 PUFA diet (H6D) or a low omega-6 diet (L6D) and behavioral, electrophysiologic and lipidomic outcomes will be measured. (Popular ketogenic diets are different as they are low omega-6 PUFA) Aim 2: Determine the effects of H6D on DRG neuronal membrane lipid content and PLA2 isozyme(s) expression and mechanisms for regulating nociceptor activities. Aim 3: Determine whether switching to a L6D or to a high omega-3:Low omega 6 diet reverses the effects of a H6D on nociception. This project has substantial scientific and medical significance as the central hypothesis predicts that H6D will predispose patients to chronic pain conditions and offers new targets for analgesic drug development.

尽管有关饮食的医学建议是针对心血管疾病和糖尿病提出的，但这不是 大多数疼痛障碍的情况。但是，饮食可能是慢性疼痛状况的危险因素 （LA）和蛛网膜（AA）酸是必需的Omega-6多不饱和脂肪酸（ω-6 PUFA），其中它们的细胞 膜水平受饮食摄入的调节。重要的是，LA或AA的氧化代谢物具有有效 激活靶标（例如瞬态接收器电位（TRP）通道）的生物学作用， 以初级传入的伤害感受器表示。那是从 细胞膜在调节伤害感受活动（包括疼痛）中起关键作用。我们的中心假设是 饮食中的omega-6 PUFA诱导的伤害感受器活动的增加是由PLA2的活性介导的 亚型，导致神经元接收器/通道的激活。这是由Mulitple线的支持 使用一组强大的行为，电生理，成像和RNASEQ方法的鲁棒性数据。 AIM 1。确定哪些DRG传入的亚类介导HFD诱导的伤害感受。我们将使用六个 CRE+/ - DTA +/-鼠标线生成，用于表达NAV1.8神经元的条件消融（全部） 伤害感受器），TRPV1（伤害感受器），CGRP（肽性伤害感受器），MRGPRD（非肽性伤害感受器）， TRKC（Aβ低阈值机理感受器（LTMR））和TRKB（AδLTMR纤维）（表1）。小鼠将被喂食 高omega-6 PUFA饮食（H6D）或低omega-6饮食（L6D）以及行为，电生理学和脂肪组 结果将被衡量。 （流行的生酮饮食不同，因为它们是低omega-6 PUFA） 目标2：确定H6D对DRG神经元膜脂质含量和PLA2同工酶的影响（S） 调节伤害感受器活性的表达和机制。 AIM 3：确定切换到L6D还是高omega-3：低欧米茄6饮食会逆转A的影响 H6D受伤害感受。 该项目具有实质性的科学和医学意义，因为H6D将会提出中心假设的预测 使患者容易患慢性疼痛状况，并为镇痛药的发育提供了新的靶标。