Mechanisms for Omega-6 Modulation of Primary Afferent Nociceptors

尽管关于心血管疾病和糖尿病的饮食有医学建议，但这并不是 大多数疼痛障碍都是这样的。然而，饮食可能是慢性疼痛的危险因素，如亚油酸。 (LA)和花生四烯酸(AA)是必需的omega-6多不饱和脂肪酸(ω-6PUFA)，它们的细胞 膜水平受饮食摄入量的调节。重要的是，LA或AA的氧化代谢产物具有很强的 激活靶标的生物学作用，如瞬时受体电位(Trp)通道，这些通道是 在初级传入伤害性感受器上表达。因此，omega-6多不饱和脂肪酸的掺入和释放 细胞膜在调节包括疼痛在内的伤害性感受器活动中起着关键作用。我们的中心假设是 膳食omega-6多不饱和脂肪酸诱导的伤害性感受器活性增加是由PLA2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 使用一套稳健的行为、电生理、成像和RNAseq方法的初步数据。 目的1.确定哪些DRG传入亚类介导HFD诱导的伤害性感受。我们将使用六个 Cre/--DTA/-为条件消融表达Nav1.8(ALL)神经元而产生的小鼠系 伤害性感受器)、TRPV1(伤害性感受器)、CGRP(肽能伤害性感受器)、MRGPRD(非肽能性伤害性感受器)、 TrkC(Aβ低阈值机械感受器)和TrkB(Aδ低阈值机械感受器纤维)(表1)。小鼠将被喂以一种 高omega-6多不饱和脂肪酸饮食(H6D)或低omega-6饮食(L6D)与行为、电生理和脂类 结果将被衡量。(流行的生酮饮食是不同的，因为它们是低omega-6多不饱和脂肪酸) 目的：研究H6D对大鼠背根神经节细胞膜脂含量及PLA2同工酶的影响(S) 表达和调控伤害性感受器活动的机制。 目标3：确定转换为L6D或高omega-3：低omega-6饮食是否逆转了 H6D关于伤害性感受。 该项目具有重大的科学和医学意义，因为中心假说预测H6D将 使患者容易受到慢性疼痛的影响，并为止痛药的开发提供新的靶点。

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.