Imaging neuroglial mechanisms of neuropathic pain-opioid interaction in HIV

摘要 到目前为止，美国约有110万人和全球约3700万人感染了这种病毒 人类免疫缺陷病毒(HIV)。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 多发性神经病通常与神经病理性疼痛有关。虽然阿片类药物是目前的基石药物 在治疗这些患者的剧烈疼痛时，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敏)以及加剧艾滋病毒相关的临床疼痛。精准的 阿片类药物与病毒感染相互作用以加剧神经病理性疼痛的机制尚未得到证实 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。尽管迅速积累了 在研究这些机制的临床前研究中，目前缺乏人体证据。 为了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， 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(1HMRS)将被用来评估大脑中神经胶质标志物的水平 (18 kDa转位蛋白，TSPO和肌醇，MI)，神经元/结构完整性标记物(N-乙酰- 天冬氨酸、NAA和灰质体积)以及兴奋性和抑制性神经递质标志物 (谷氨酸和γ-氨基丁酸，GABA)。QST技术将评估痛阈值、阈值上 敏感度和时间总和。这项试验将招募四个队列：1)艾滋病毒阳性患者没有 神经性疼痛，2)HIV阳性的神经病理性疼痛不接受阿片类药物治疗，3)HIV阳性的患者 接受阿片类药物治疗的神经病理性疼痛患者和4)健康、无疼痛的艾滋病毒志愿者。 阐明HIV与阿片类药物相互作用的机制具有重要的现实意义 对疼痛管理的影响，以及针对神经胶质细胞的量身定制干预措施的发展 调制和神经递质信号。

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.