Imaging neuroglial mechanisms of neuropathic pain-opioid interaction in HIV

HIV中神经性疼痛与阿片类药物相互作用的神经胶质细胞成像机制

• 批准号: 10374777
• 负责人: Marco Luciano Loggia
• 金额: $ 62.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374777
• 关键词: Address; Affect; Anatomy; Brain; Brain imaging; Chemicals; Chronic; Development; Distal; Enrollment; Equilibrium; Glutamates; HIV; HIV Seronegativity; HIV Seropositivity; Human; Hyperalgesia; Image; Imaging technology; Individual; Inositol; Intervention; Lead; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Mediation; N-acetylaspartate; Neurologic; Neurons; Neurotransmitters; Opioid; Opioid Receptor; Pain; Pain Threshold; Pain management; Pain-Free; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Polyneuropathy; Positron-Emission Tomography; Proteins; Protons; Role; Sensory; Signal Transduction; Site; Stimulus; Substrate Interaction; Sum; Techniques; Testing; Thalamic structure; Therapeutic; Time; United States; Virus; Virus Diseases; base; chronic pain patient; clinical pain; cohort; experience; gamma-Aminobutyric Acid; glial activation; gray matter; healthy volunteer; neuroinflammation; neurotoxicity; neurotransmission; opioid therapy; opioid use; pain sensitivity; painful neuropathy; preclinical study; tool; volunteer

Abstract To date, ~1.1 million people in the United State and ~37 million people worldwide are infected with the human immunodeficiency virus (HIV). Of those infected with HIV, almost a third experience distal symmetric polyneuropathy often associated with neuropathic pain. While opioids are currently the cornerstone medication for treating severe pain in these patients, they can paradoxically lead to an increase in sensitivity to noxious stimuli (opioid-induced hyperalgesia) as well as an exacerbation of HIV-associated clinical pain. The precise mechanisms by which opioids interact with the viral infection to exacerbate neuropathic pain have yet to be fully elucidated, but likely involve the synergetic dysregulation of neuro-glial interactions, including glial activation and alterations in the excitation-inhibition balance of the brain. Despite the rapid accumulation of preclinical studies investigating these mechanisms, human evidence is currently lacking. To evaluate the role of neuro-glial dysregulation as a mechanism underlying HIV-opioids interaction, in humans, we will use advanced brain imaging technologies and quantitative sensory testing (QST). Specifically, integrated [11C]PBR28 Positron Emission Tomography / Magnetic Resonance (PET/MR) and high field (7T) proton magnetic resonance spectroscopy (1H MRS) will be used to evaluate brain levels of glial markers (18kDa translocator protein, TSPO, and myo-inositol, mI), neuronal / structural integrity markers (N-acetyl- aspartate, NAA and gray matter volume) as well as excitatory and inhibitory neurotransmission markers (glutamate and gamma-aminobutyric acid, GABA). QST techniques will assess pain threshold, suprathreshold sensitivity and temporal summation. Four cohorts will be enrolled in this trial: 1) HIV-positive patients without neuropathic pain, 2) HIV-positive patients with neuropathic pain not on opioid therapy, 3) HIV-positive patients with neuropathic pain on opioid therapy and 4) healthy, pain-free HIV- volunteers. Elucidating the mechanisms mediating the HIV-opioid interaction will have important practical implications for pain management, and toward the development of tailored interventions focused on glial modulation and neurotransmitter signaling.

摘要 到目前为止，美国约有110万人，全世界约有3700万人感染了 人类免疫缺陷病毒（艾滋病毒）。在那些感染艾滋病毒的人中，几乎三分之一的人经历了远端对称性 常与神经性疼痛有关的多发性神经病。虽然阿片类药物目前是基础药物 对于治疗这些患者的严重疼痛，它们反而会导致对有害物质的敏感性增加。 刺激（阿片样物质诱导的痛觉过敏）以及HIV相关临床疼痛的加重。的精确 阿片类药物与病毒感染相互作用以加剧神经性疼痛的机制尚未被阐明。 完全阐明，但可能涉及神经胶质细胞相互作用的协同失调，包括胶质细胞 激活和改变大脑的兴奋-抑制平衡。尽管快速积累的 研究这些机制的临床前研究，目前缺乏人体证据。 评价神经胶质细胞失调作为HIV-阿片类药物相互作用机制的作用， 对于人类，我们将使用先进的大脑成像技术和定量感觉测试（QST）。具体地说， 集成[11 C] PBR 28正电子发射断层扫描/磁共振（PET/MR）和高场（7 T） 将使用质子磁共振波谱（1H MRS）评价脑胶质细胞标记物水平 （18 kDa转运蛋白，TSPO和肌醇，mI），神经元/结构完整性标志物（N-乙酰基- 天冬氨酸、NAA和灰质体积）以及兴奋性和抑制性神经传递标记物 （谷氨酸和γ-氨基丁酸，GABA）。QST技术将评估痛阈、阈上 灵敏度和时间总和。本试验将入组四个队列：1）HIV阳性患者， 神经性疼痛，2）未接受阿片类药物治疗的神经性疼痛HIV阳性患者，3）HIV阳性患者 接受阿片类药物治疗的神经性疼痛患者和4）健康、无痛的HIV志愿者。 阐明介导HIV-阿片相互作用的机制将具有重要的实际意义。 对疼痛管理的影响，以及针对神经胶质细胞的定制干预措施的发展， 调节和神经递质信号传导。