Department of Medicine, Division of Clinical Pharmacology, Baylor College of Medicine, Houston, TX, USA.
Int J Dermatol. 2019 Aug;58(8):880-891. doi: 10.1111/ijd.14252. Epub 2018 Oct 26.
Chloroquine (CQ) is an antimalarial drug that elicits severe pruritus in black Africans with malaria fever. This acute itching (2-7 days duration) exhibits age dependency and a racial and genetic predilection. CQ itch is non-histaminergic, which makes it both a good model and a tool to probe the mechanisms of chronic itch. This review focuses on recently discovered mechanisms, neuroscience, mediators, and receptors that are implicated in molecular studies of CQ pruritus. CQ pruritus mechanisms are also compared to that of itching following other systemic diseases, such as chronic kidney disease, chronic liver disease, skin disorders, and burns. There are striking similarities between CQ itching pathways and other chronic itch secondary to systemic disease with or without skin lesions, which have not been previously highlighted. Prominent among these are the shared roles of skin, neural and spinal μ opiate receptors, kappa opiate receptor, nitric oxide, serotonin via 5HT1B/D receptors, cytokines, especially interleukins, and tumor necrosis factor. There is elaborate "cross talk" among the diverse mediators and receptors involved in CQ-induced pruritus. CQ also binds to the mas-related G protein coupled receptors MrgprA3/MrgprX1 present in a small proportion (4-5%) of dorsal root ganglion neurons and skin. The mrgprA3 CQ receptors are coupled to PLC-β3 and a chloride channel to initiate skin itch action potentials in C nerve fibers. Mrgpra3/X1 couples to TRPA1 for calcium influx into neuronal cells at noncutaneous sites. Central CQ itch occurs via gastrin-related peptide (GRP) and its receptor (GRPR) in the dorsal spinothalamic tracts, as well as glutamic mediated GRP projection to parabrachial nucleus. The possibility of chronic itch therapy based on personalized medicine, genetics, and transcriptomics or the use of itch "polypill/polycream" are discussed.
氯喹（CQ）是一种抗疟药物，会引起患有疟疾发热的黑种人严重瘙痒。这种急性瘙痒（持续 2-7 天）表现出年龄依赖性和种族和遗传倾向。CQ 瘙痒是非组胺能的，这使其既是慢性瘙痒机制研究的良好模型，也是工具。本综述重点介绍了最近发现的机制、神经科学、介质和受体，这些都与 CQ 瘙痒的分子研究有关。还将 CQ 瘙痒机制与其他系统性疾病（如慢性肾病、慢性肝病、皮肤疾病和烧伤）引起的瘙痒进行了比较。CQ 瘙痒途径与其他系统性疾病引起的慢性瘙痒（有或没有皮肤损伤）之间存在许多相似之处，这些相似之处以前并未被强调。其中突出的是皮肤、神经和脊髓 μ 阿片受体、κ 阿片受体、一氧化氮、通过 5HT1B/D 受体的血清素、细胞因子（尤其是白细胞介素）和肿瘤坏死因子的共同作用。参与 CQ 诱导瘙痒的各种介质和受体之间存在着精细的“串扰”。CQ 还与 MrgprA3/MrgprX1 等 Mas 相关 G 蛋白偶联受体结合，MrgprA3/MrgprX1 存在于一小部分（4-5%）背根神经节神经元和皮肤中。mrgprA3 CQ 受体与 PLC-β3 和氯离子通道偶联，以在 C 神经纤维中引发皮肤瘙痒动作电位。Mrgpra3/X1 在非皮肤部位与 TRPA1 偶联，以将钙内流入神经元细胞。中枢 CQ 瘙痒通过背侧脊髓丘脑束中的胃泌素相关肽（GRP）及其受体（GRPR）以及谷氨酸介导的 GRP 投射到臂旁核发生。基于个性化医学、遗传学和转录组学或使用瘙痒“多药/多乳膏”进行慢性瘙痒治疗的可能性也进行了讨论。
