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

高脂肪饮食对吗啡治疗和滥用相关作用的影响

• 批准号: 10628496
• 负责人: Katherine Marie Serafine
• 金额: $ 15.14万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628496
• 关键词: Acute; Adverse effects; Analgesics; Animal Model; Behavioral; Biological Assay; Brain region; Carbohydrates; Chronic; Communication; Constipation; Consumption; Corpus striatum structure; Data; Data Analyses; Data Collection; Dependence; Development; Diagnosis; Diet; Dietary History; Dietary intake; Dopamine Receptor; Eating; Experimental Designs; FOS gene; Fat-Restricted Diet; Fatty acid glycerol esters; Food; Future; Gastrointestinal Transit; Health; High Fat Diet; Hispanic-serving Institution; Hypothalamic structure; IRS2 gene; Individual; Injections; Insulin; Insulin-Like Growth Factor I; Leptin; Link; Measures; Mentors; Mentorship; Methods; Morphine; Naloxone; Nociception; Obesity; Opioid; Opioid Analgesics; Outcome; Pain management; Patients; Pharmaceutical Preparations; Physiological; Prevalence; Proto-Oncogene Proteins c-akt; Public Health; Publications; Rattus; Recording of previous events; Recreation; Research; Rewards; Risk; Rodent; Slice; Source; Stimulant; Students; System; Tail; Texas; Therapeutic; Therapeutic Effect; Training; Treatment Protocols; Underrepresented Minority; United States National Institutes of Health; Universities; Water; Weight Gain; Withdrawal; Withdrawal Symptom; abuse liability; antinociception; behavioral sensitization; brain tissue; chronic pain management; chronic painful condition; comorbidity; conditioned place preference; delta opioid receptor; dietary control; experience; feeding; graduate student; high risk; indexing; kappa opioid receptors; ketogenic diet; midbrain central gray substance; minority scientist; molecular marker; morphine administration; mortality; neural; neurochemistry; opioid overdose; opioid use disorder; overdose death; pain sensitivity; prescription opioid; reward processing; therapeutic effectiveness; undergraduate student; underrepresented minority student

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.

项目摘要 阿片类药物使用障碍（OUD）和肥胖是主要的共病公共卫生问题， 在全国流行。在美国，OUD占所有药物过量死亡的68%， 肥胖是全因死亡率的主要来源。被诊断患有肥胖的患者也经常 被诊断患有慢性疼痛疾病，更有可能被处方阿片类药物。此外，肥胖是 在OUD患者中非常普遍，并且与阿片类药物过量的风险较高相关。 这表明，肥胖患者服用阿片类药物的风险增加， 镇痛药和发展OUD;然而，这些风险背后的生理机制是 没有很好地理解。肥胖与高脂肪饮食有关;然而，尚不清楚是否 在诊断为肥胖的患者中，与OUD相关的风险是由于这种饮食史。这个NIH SuRE R16提案调查了饮食对治疗、奖励和不良反应的影响 吗啡，在大鼠中使用行为和生理测定。此外，根据最近的证据， 这表明高脂肪、低碳水化合物生酮饮食可能对肥胖有益， 除了低脂饮食控制外，拟议的目标还将探讨生酮饮食的影响。 条件为探讨饮食对大鼠吗啡敏感性的影响， 吗啡的治疗效果（即，通过温水尾部撤回和von Frey爪收回测定）和奖励（即，条件性位置偏好和行为 致敏性）将在目标1中进行审查。此外，吗啡的副作用包括 便秘（减少胃肠道传输）和依赖性（如通过存在或 慢性吗啡给药后无戒断症状）也将在Aim 2模仿患者长期服用阿片类药物进行疼痛管理或娱乐的经历 使用.最后，在目标3中，该提案还将评估特定脑内分子标记物的变化， 与奖赏处理、进食和伤害感受相关的区域，以确定未来的目标。 机制驱动的评估。这些项目将提供一个清晰的图片的方式，饮食 历史可能会影响阿片类药物的治疗效果，以及它们的滥用倾向， 具有预防意义的评估侧重于两个相互融合和日益增加的公共卫生问题： 肥胖和OUD。这些目标还包括培训代表性不足的少数民族毕业生， 本科生，在西班牙裔服务机构，得克萨斯大学埃尔帕索，根据 PI的方向，他也是一个代表性不足的少数民族科学家。学生将参与所有 提出的目标的阶段，包括实验设计，数据收集，数据分析和 口译，并将成为出版物和演讲的第一作者或共同作者。