Departments of Pharmacology and Toxicology,
Anatomy and Neurobiology, Institute for Drug and Alcohol Studies, and.
J Neurosci. 2014 Sep 17;34(38):12850-64. doi: 10.1523/JNEUROSCI.5351-13.2014.
Synaptodendritic injury is thought to underlie HIV-associated neurocognitive disorders and contributes to exaggerated inflammation and cognitive impairment seen in opioid abusers with HIV-1. To examine events triggering combined transactivator of transcription (Tat)- and morphine-induced synaptodendritic injury systematically, striatal neuron imaging studies were conducted in vitro. These studies demonstrated nearly identical pathologic increases in dendritic varicosities as seen in Tat transgenic mice in vivo. Tat caused significant focal increases in intracellular sodium ([Na(+)]i) and calcium ([Ca(2+)]i) in dendrites that were accompanied by the emergence of dendritic varicosities. These effects were largely, but not entirely, attenuated by the NMDA and AMPA receptor antagonists MK-801 and CNQX, respectively. Concurrent morphine treatment accelerated Tat-induced focal varicosities, which were accompanied by localized increases in [Ca(2+)]i and exaggerated instability in mitochondrial inner membrane potential. Importantly, morphine's effects were prevented by the μ-opioid receptor antagonist CTAP and were not observed in neurons cultured from μ-opioid receptor knock-out mice. Combined Tat- and morphine-induced initial losses in ion homeostasis and increases in [Ca(2+)]i were attenuated by the ryanodine receptor inhibitor ryanodine, as well as pyruvate. In summary, Tat induced increases in [Na(+)]i, mitochondrial instability, excessive Ca(2+) influx through glutamatergic receptors, and swelling along dendrites. Morphine, acting via μ-opioid receptors, exacerbates these excitotoxic Tat effects at the same subcellular locations by mobilizing additional [Ca(2+)]i and by further disrupting [Ca(2+)]i homeostasis. We hypothesize that the spatiotemporal relationship of μ-opioid and aberrant AMPA/NMDA glutamate receptor signaling is critical in defining the location and degree to which opiates exacerbate the synaptodendritic injury commonly observed in neuroAIDS.
突触树突损伤被认为是 HIV 相关神经认知障碍的基础，并导致 HIV-1 合并阿片类药物滥用者中炎症加剧和认知障碍。为了系统地研究触发共转录激活剂（Tat）和吗啡诱导的突触树突损伤的事件，我们进行了体外纹状体神经元成像研究。这些研究表明，树突棘的病理性增加与体内 Tat 转基因小鼠几乎完全相同。Tat 导致树突内的细胞内钠离子（[Na(+)]i）和钙离子（[Ca(2+)]i）显著局灶性增加，伴随着树突棘的出现。这些效应主要但不完全被 NMDA 和 AMPA 受体拮抗剂 MK-801 和 CNQX 减弱。同时给予吗啡处理加速了 Tat 诱导的局灶性棘突，伴随着局部 [Ca(2+)]i 增加和线粒体内膜电位不稳定加剧。重要的是，吗啡的作用被 μ-阿片受体拮抗剂 CTAP 阻止，并且在 μ-阿片受体敲除小鼠培养的神经元中未观察到。Tat-和吗啡联合诱导的初始离子稳态丧失和 [Ca(2+)]i 增加被肌醇 1,4,5-三磷酸受体抑制剂肌醇 1,4,5-三磷酸和丙酮酸减弱。总之，Tat 诱导 [Na(+)]i 增加、线粒体不稳定、通过谷氨酸能受体过度钙内流以及树突肿胀。吗啡通过 μ-阿片受体作用，通过动员额外的 [Ca(2+)]i 并进一步破坏 [Ca(2+)]i 稳态，在相同的亚细胞位置加剧这些兴奋性 Tat 效应。我们假设 μ-阿片和异常 AMPA/NMDA 谷氨酸受体信号的时空关系对于定义阿片类药物加剧神经艾滋病中常见的突触树突损伤的位置和程度至关重要。
