Mechanisms for Omega-6 Modulation of Primary Afferent Nociceptors

虽然关于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。然而，饮食可能是慢性疼痛的危险因素， (LA)和花生四烯酸（AA）是必需的ω-6多不饱和脂肪酸（ω-6 PUFA）， 膜水平由饮食摄入调节。重要的是，LA或AA的氧化代谢物具有有效的 在激活靶点如瞬时受体电位（TRP）通道中的生物学作用， 在初级传入伤害感受器上表达。因此，ω-6多不饱和脂肪酸的掺入和释放， 细胞膜在调节包括疼痛的伤害感受器活动中起关键作用。我们的核心假设是 饮食ω-6 PUFA诱导的伤害感受器活性增加是由PLA 2的活性介导的， 亚型，导致神经元受体/通道的激活。这是由多行支持的 使用一组强大的行为、电生理、成像和RNAseq方法学的初步数据。 目标1.确定哪些DRG传入神经亚类介导HFD诱导的伤害性感受。我们将使用六个 产生Cre+/--DTA+/-小鼠系，用于表达Nav1.8的神经元的条件性消融（所有 伤害感受器），TrpV 1（伤害感受器），CGRP（肽能伤害感受器），Mrgprd（非肽能伤害感受器）， TrkC（Aβ低阈值机械感受器（LTMR））和TrkB（Aδ LTMR纤维）（表1）。小鼠将被喂食 高omega-6 PUFA饮食（H6 D）或低omega-6饮食（L 6D）以及行为、电生理和脂质组学 将衡量成果。（流行的生酮饮食是不同的，因为它们是低omega-6 PUFA） 目的2：观察H6 D对DRG神经元膜脂含量及PLA 2同工酶的影响。 表达和调节伤害感受器活性的机制。 目标3：确定转换为L 6D或高omega-3：低omega-6饮食是否会逆转 H6 D对伤害感受的影响 该项目具有重大的科学和医学意义，因为中心假设预测H6 D将 使患者易患慢性疼痛疾病，并为镇痛药物开发提供了新的靶点。

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.