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: 9893840
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893840
• 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; Pharmaceutical Preparations; Pharmacology; Polyneuropathy; Positron-Emission Tomography; Proteins; Protons; Role; Sensory; Signal Transduction; Site; Stimulus; Structure; 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.

抽象的 迄今为止，美国约有 110 万人、全世界约有 3700 万人感染了该病毒 人类免疫缺陷病毒（HIV）。在艾滋病毒感染者中，近三分之一经历远端对称性 多发性神经病通常与神经性疼痛有关。虽然阿片类药物目前是基石药物 为了治疗这些患者的严重疼痛，它们可能会矛盾地导致对有害物质的敏感性增加 刺激（阿片类药物引起的痛觉过敏）以及 HIV 相关临床疼痛的加剧。精确的 阿片类药物与病毒感染相互作用从而加剧神经性疼痛的机制尚未明确 已完全阐明，但可能涉及神经胶质细胞相互作用的协同失调，包括神经胶质细胞 大脑兴奋-抑制平衡的激活和改变。尽管积累迅速 目前缺乏调查这些机制的临床前研究人类证据。 评估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， 人类，我们将使用先进的大脑成像技术和定量感官测试（QST）。具体来说， 集成 [11C]PBR28 正电子发射断层扫描/磁共振 (PET/MR) 和高场 (7T) 质子磁共振波谱（1H MRS）将用于评估大脑神经胶质标记物的水平 （18kDa 易位蛋白，TSPO 和肌醇，mI），神经元/结构完整性标记（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 技术将评估疼痛阈值、阈上阈值 敏感性和时间总和。本试验将招募四个队列：1) 没有感染的 HIV 阳性患者 神经性疼痛，2) 未接受阿片类药物治疗但患有神经性疼痛的 HIV 阳性患者，3) HIV 阳性患者 接受阿片类药物治疗后出现神经性疼痛的患者和 4) 健康、无痛的 HIV 志愿者。 阐明艾滋病毒-阿片类药物相互作用的介导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开发 调制和神经递质信号传导。