The Effects of Ketogenic Diets on Inflammation and Chronic Pain

描述（由申请人提供）：对于非成瘾性和/或解决目前难以治疗的疼痛的疼痛治疗存在巨大的未满足需求。阿片类药物是治疗疼痛最有效的药物，有严重的副作用和上瘾的可能性，有时是无效的。两种主要的非阿片类药物治疗疼痛的策略集中在减少炎症和炎症性疼痛（特别是与关节炎有关）或减少神经活动和神经性疼痛（特别是与糖尿病和神经损伤有关）。越来越多的证据表明生酮饮食可以减轻疼痛。生酮饮食是一种高脂肪低碳水化合物的饮食，类似于阿特金斯饮食法。碳水化合物的限制减少了葡萄糖的代谢，增加了酮的代谢。迄今为止，生酮饮食已证明对癫痫的临床疗效，并在几种急性和慢性脑损伤中显示出神经保护的基础研究潜力。生酮饮食的一些生化后果——活性氧减少，神经活动减少，腺苷增加和过氧化物酶体增殖激活受体的激活——都表明生酮饮食将有效提高基线疼痛阈值，减少炎症和神经性疼痛。我们的中心假设是，生酮饮食可以减轻疼痛，包括顽固性疼痛，这是基于它的抗炎潜力，类似于它在治疗顽固性癫痫方面的成功。尽管有多种证据支持我们的中心假设，但生酮饮食治疗疼痛的功效尚未在临床或动物模型中进行测试。目前的目的是测试生酮饮食对基线疼痛阈值、炎症性疼痛（特异性目标1）和神经性疼痛（特异性目标2）的影响。在完善的动物模型中验证我们的假设是可行的，并且可能为缓解疼痛提供新的治疗机会，并为开发既有效又不成瘾性的疼痛治疗提供新的途径。

DESCRIPTION (provided by applicant): A great unmet need exists for pain therapies that are non-addictive and/or address pain that remains intractable to treatments available currently. Opiates, the most powerful drugs to treat pain, pose serious side effects and addictive potential and are sometimes ineffective. Two major non-opioid strategies to address pain are focused on either reducing inflammation and inflammatory pain (particularly relevant to arthritis) or reducing neural activity and neuropathic pain (particularly relevant to diabetes and nerve injury). There is emerging evidence to suggest that a ketogenic diet may alleviate pain. A ketogenic diet is a regimen that it is high in fat and low in carbohydrates, similar to the Atkins diet. The carbohydrate restriction decreases the metabolism of glucose and increases the metabolism of ketones. To date, the ketogenic diet has shown proven clinical efficacy in epilepsy and demonstrated basic research potential for neuroprotection in several types of acute and chronic brain injuries. A number of biochemical consequences of a ketogenic diet - decreased reactive oxygen species, decreased neural activity, increased adenosine and activation of peroxisome proliferator-activated receptors - all suggest that a ketogenic diet will be effective in increasing baseline pain thresholds and reducing both inflammatory and neuropathic pain. Our central hypothesis is that a ketogenic diet will alleviate pain, including intractable pain, based on its anti-inflammatory potential and akin to its success in treating intractable epilepsy. Despite multiple lines of evidence supporting our central hypothesis, the efficacy of a ketogenic diet in treating pain has not been tested either clinically or in animal models. The present objective is to test the effects of a ketogenic diet on baseline pain thresholds, inflammatory pain (Specific Aim 1) and neuropathic pain (Specific Aim 2). Testing our hypothesis in well-established animal models is feasible and may yield new therapeutic opportunities for pain relief and a new avenue for developing pain treatments that are both effective and non-addictive. PUBLIC HEALTH RELEVANCE: Chronic pain is a common and debilitating condition, strikingly reducing the costing the health care industry tens of billions of dollars annually. Evidence suggests that a ketogenic (very low carbohydrate/high fat) diet should provide relief in two types of chronic pain, inflammatory and neuropathic pain, found most commonly in rheumatoid arthritis and diabetes, respectively. This proposal will quantify the preventative and palliative effects of two ketogenic diets in well-characterized animal models of inflammatory and neuropathic pain.