Multimodal Investigation of the Neuroimmune System in Opioid Use Disorder

项目总结/摘要 阿片类药物使用障碍（OUD）在美国已达到流行规模。OUD是一种复杂的神经- 受神经生物学、遗传和环境因素影响的行为障碍。最近， 神经免疫系统在OUD中的作用引起了越来越多的兴趣。神经免疫信号已经被 显示影响食欲（例如，阿片样物质渴求，阿片样物质寻求行为）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， 给药在外周和脑中都引起促炎反应。然而， 慢性阿片类药物滥用对体内神经免疫系统的影响还不清楚。本研究的目的是 应用多模式成像来研究OUD患者的神经免疫系统是否受到破坏， 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。我们特别 将使用正电子发射断层扫描（PET）α-[11 C]甲基-L-色氨酸（[11 C]AMT）和质子磁共振成像（MRI）。 OUD患者中的核磁共振波谱（1H MRS）肌肌醇成像与匹配良好的 健康志愿者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， 确定阿片类药物失效的时间PET [11 C]AMT成像有助于定量测量代谢活动， 犬尿氨酸途径：对促炎性神经免疫刺激敏感的途径。1H MRS myo- 肌醇是一种公认的胶质细胞标志物，被认为是由星形胶质细胞激活上调。总之，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破坏有关，以及 治疗早期神经免疫标志物水平前瞻性预测标准治疗中的治疗反应 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信息，例如 神经胶质调节剂药物，以补充OUD患者的药物辅助治疗。这个职业 发展奖将促进伍德考克博士朝着他的最终职业目标的进展， 独立研究项目，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.