Adenosine receptors are a family of purinergic G protein-coupled receptors that are widely distributed in bodily organs and in the peripheral and central nervous systems. Recently, antihyperalgesic actions have been suggested for the adenosine A3 receptor, and its agonists have been proposed as new neuropathic pain treatments. We hypothesized that these receptors may be expressed in nociceptive primary afferent neurons. However, RNA sequencing across species, eg, rat, mouse, dog, and human, suggests that dorsal root ganglion (DRG) expression of ADORA3 is inconsistent. In rat and mouse, Adora3 shows very weak to no expression in DRG, whereas it is well expressed in human DRG. However, the cell types in human DRG that express ADORA3 have not been delineated. An examination of DRG cell types using in situ hybridization clearly detected ADORA3 transcripts in peripheral macrophages that are in close apposition to the neuronal perikarya but not in peripheral sensory neurons. By contrast, ADORA1 was found primarily in neurons, where it is broadly expressed at low levels. These results suggest that a more complex or indirect mechanism involving modulation of macrophage and/or microglial cells may underlie the potential analgesic action of adenosine A3 receptor agonism.

中文翻译：

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镇痛候选腺苷 A3 受体由人背根神经节和脊髓小胶质细胞的神经周围外周巨噬细胞表达。

腺苷受体是嘌呤能G蛋白偶联受体家族，广泛分布于身体器官以及外周和中枢神经系统中。最近，有人提出腺苷 A3 受体具有抗痛觉过敏作用，并且其激动剂已被提议作为新的神经性疼痛治疗方法。我们假设这些受体可能在伤害性初级传入神经元中表达。然而，跨物种（例如大鼠、小鼠、狗和人类）的RNA测序表明ADORA3的背根神经节（DRG）表达不一致。在大鼠和小鼠中，Adora3 在 DRG 中表达非常弱甚至没有表达，而在人 DRG 中表达良好。然而，人类 DRG 中表达 ADORA3 的细胞类型尚未确定。使用原位杂交对 DRG 细胞类型进行的检查清楚地检测到外周巨噬细胞中的 ADORA3 转录本，这些巨噬细胞与神经元周核细胞紧密相连，但在外周感觉神经元中却没有。相比之下，ADORA1 主要存在于神经元中，并以低水平广泛表达。这些结果表明，涉及巨噬细胞和/或小胶质细胞调节的更复杂或间接机制可能是腺苷 A3 受体激动剂潜在镇痛作用的基础。