The Effects of Ketogenic Diets on Inflammation and Chronic Pain

描述(由申请人提供)：存在对非成瘾和/或解决目前可用治疗方法仍难以解决的疼痛疗法的巨大未满足需求。鸦片类药物是治疗疼痛的最有效药物，具有严重的副作用和成瘾潜力，有时效果不佳。治疗疼痛的两种主要非阿片类药物策略侧重于减少炎症和炎症性疼痛(特别与关节炎有关)或减少神经活动和神经病理性疼痛(特别与糖尿病和神经损伤有关)。越来越多的证据表明，生酮饮食可能会减轻疼痛。生酮饮食是一种高脂肪、低碳水化合物的饮食方案，类似于阿特金斯饮食。碳水化合物的限制降低了葡萄糖的代谢，增加了酮类的代谢。到目前为止，生酮饮食已经证明了对癫痫的临床疗效，并展示了在几种类型的急性和慢性脑损伤中进行神经保护的基础研究潜力。生酮饮食的一系列生化后果--活性氧减少、神经活动减少、腺苷增加和过氧化物体增殖物激活受体激活--都表明生酮饮食将有效地提高基线痛阈值，减轻炎症性和神经病理性疼痛。我们的中心假设是，生酮饮食将缓解疼痛，包括顽固性疼痛，基于其抗炎潜力，并类似于其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，但生酮饮食在治疗疼痛方面的有效性尚未在临床或动物模型中进行测试。目前的目标是测试生酮饮食对基线痛阈值、炎症性疼痛(特定目标1)和神经病理性疼痛(特定目标2)的影响。在成熟的动物模型中验证我们的假设是可行的，可能会为缓解疼痛提供新的治疗机会，并为开发既有效又不会上瘾的疼痛治疗提供新的途径。 与公共卫生相关：慢性疼痛是一种常见的、令人衰弱的疾病，它显著地减少了医疗保健行业每年数百亿美元的成本。有证据表明，生酮(极低碳水化合物/高脂肪)饮食应该可以缓解两种类型的慢性疼痛：炎症性疼痛和神经病理性疼痛，这两种疼痛分别最常见于类风湿性关节炎和糖尿病。这项建议将量化两种生酮饮食在炎症性和神经病理性疼痛动物模型中的预防和缓解效果。

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.