Potential mechanisms underlying a relationship between long-chain polyunsaturated fatty acids and overlapping pain conditions in adults

长链多不饱和脂肪酸与成人重叠疼痛状况之间关系的潜在机制

• 批准号: 10025509
• 负责人: Anne E. Sanders
• 金额: $ 19.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025509
• 关键词: Adult; Anabolism; Analgesics; Anti-Anxiety Agents; Antiinflammatory Effect; Anxiety; Arthritis; Chronic; Clinical Trials; Communities; Data; Diabetes Mellitus; Diet; Dietary Intervention; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enzymes; Epidemiologist; Equilibrium; Erythrocytes; Evaluation; FDA approved; Fatty Acid Desaturases; Fibromyalgia; Frequencies; Future; Gene Cluster; Genes; Genetic; Genotype; Goals; Headache; Health; Individual; Inflammation; Inflammatory; Irritable Bowel Syndrome; Light; Linoleic Acids; Liquid Chromatography; Low Back Pain; Malignant Neoplasms; Measures; Mechanics; Mental Depression; Methods; Migraine; Modality; N-3 polyunsaturated fatty acid; Names; Nociception; Nutritional; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Orofacial Pain; Pain; Pain Disorder; Pain management; Participant; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Polyunsaturated Fatty Acids; Process; Psychometrics; Quality of life; Questionnaires; Risk Assessment; Safety; Sensory; Series; Spectrometry; Temporomandibular Joint Disorders; Tension Headache; Testing; Therapeutic; Therapeutic Effect; Woman; Work; alpha-Linolenic Acid; anxiety symptoms; base; chronic pain; chronic painful condition; clinical pain; comorbidity; cost; delta-5 fatty acid desaturase; depressive symptoms; epidemiology study; fatty acid metabolism; genetic variant; high reward; high risk; linoleoyl-CoA desaturase; pain sensitivity; pressure; prevent; prospective; psychologic; psychological distress; risk variant; tandem mass spectrometry

Chronic pain therapies typically target one of three pain pathways: nociception, inflammation or psychological processes. The goal is almost always therapeutic, not preventive. We challenge that premise in light of new evidence that chronic pain can be prevented by targeting all three pathways through diets with a favorable balance of omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs). The anti-inflammatory effects of long-chain (LC) omega-3 (n-3) PUFAs on pain disorders such as arthritis are well recognized. A more recent discovery is that LC n-3 eicosapentaenoic acid and n-3 docosahexaenoic acid metabolites lower concentrations of pronociceptive derivatives, and increase concentrations of antinociceptive and analgesic derivatives. By contrast, omega-6 (n-6) PUFA metabolites have mostly inflammatory and pronociceptive effects. Furthermore, LC n-3 derivatives have anxiolytic effects, alleviating depressive symptoms and anxiety that are often comorbid with chronic pain. The extent to which n-6 and n-3 PUFAs are synthesized into bioactive LC PUFAs by fatty acid desaturase (FADS) enzymes, encoded by the FADS gene cluster, differs according to genetic variability in key enzymes in PUFA metabolism: delta-5 desaturase (FADS1) and delta-6 desaturase (FADS2). Hence gene-PUFA interactions influence the biosynthesis of PUFA derivatives that have putative and therapeutic effects on chronic pain. We plan to study associations between PUFAs and chronic overlapping pain conditions (COPCs) cross-sectionally using existing data and stored erythrocytes from 655 genotyped adult participants (69% women) in our community-based study named “Orofacial Pain: Prospective Evaluation and Risk Assessment” (OPPERA-II). OPPERA-II assessed overlap of temporomandibular disorder, migraine or tension-type headache, fibromyalgia, low back pain, and irritable bowel syndrome. Aim 1 will evaluate associations between pain conditions and erythrocyte concentrations of PUFAs and their metabolites. PUFAs will be quantified using liquid chromatography tandem mass spectrometry. We hypothesize that high concentrations of the n-6 series, and low concentrations the n-3 series are positively associated with occurrence of each pain condition and the total number of COPCs. Aim 2 will evaluate associations between intermediate phenotypes (nociception, anxiety and depression) and PUFA concentrations. Anxiety and depressive symptoms were measured by psychometrically validated questionnaires. Quantitative sensory testing determined sensitivity to three modalities of nociception: blunt pressure pain, mechanical pain, and thermal heat pain. Aim 3 will assess whether FADS genetic variants modify associations of PUFAs and their metabolites with COPCs. This is a high risk project because community-based studies of pain have never assessed PUFAs’ potential for preventing COPCs. Such a study is a necessary pre-requisite for a future clinical trial. The project has potentially high-reward because current treatments for pain are unsatisfactory whereas n-3 PUFAs have excellent safety profiles and can plausibly be used to prevent chronic pain.

慢性疼痛治疗通常针对三种疼痛途径之一：伤害感受、炎症或心理 我们的目标几乎总是治疗性的，而不是预防性的。 有证据表明，可以通过针对所有三种途径的饮食来预防慢性疼痛 omega-6 (n-6) 和 omega-3 (n-3) 多不饱和脂肪酸 (PUFA) 的平衡。 长链 (LC) omega-3 (n-3) PUFA 对关节炎等疼痛疾病的作用已得到广泛认可。 最近的发现是，LC n-3 二十碳五烯酸和 n-3 二十二碳六烯酸代谢物较低 促伤害感受衍生物的浓度，并增加抗伤害感受药和镇痛药的浓度 相比之下，omega-6 (n-6) PUFA 代谢物主要具有炎症性和促伤害性。 此外，LC n-3 衍生物具有抗焦虑作用，可减轻抑郁症状和焦虑。 通常与慢性疼痛共存 n-6 和 n-3 PUFA 合成的程度。 由 FADS 基因簇编码的脂肪酸去饱和酶 (FADS) 产生的生物活性 LC PUFA 有所不同 根据 PUFA 代谢中关键酶的遗传变异性：delta-5 去饱和酶 (FADS1) 和 delta-6 因此，基因-PUFA 相互作用会影响具有去饱和酶（FADS2）的 PUFA 衍生物的生物合成。 我们计划研究 PUFA 与慢性疼痛之间的关联。 使用现有数据和存储的 655 个红细胞进行横截面重叠疼痛状况 (COPC) 在我们名为“口面部疼痛：前瞻性”的社区研究中，对成人参与者（69% 为女性）进行了基因分型 “评估和风险评估”（OPPERA-II）评估了颞下颌疾病的重叠， 偏头痛或紧张型头痛、纤维肌痛、腰痛和肠易激综合症。 评估疼痛状况与 PUFA 及其代谢物的红细胞浓度之间的关联。 PUFA 将使用液相色谱串联质谱法进行定量。 n-6 系列的浓度和 n-3 系列的低浓度呈正相关 目标 2 将评估每种疼痛状况的发生率和 COPC 总数之间的关联。 中间表型（伤害感受、焦虑和抑郁）和 PUFA 浓度。 通过心理测量验证的定量感官问卷来测量抑郁症状。 测试确定了对三种伤害感受的敏感性：钝压痛、机械痛和 目标 3 将评估 FADS 基因变异是否会改变 PUFA 及其关联。 这是一个高风险项目，因为基于社区的疼痛研究从未有过。 评估 PUFA 预防 COPC 的潜力。此类研究是未来的必要先决条件。 该项目具有潜在的高回报，因为目前的疼痛治疗方法并不令人满意。 而 n-3 PUFA 具有出色的安全性，可以用于预防慢性疼痛。