Effects of a High Omega-6 Diet on Orofacial Allodynia

摘要 据估计，高达25%的成年人会经历慢性口腔疼痛，这在很大程度上 会降低生活质量。口腔面部疼痛的常见主诉是机械刺激。当前的治疗方法 对于各种口腔面部疼痛情况是有限的。医生建议采取饮食干预措施来管理 心血管疾病和糖尿病等疾病，但人们对饮食如何缓解疼痛知之甚少。它 饮食也可能导致慢性口腔面部疼痛，如omega-6多不饱和脂肪 酸(PUFA)，如亚油酸(LA)和花生四烯酸(AA)，是必需的PUFA，受 饮食摄入量和已知的促伤害性。我们的数据表明，喂食8周高价omega-6的小鼠 饮食(H6D)使背根神经节(DRG)质膜LA和AA水平升高 后爪对机械刺激的敏感性。LA、AA及其代谢物可能通过 初级传入伤害性感受器通道的激活。更具体地说，LA和AA是从膜上切割出来的 通过磷脂酶A2(PLA2)同工酶，它们可以被氧化成具有生物活性的代谢物，这 可以激活表达在初级传入伤害性感受器上的瞬时受体电位通道等靶点。 因此，从细胞膜中释放omega-6多不饱和脂肪酸可能在调节伤害性感受器中起关键作用。 活动和疼痛。然而，H6D是否是口腔面部组织中的疼痛风险因素尚不清楚。 三叉神经节(TG)传入神经元。鉴于Tg和Tg之间存在明显的分子表达差异 对于DRG神经元，必须在TG系统中研究H6D作为口面部疼痛的危险因素的作用。 我们的初步数据显示，喂食H6D 8周的小鼠口腔面部显著增加 对机械刺激细丝的反应性。关于这种机制，人们的认识存在很大差距。 饮食中摄入omega-6脂类是口腔面部疼痛的危险因素。基于最近的研究和 我们的初步数据，我们建议检验饮食中omega-6 PUFAs增加的中心假设 致敏三叉神经感觉神经元和增加伤害性行为的临床前模型 神经元型磷脂酶A2引起的炎症性和神经性口面部疼痛。为了研究饮食的作用 关于口面部疼痛，我们将1)检查H6D在感觉神经元敏化中的作用，2)确定H6D是否 口腔面部疼痛模型中的致痛危险因素，以及3)鉴定PLA2同工酶介导的H6D- 机械伤害性行为的诱导效应。其科学意义是基于一种创新的 假说，并可能导致口腔面部疼痛的新的治疗干预措施。虽然在饮食上 针对许多疾病提出了建议，它们代表了一种管理口腔面部疼痛的新方法。 这些饮食干预措施可以以相对较低的成本和 不良影响。同样重要的是，技术和研究经验构成了出色的培训 为我未来的职业生涯提供工具，成为一名学术临床医生兼科学家。

ABSTRACT Chronic orofacial pain is estimated to be experienced by up to 25% of the adult population, which greatly decreases quality of life. A common complaint of orofacial pain is from mechanical stimuli. Current treatments for various orofacial pain conditions are limited. Physicians recommend dietary interventions for management of disorders such as cardiovascular disease and diabetes, but less is known about how diet may alleviate pain. It is possible that diet may also contribute to chronic orofacial pain conditions, as omega-6 polyunsaturated fatty acids (PUFAs) such as linoleic acid (LA) and arachidonic acid (AA), are essential PUFAs that are regulated by dietary intake and known to be pronociceptive. Our data demonstrate that mice fed an 8-week high omega-6 diet (H6D) exhibit increased plasma membrane levels of LA and AA in dorsal root ganglia (DRG) and increased hindpaw sensitivity to mechanical stimuli. LA, AA, and their metabolites could be regulating nociception through activation of channels in primary afferent nociceptors. More specifically, LA and AA are cleaved from membranes by phospholipase A2 (PLA2) isozymes where they can be oxidized into biologically active metabolites, which can activate targets like transient receptor potential channels expressed on primary afferent nociceptors. Therefore, the release of omega-6 PUFAs from cellular membranes may play a key role in regulating nociceptor activities and pain. However, it is unknown whether a H6D is a pain risk factor in orofacial tissues innerved by trigeminal ganglia (TG) afferent neurons. Given the distinct molecular expression differences between TG and DRG neurons, studies on the role of H6D as a risk factor for orofacial pain must be conducted in the TG system. Our preliminary data demonstrates that mice fed a H6D for 8-weeks exhibit significantly increased orofacial responsiveness to mechanical stimuli filaments. There is a large gap in knowledge as to the mechanisms by which dietary intake of omega-6 lipids serves as a risk factor for orofacial pain. Based on recent studies and our preliminary data, we propose to test the central hypothesis that increased dietary omega-6 PUFAs sensitize trigeminal sensory neurons and increase nociceptive behaviors in preclinical models of inflammatory and neuropathic orofacial pain via neuronal phospholipase A2. To investigate the role of diet on orofacial pain, we will 1) examine the role of H6D in sensitization of sensory neurons, 2) determine if H6D is a pronociceptive risk factor in models of orofacial pain conditions, and 3) identify PLA2 isozymes mediated H6D- induced effects on mechanical nociceptive behaviors. The scientific significance is based on an innovative hypothesis and may lead to novel therapeutic interventions for orofacial pain conditions. Although dietary recommendations are made for many diseases, they represent a new approach for managing orofacial pain. These dietary interventions may offer considerable clinical translational applications with relatively low cost and adverse effects. Equally important, techniques and research experiences comprise an outstanding training vehicle for my future career as an academic clinician-scientist.