Effects of a High Omega-6 Diet on Orofacial Allodynia

高 Omega-6 饮食对口面部异常性疼痛的影响

• 批准号: 10649595
• 负责人: Meilinn Tram
• 金额: $ 5.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649595
• 关键词: Acids; Address; Adjuvant; Adult; Adverse effects; Afferent Neurons; Analgesics; Arachidonic Acids; Behavior; Biochemical; Cardiovascular Diseases; Cell membrane; Cellular Membrane; Chronic; Computers; Data; Development; Diabetes Mellitus; Diet; Dietary Intervention; Dietary intake; Disease; Disease Management; Dose; Electrophysiology (science); Essential Fatty Acids; Exhibits; Filament; Foundations; Frequencies; Future; Hypersensitivity; Inflammatory; Isoenzymes; Knowledge; Linoleic Acids; Lipids; Maintenance; Maxilla; Measures; Mechanics; Mediating; Membrane; Membrane Lipids; Methods; Migraine; Modeling; Molecular; Mus; Nerve; Neurons; Neuropathy; Nociception; Nociceptors; Omega-6 Fatty Acids; Orofacial Pain; Pain; Pain Disorder; Peripheral; Phenotype; Phospholipase A2; Physicians; Play; Polyunsaturated Fatty Acids; Population; Pre-Clinical Model; Preparation; Property; Proteins; Quality of life; Recommendation; Research; Risk; Risk Factors; Role; Scientist; Skin; Spinal; Spinal Ganglia; Structure of trigeminal ganglion; Substance Use Disorder; System; TRP channel; Techniques; Testing; Therapeutic; Tissues; Training; Trigeminal Neuralgia; Trigeminal System; Vertebral column; afferent nerve; allodynia; behavioral pharmacology; behavioral response; career; chronic constriction injury; chronic pain; chronic pain management; clinical translation; cost; dietary; dorsal horn; experience; inflammatory pain; inhibitor; innovation; insight; lipidomics; mechanical behavior; mechanical stimulus; nerve supply; neuronal excitability; novel; novel strategies; novel therapeutic intervention; novel therapeutics; orofacial; painful neuropathy; pharmacologic; side effect; small hairpin RNA; spontaneous pain; translational applications

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.

抽象的 据估计，多达 25% 的成年人患有慢性口面部疼痛，这极大地影响了 降低生活质量。口面部疼痛的常见症状是机械刺激引起的。目前的治疗方法 对于各种口面部疼痛的情况是有限的。医生建议通过饮食干预来管理 心血管疾病和糖尿病等疾病，但人们对饮食如何减轻疼痛知之甚少。它 饮食也可能会导致慢性口面部疼痛，因为 omega-6 多不饱和脂肪 亚油酸 (LA) 和花生四烯酸 (AA) 等多不饱和脂肪酸 (PUFA) 是必需的多不饱和脂肪酸，受 饮食摄入并已知具有促伤害性。我们的数据表明小鼠喂食 8 周高 omega-6 饮食（H6D）表现出背根神经节（DRG）中 LA 和 AA 质膜水平增加，并且增加 后爪对机械刺激敏感。 LA、AA 及其代谢物可以通过调节伤害感受 初级传入伤害感受器通道的激活。更具体地说，LA 和 AA 从膜上裂解 被磷脂酶 A2 (PLA2) 同工酶氧化成具有生物活性的代谢物， 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，细胞膜释放 omega-6 PUFA 可能在调节伤害感受器方面发挥关键作用 活动和疼痛。然而，目前尚不清楚 H6D 是否是由 H6D 神经支配的口面部组织的疼痛危险因素。 三叉神经节（TG）传入神经元。鉴于 TG 和 TG 之间明显的分子表达差异 DRG 神经元，关于 H6D 作为口面部疼痛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 H6D 8 周的小鼠表现出口面部显着增加 对机械刺激丝的反应能力。对于其机制的认识存在很大差距 饮食中摄入 omega-6 脂质是口面部疼痛的危险因素。根据最近的研究和 根据我们的初步数据，我们建议检验增加膳食 omega-6 PUFA 的中心假设 在临床前模型中使三叉神经感觉神经元敏感并增加伤害感受行为 通过神经元磷脂酶 A2 缓解炎症性和神经性口面部疼痛。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 口面部疼痛模型中的伤害感受危险因素，3) 识别 PLA2 同工酶介导的 H6D- 对机械伤害感受行为的诱导作用。科学意义基于创新 假设并可能导致口面部疼痛的新治疗干预措施。虽然节食 针对许多疾病提出了建议，它们代表了治疗口面部疼痛的新方法。 这些饮食干预措施可能以相对较低的成本和较低的成本提供大量的临床转化应用。 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 我未来作为学术临床医生科学家的职业生涯的工具。