Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Methods Mol Biol. 2021;2201:139-162. doi: 10.1007/978-1-0716-0884-5_13.
Opioid use has substantially increased over recent years and remains a major driver of new HIV infections worldwide. Clinical studies indicate that opioids may exacerbate the symptoms of HIV-associated neurocognitive disorders (HAND), but the mechanisms underlying opioid-induced cognitive decline remain obscure. We recently reported that the μ-opioid agonist morphine increased neuronal iron levels and levels of ferritin proteins that store iron, suggesting that opioids modulate neuronal iron homeostasis. Additionally, increased iron and ferritin heavy chain protein were necessary for morphine's ability to reduce the density of thin and mushroom dendritic spines in cortical neurons, which are considered critical mediators of learning and memory, respectively. As altered iron homeostasis has been reported in HAND and related neurocognitive disorders like Alzheimer's, Parkinson's, and Huntington's disease, understanding how opioids regulate neuronal iron metabolism may help identify novel drug targets in HAND with potential relevance to these other neurocognitive disorders. Here, we review the known mechanisms of opioid-mediated regulation of neuronal iron and corresponding cellular responses and discuss the implications of these findings for patients with HAND. Furthermore, we discuss a new molecular approach that can be used to understand if opioid modulation of iron affects the expression and processing of amyloid precursor protein and the contributions of this pathway to HAND.
近年来，阿片类药物的使用大幅增加，仍然是全球新的 HIV 感染的主要驱动因素。临床研究表明，阿片类药物可能会加重与 HIV 相关的神经认知障碍 (HAND) 的症状，但阿片类药物引起认知能力下降的机制仍不清楚。我们最近报告说，μ-阿片类激动剂吗啡会增加神经元中的铁含量和储存铁的铁蛋白水平，这表明阿片类药物可以调节神经元铁的动态平衡。此外，铁和铁蛋白重链蛋白的增加是吗啡降低皮质神经元中薄而蘑菇状树突棘密度的能力所必需的，这些树突棘分别被认为是学习和记忆的关键介质。由于 HAND 以及阿尔茨海默病、帕金森病和亨廷顿病等相关神经认知障碍中已经报道了铁稳态的改变，了解阿片类药物如何调节神经元铁代谢可能有助于确定 HAND 中的新型药物靶点，这些靶点可能与这些其他神经认知障碍有关。在这里，我们回顾了阿片类药物介导的神经元铁调节和相应细胞反应的已知机制，并讨论了这些发现对 HAND 患者的影响。此外，我们还讨论了一种新的分子方法，可用于了解阿片类药物对铁的调节是否会影响淀粉样前体蛋白的表达和加工，以及该途径对 HAND 的贡献。
