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面疼痛，这大大增加了 降低生活质量。口面疼痛的常见主诉是来自机械刺激。当前治疗 对于各种口面疼痛条件是有限的。医生建议饮食干预管理 然而，人们对饮食如何缓解疼痛却知之甚少。它 饮食也可能导致慢性口面疼痛，因为ω-6多不饱和脂肪酸 脂肪酸（PUFA），如亚油酸（LA）和花生四烯酸（AA），是必需的PUFA，其由 饮食摄入和已知的pronociceptive。我们的数据表明，小鼠喂养8周高欧米茄-6 饲料（H6 D）显示背根神经节（DRG）中LA和AA的质膜水平增加， 后爪对机械刺激的敏感性。LA、AA及其代谢产物可能通过以下途径调节伤害性感受 初级传入伤害感受器中通道的激活。更具体地，LA和AA从膜上裂解 磷脂酶A2（PLA 2）同工酶，在那里它们可以被氧化成生物活性代谢物， 可以激活初级传入伤害感受器上表达的瞬时受体电位通道等靶标。 因此，从细胞膜释放的ω-6多不饱和脂肪酸可能在调节伤害感受器中起关键作用 活动和疼痛。然而，目前尚不清楚H6 D是否是受神经支配的口面组织中的疼痛风险因素。 三叉神经节（TG）传入神经元。考虑到TG和TG之间不同的分子表达差异， DRG神经元，H6 D作为口面疼痛的危险因素的作用的研究必须在TG系统中进行。 我们的初步数据表明，喂食H6 D 8周的小鼠表现出显著增加的口面部 对机械刺激细丝的反应。在知识上存在很大差距， 其中ω-6脂肪的饮食摄入是口面疼痛的危险因素。根据最近的研究和 我们的初步数据，我们建议测试的核心假设，增加饮食ω-6多不饱和脂肪酸 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 通过神经元磷脂酶A2的炎性和神经性口面疼痛。研究饮食的作用 在口面疼痛中，我们将1）检查H6 D在感觉神经元敏化中的作用，2）确定H6 D是否是 口面疼痛病症模型中的原伤害感受风险因子，和3）鉴定PLA 2同工酶介导的H6 D- 对机械伤害性行为的诱导作用。其科学意义是基于一种创新的 这一假说可能导致口面疼痛状况的新的治疗干预。虽然膳食 虽然对许多疾病提出了建议，但它们代表了管理口面疼痛的新方法。 这些饮食干预可以提供相当大的临床转化应用，成本相对较低， 不良影响同样重要的是，技术和研究经验包括一个优秀的培训 我未来作为一名学术临床科学家的职业生涯的工具。

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.