Multimodal Investigation of the Neuroimmune System in Opioid Use Disorder

项目摘要/摘要 阿片类药物使用障碍(OUD)在美国已经达到流行的程度。奥德是一种复杂的神经- 行为障碍受神经生物学、遗传和环境因素影响的行为障碍最近，有 人们对神经免疫系统在OUD中的作用越来越感兴趣。神经免疫信号一直是 被证明影响食欲(例如，阿片类药物渴望、阿片类药物寻求行为)和烦躁不安(例如，疼痛 敏感性、阿片类药物戒断症状)成瘾过程。临床前研究结果表明，急性阿片类药物 给药会在外周和大脑中引发促炎反应。然而，它的影响 慢性阿片类药物滥用对体内神经免疫系统的影响尚不清楚。这项研究的目标是 应用多模式成像研究慢性阻塞性肺疾病患者的神经免疫系统是否受损 均在门诊早期接受美沙酮维持治疗，病情稳定，未滥用非法阿片类药物。具体来说，我们 将使用正电子发射断层扫描α-[11C]甲基-L色氨酸([11C]AMT)和质子磁性 OUD患者与配型良好的患者的磁共振波谱(1H MRS)肌醇成像的对比 健康的志愿者。OUD患者将通过每周三次的尿液药物筛查进行长达六个月的监测，以 确定阿片类药物失效的时间。PET[11C]AMT成像有助于定量测量患者的代谢活性 犬尿氨酸途径：对促炎神经免疫刺激敏感的途径。1H梅奥女士- 肌醇是一种可能的胶质标记物，被认为是星形胶质细胞激活后上调的。加在一起，这些标记 将澄清慢性阿片类药物滥用是否与神经免疫系统紊乱有关，以及 早期治疗中神经免疫标记物水平可预测标准护理中的治疗反应 门诊美沙酮维持治疗。这项研究的结果可能会为新的干预措施提供参考，例如 神经胶质调节药物，以补充药物辅助治疗的OUD患者。这份职业 发展奖将促进伍德科克博士朝着他的最终职业目标前进 独立的研究项目，调查神经免疫系统在成瘾中的作用。

Project Summary/Abstract Opioid use disorder (OUD) has reached an epidemic scale in the United States. OUD is a complex neuro- behavioral disorder influenced by neurobiological, genetic, and environmental factors. Recently, there has been increased interest in the role of the neuroimmune system in OUD. Neuroimmune signaling has been shown to influence both appetitive (e.g., opioid craving, opioid-seeking behavior) and dysphoric (e.g., pain sensitivity, opioid withdrawal symptoms) addiction processes. Preclinical findings indicate that acute opioid administration evokes pro-inflammatory responses in both the periphery and brain. However, the effects of chronic opioid abuse on the in vivo neuroimmune system are not well-understood. The goal of this study is to apply multi-modal imaging to investigate whether the neuroimmune system is disrupted in OUD patients who are early in outpatient methadone maintenance therapy, stable, and not abusing illicit opioids. Specifically, we will use Positron Emission Tomography (PET) α-[11C]methyl-L-tryptophan ([11C]AMT) and proton magnetic resonance spectroscopy (1H MRS) myo-Inositol imaging among OUD patients contrasted with well-matched healthy volunteers. OUD patients will be monitored for up to six months via thrice weekly urine drug screens to determine time to opioid lapse. PET [11C]AMT imaging facilitates quantitative measure of metabolic activity in the kynurenine pathway: a pathway that is sensitive to pro-inflammatory neuroimmune stimuli. 1H MRS myo- Inositol is a putative glial marker thought to be upregulated by astrocyte activation. Together, these markers will clarify whether chronic opioid abuse is associated with neuroimmune system disruption and whether neuroimmune marker levels early-in-treatment prospectively predict treatment response in standard-of-care outpatient methadone maintenance therapy. Results from this study may inform novel interventions, such as glial modulator medications, to supplement medication-assisted therapies for patients with OUD. This Career Development Award will facilitate Dr. Woodcock’s progression toward his ultimate career goal of an independent research program investigating the role of the neuroimmune system in addiction.