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：伤害性、炎症或心理 流程。目标几乎总是治疗性的，而不是预防性的。我们对这一前提提出了挑战，因为 有证据表明，通过有利的饮食，针对所有三种途径可以预防慢性疼痛 Omega-6(n-6)和omega-3(n-3)多不饱和脂肪酸(PUFAs)的平衡。消炎药 长链(LC)omega-3(n-3)多不饱和脂肪酸对关节炎等疼痛障碍的作用已得到公认。一个 更新的发现是，LC n-3二十碳五烯酸和n-3二十二碳六烯酸的代谢物较低 原伤害性衍生物的浓度，以及增加抗伤害性和止痛剂的浓度 衍生品。相比之下，omega-6(n-6)多不饱和脂肪酸代谢产物大多具有炎症性和促伤害性 效果。此外，LC n-3衍生物具有抗焦虑作用，可缓解抑郁症状和焦虑。 这些症状通常与慢性疼痛并存。N-6和n-3多不饱和脂肪酸合成的程度 由脂肪酸去饱和酶(FADS)基因簇编码的具有生物活性的LC多不饱和脂肪酸不同 根据多不饱和脂肪酸代谢关键酶的遗传变异：Delta-5去饱和酶(FADS1)和Delta-6 去饱和酶(FADS2)。因此，基因-多不饱和脂肪酸相互作用影响具有以下特征的多不饱和脂肪酸衍生物的生物合成 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与慢性疾病之间的联系 重叠疼痛条件(COPC)使用现有数据和存储的655红细胞进行横断面分析 在我们以社区为基础的研究中，成年参与者(69%为女性)进行了基因分型研究，研究名称为：口腔面部疼痛：前瞻性研究 评价和风险评估“(OPPERA-II)。OPPERA-II评估重叠的颞下颌关节紊乱病， 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中多不饱和脂肪酸及其代谢物浓度的关系。 多不饱和脂肪酸将用液相色谱串联质谱进行定量。我们假设这么高 N-6系列的浓度和n-3系列的低浓度与 每种疼痛情况的发生情况和COPC总数。目标2将评估两者之间的关联 中间表型(伤害、焦虑和抑郁)和多不饱和脂肪酸浓度。焦虑和 抑郁症状通过心理测量学验证的问卷进行测量。定量感官 测试确定了对三种形式的伤害的敏感性：钝性压力性疼痛、机械性疼痛和 热的痛感。目标3将评估FADS基因变异是否会改变多不饱和脂肪酸与其 含有COPC的代谢物。这是一个高风险的项目，因为基于社区的疼痛研究从未 评估了多不饱和脂肪酸在预防COPC方面的潜力。这样的研究是未来的必要前提。 临床试验。该项目具有潜在的高额回报，因为目前的疼痛治疗方法并不令人满意 而n-3多不饱和脂肪酸具有极好的安全性，似乎可以用于预防慢性疼痛。

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.