Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, CA, United States; Department of Basic Sciences, Loma Linda University, Loma Linda, CA, United States; Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, United States.
Neuroscience. 2013;255:1-18. doi: 10.1016/j.neuroscience.2013.09.012. Epub 2013 Sep 14.
Chronic neuropathic pain is a frequent comorbidity following spinal cord injury (SCI) and often fails to respond to conventional pain management strategies. Preventive administration of docosahexaenoic acid (DHA) or the consumption of a diet rich in omega-3 polyunsaturated fatty acids (O3PUFAs) confers potent prophylaxis against SCI and improves functional recovery. The present study examines whether this novel dietary strategy provides significant antinociceptive benefits in rats experiencing SCI-induced pain. Rats were fed control chow or chow enriched with O3PUFAs for 8weeks before being subjected to sham or cord contusion surgeries, continuing the same diets after surgery for another 8 more weeks. The paw sensitivity to noxious heat was quantified for at least 8weeks post-SCI using the Hargreaves test. We found that SCI rats consuming the preventive O3PUFA-enriched diet exhibited a significant reduction in thermal hyperalgesia compared to those consuming the normal diet. Functional neurometabolomic profiling revealed a distinctive deregulation in the metabolism of endocannabinoids (eCB) and related N-acyl ethanolamines (NAEs) at 8weeks post-SCI. We found that O3PUFAs consumption led to a robust accumulation of novel NAE precursors, including the glycerophospho-containing docosahexaenoyl ethanolamine (DHEA), docosapentaenoyl ethanolamine (DPEA), and eicosapentaenoyl ethanolamine (EPEA). The tissue levels of these metabolites were significantly correlated with the antihyperalgesic phenotype. In addition, rats consuming the O3PUFA-rich diet showed reduced sprouting of nociceptive fibers containing CGRP and dorsal horn neuron p38 mitogen-activated protein kinase (MAPK) expression, well-established biomarkers of pain. The spinal cord levels of inositols were positively correlated with thermal hyperalgesia, supporting their role as biomarkers of chronic neuropathic pain. Notably, the O3PUFA-rich dietary intervention reduced the levels of these metabolites. Collectively, these results demonstrate the prophylactic value of dietary O3PUFA against SCI-mediated chronic pain.
慢性神经性疼痛是脊髓损伤（SCI）后的常见合并症，通常对常规疼痛管理策略无反应。二十二碳六烯酸（DHA）的预防性给药或富含ω-3 多不饱和脂肪酸（O3PUFA）的饮食的消耗赋予了对 SCI 的有力预防作用，并改善了功能恢复。本研究检查了这种新的饮食策略是否为经历 SCI 诱导性疼痛的大鼠提供了显著的镇痛益处。大鼠在接受假手术或脊髓挫伤手术后 8 周内接受对照饲料或富含 O3PUFA 的饲料喂养，手术后再继续喂养 8 周以上。使用 Hargreaves 测试至少在 SCI 后 8 周内量化对有害热的爪敏感性。我们发现，与食用正常饮食的大鼠相比，食用预防性 O3PUFA 丰富饮食的 SCI 大鼠的热痛觉过敏明显减轻。功能神经代谢组学分析显示，在 SCI 后 8 周时，内源性大麻素（eCB）和相关 N-酰基乙醇胺（NAE）的代谢出现明显失调。我们发现，O3PUFA 的消耗导致新型 NAE 前体的大量积累，包括含有甘油磷酸的二十二碳六烯酰乙醇胺（DHEA），二十二碳五烯酰乙醇胺（DPEA）和二十碳五烯酰乙醇胺（EPEA）。这些代谢物的组织水平与抗痛觉过敏表型显着相关。此外，食用富含 O3PUFA 的饮食的大鼠表现出伤害感受纤维中 CGRP 和背角神经元 p38 丝裂原活化蛋白激酶（MAPK）表达的减少，这是疼痛的公认生物标志物。肌醇的脊髓水平与热痛觉过敏呈正相关，支持其作为慢性神经性疼痛的生物标志物的作用。值得注意的是，富含 O3PUFA 的饮食干预降低了这些代谢物的水平。总的来说，这些结果表明饮食 O3PUFA 对 SCI 介导的慢性疼痛具有预防作用。
