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: 10213009
• 负责人: Anne E. Sanders
• 金额: $ 23.33万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213009
• 关键词: Adult; Anabolism; Analgesics; Anti-Anxiety Agents; Antiinflammatory Effect; Anxiety; Arthritis; Chronic; Clinical Trials; Communities; Data Store; 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; dietary; 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; Adult; Anabolism; Analgesics; Anti-Anxiety Agents; Antiinflammatory Effect; Anxiety; Arthritis; Chronic; Clinical Trials; Communities; Data Store; 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; dietary; 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.

慢性疼痛疗法通常针对三种疼痛途径之一：炎症，炎症或心理 过程。目标几乎总是治疗的，而不是预防性的。我们鉴于新的挑战 可以通过饮食来靶向所有三种途径可以预防慢性疼痛的证据 omega-6（N-6）和omega-3（n-3）多不饱和脂肪酸（PUFAS）的平衡。抗炎 长链（LC）Omega-3（N-3）PUFA对关节炎等疼痛疾病的影响。一个 最新发现是LC N-3 Eicosapentaenoic酸和N-3 Docosahexaenoic Acid代谢物较低 引起摄影性衍生物的浓度，并增加抗伤害感受和镇痛的浓度 衍生物。相比之下，omega-6（n-6）PUFA代谢产物主要具有炎症性和引起感性的 效果。此外，LC N-3衍生物具有抗焦虑作用，减轻抑郁症状和焦虑 通常与慢性疼痛合并。 N-6和N-3 Pufas合成的程度 脂肪酸去饱和酶（FADS）酶的生物活性LC PUFA，由FADS基因簇编码，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 去饱和酶（FADS2）。因此，基因-PUFA相互作用会影响具有PUFA衍生物的生物合成 推定和治疗对慢性疼痛的影响。我们计划研究Pufas和慢性的关联 使用现有数据并储存655的红细胞在横截面上重叠疼痛条件（COPC） 基因分型的成人参与者（69％女性）在我们的社区研究中名为“ Orofacial痛苦：前瞻性 评估和风险评估”（oppera-ii）。oppera-ii评估了颞下颌疾病的重叠， 偏头痛或张力型标题，纤维肌痛，下背痛和肠易激综合征。目标1意志 评估PUFAS及其代谢产物的疼痛条件与红细胞浓度之间的关联。 PUFA将使用液相色谱串联质谱法对PUFA进行定量。我们假设那个高 N-6系列的浓度和低浓度N-3系列与 AIM 2将评估关联 中间表型（伤害感受，焦虑和抑郁）和PUFA浓度。焦虑和 抑郁症状是通过心理验证的问卷测量的。定量感觉 测试确定了对三种肉体的敏感性：钝性压力疼痛，机械疼痛和 热热疼痛。 AIM 3将评估FADS遗传变异是否修改PUFA及其的关联 带有COPC的代谢产物。这是一个高风险项目，因为基于社区的痛苦研究从未 评估了Pufas预防COPC的潜力。这样的研究是未来的必要前提条件 临床试验。该项目具有潜在的高度回报，因为目前的疼痛治疗不令人满意 而N-3 PUFA具有出色的安全性，可以合理地用于防止慢性疼痛。