The effects of eating a high fat diet on the therapeutic and abuse-related effects of morphine

项目摘要 阿片类药物使用障碍(OUD)和肥胖是日益严重的公共卫生问题 在全国流行。在美国，大约68%的药物过量死亡是由OUD造成的， 肥胖症是全因死亡的主要来源。被诊断为肥胖的患者也经常 被诊断为慢性疼痛的人更有可能被开出阿片类药物。此外，肥胖是 在OUD患者中非常普遍，并与阿片类药物过量的风险较高有关。 这表明肥胖者服用阿片类药物的风险增加。 止痛药和发育不良；然而，这些风险背后的生理机制是 不是很清楚。肥胖与食用高脂肪饮食有关；然而，目前尚不清楚 在被诊断为肥胖的患者中，与OUD相关的风险是由于这种饮食历史。这家美国国立卫生研究院 Sure R16提案调查了饮食对治疗、有益和不良反应的影响 使用大鼠的行为和生理测试。此外，鉴于最近的证据 这表明，高脂肪、低碳水化合物的生酮饮食可能对肥胖有好处， 提议的目标还将探讨除控制低脂肪饮食外，生酮饮食的影响。 条件。为了探讨饮食对大鼠对吗啡敏感性的影响，建立了大鼠不同剂量吗啡依赖的动物模型。 吗啡的治疗作用(即以温水甩尾和von为指标的抗伤害作用 Frey爪子抽离实验)和奖赏(即条件性位置偏好和行为 致敏作用)将在目标1中进行检查。此外，吗啡的副作用包括 便秘(胃肠道转运减少)和依赖(以存在或 长期使用吗啡后没有戒断症状)也将在AIM中进行探索 2模仿患者长期服用阿片类药物以止痛或消遣的经历 使用。最后，在目标3中，这项建议还将评估特定大脑中分子标记的变化 与奖励处理、摄食和伤害感受相关的区域，以识别未来的目标 机制驱动的评估。这些项目将提供一幅清晰的图景，说明饮食的方式 历史可能会影响阿片类药物的治疗效果，以及它们的滥用责任，提供 与翻译相关的评估侧重于两个日益集中和日益增长的公共卫生问题： 肥胖和肥胖。这些目标还将包括培训代表不足的少数族裔毕业生和 德克萨斯大学埃尔帕索分校西班牙裔服务机构的本科生 他也是一名代表不足的少数族裔科学家。学生们将参与到所有 拟议目标的各个阶段，包括实验设计、数据收集、数据分析和 他将成为出版物和演示文稿的第一作者或合著者。

Project Summary Opioid use disorder (OUD) and obesity are major comorbid public health concerns that are increasing in national prevalence. OUD contributes to approximately 68% of all drug overdose deaths in the U.S., and obesity is a leading source of all-cause mortality. Patients diagnosed with obesity are also frequently diagnosed with chronic pain conditions and are more likely to be prescribed opioids. Further, obesity is highly prevalent among individuals with OUD, and is associated with higher risk for opioid overdose. This suggests that individuals with obesity have an increased risk both of being prescribed opioid analgesics and developing OUD; however, the physiological mechanisms that underlie these risks are not well understood. Obesity is linked to the consumption of high fat diets; however, it is not known if the risks related to OUD among patients diagnosed with obesity are due to this dietary history. This NIH SuRE R16 proposal investigates the impact of diet on the therapeutic, rewarding, and adverse effects of morphine, using behavioral and physiological assays in rats. Further, given recent evidence suggesting that high fat, low carbohydrate ketogenic diets might have beneficial effects for obesity, the proposed aims will also explore the effects of a ketogenic diet in addition to a low fat diet control condition. To explore the impact of diet on sensitivity of rats to morphine, animal models of the therapeutic effects of morphine (i.e., antinociception indexed via warm water tail withdrawal and von Frey paw withdrawal assays) and reward (i.e., conditioned place preference and behavioral sensitization) will be examined in Aim 1. Additionally, the adverse effects of morphine including constipation (decreased gastrointestinal transit) and dependence (as measured by the presence or absence of withdrawal symptoms following chronic morphine administration) will also be explored in Aim 2 to mimic the experiences of patients taking opioids chronically for pain management or recreational use. Finally, in Aim 3 this proposal will also evaluate changes in molecular markers within specific brain regions associated with reward processing, feeding, and nociception, to identify targets for future mechanism-driven assessments. These projects will provide a clear picture of the ways that dietary history might impact the therapeutic effectiveness of opioids, as well as their abuse liability, providing a translationally relevant assessment focused on two converging and increasing public health concerns: obesity and OUD. These aims will also involve the training of underrepresented minority graduate and undergraduate students, at a Hispanic-Serving Institution, the University of Texas at El Paso, under the direction of the PI, who is also an underrepresented minority scientist. Students will be involved in all stages of the proposed aims including experimental design, data collection, data analysis and interpretation, and will become first- or co-authors on publications and presentations.