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110万人和全球约3700万人感染了 人类免疫缺陷病毒（HIV）。在感染艾滋病毒的人中，几乎三分之一的体验远端对称性 多神经病通常与神经性疼痛有关。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，它们可以矛盾地导致对有害的敏感性提高 刺激（阿片类药物诱导的痛觉过敏）以及与HIV相关的临床疼痛的加剧。确切的 阿片类药物与病毒感染相互作用以加重神经性疼痛的机制尚未 完全阐明，但可能涉及神经相互作用的协同失调，包括神经胶质 大脑激发抑制平衡的激活和改变。尽管迅速积累了 临床前研究研究了这些机制，目前缺乏人类证据。 评估神经胶质失调作为一种基本的HIV - 阿片类药物相互作用的机制的作用，在 人类，我们将使用先进的大脑成像技术和定量感觉测试（QST）。具体来说， 综合[11C] PBR28正电子发射断层扫描 /磁共振（PET / MR）和高场（7T） 质子磁共振光谱（1H MRS）将用于评估胶质标记的大脑水平 （18KDA易位蛋白，TSPO和Myo-Inositol，MI），神经 /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，上方 灵敏度和时间求和。该试验将招募四个队列：1）没有HIV阳性患者 神经性疼痛，2）神经性疼痛的HIV阳性患者而不是阿片类药物治疗，3）HIV阳性患者 阿片类药物治疗上的神经性疼痛和4）健康，无痛的HIV志愿者。 阐明介导HIV - 阿片类药物相互作用的机制将具有重要的实用性 对疼痛管理的影响，以及针对神经胶质的量身定制干预措施的发展 调节和神经递质信号传导。