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

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 流程.目标几乎总是治疗性的，而不是预防性的。我们挑战这一前提，根据新的 证据表明，慢性疼痛可以通过针对所有三个途径，通过饮食， ω-6（n-6）和ω-3（n-3）多不饱和脂肪酸（PUFA）的平衡。抗炎 长链（LC）ω-3（n-3）PUFA对疼痛疾病如关节炎的作用是公认的。一 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降低了 增加致伤害性衍生物的浓度，并增加抗伤害性和镇痛剂的浓度。 衍生物.相比之下，ω-6（n-6）PUFA代谢物主要具有炎症和疼痛感受性。 方面的影响.此外，LC n-3衍生物具有抗焦虑作用，减轻抑郁症状和焦虑 经常与慢性疼痛并存。n-6和n-3 PUFA合成为 由脂肪酸去饱和酶（FADS）酶（由FADS基因簇编码）产生的生物活性LC PUFA与 根据PUFA代谢中关键酶的遗传变异性：δ-5去饱和酶（FADS 1）和δ-6 去饱和酶（FADS 2）。因此，基因-PUFA相互作用影响PUFA衍生物的生物合成， 对慢性疼痛的推定和治疗效果。我们计划研究多不饱和脂肪酸和慢性 使用现有数据和来自655名患者的储存红细胞， 在我们的一项名为“口面疼痛：前瞻性研究”的基于社区的研究中， 评价和风险评估”（OPPERA-II）。OPPERA-II评估了颞下颌关节紊乱病的重叠， 偏头痛或紧张型头痛、纤维肌痛、腰痛和肠易激综合征。目标1将 评估疼痛状况与红细胞PUFA浓度及其代谢物之间的关联。 将使用液相色谱串联质谱法定量PUFA。我们假设， 浓度的n-6系列，和低浓度的n-3系列正相关 每种疼痛状况的发生率和COPC的总数。目标2将评估 中间表型（伤害感受、焦虑和抑郁）和PUFA浓度。焦虑和 抑郁症状通过心理测量学验证的问卷进行测量。定量感觉 测试确定了对三种伤害性感受方式的敏感性：钝性压迫疼痛、机械性疼痛和 热性疼痛。目的3将评估FADS遗传变异是否改变PUFA及其 代谢产物与COPCs。这是一个高风险的项目，因为基于社区的疼痛研究从未 评估PUFA预防COPC的潜力。这样的研究是未来的一个必要的先决条件。 临床试验该项目具有潜在的高回报，因为目前的疼痛治疗是不令人满意的 而n-3 PUFA具有优异的安全性特征，并且可用于预防慢性疼痛。

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.