Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway may play an important role in the regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G-protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER⁺ neurons in the RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER⁺ neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER⁺ neurons abrogated itch responses, indicating that GPER⁺ neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by the µ type opioid receptor (MOR) antagonism. Additionally, significant MOR phosphorylation in the RVM was detected in chronic itch models in wild-type but not in GPER^–/– rats. Therefore, GPER not only identifies a population of medullary antipruritic neurons but may also determine the descending antipruritic tone through regulating µ opioid signaling.

SIGNIFICANCE STATEMENT Therapeutic options for itch are limited because of an as yet incomplete understanding of the mechanisms of itch processing. Our data have provided novel insights into the cellular organization and molecular mechanisms of descending regulation of itch in normal and pathologic conditions. GPER⁺ neurons (largely GABAergic) in the RVM are antipruritic neurons under tonic opioidergic inhibition, activation of GPER promotes phosphorylation of MOR and disinhibition of the antipruritic GPER⁺ neurons from inhibitory opioidergic inputs, and failure to mobilize GPER⁺ neurons may result in the exacerbation of itch. Our data also illuminate on some of the outstanding questions in the field, such as the mechanisms underlying sex bias in itch, pain, and opioid analgesia and the paradoxical effects of morphine on pain and itch.

慢性瘙痒是一种麻烦的疾病，通常难以治愈。新出现的证据表明，导水管周围灰质 (PAG)-延髓头端腹内侧 (RVM) 通路可能在瘙痒的调节中起重要作用，但细胞组织和分子机制仍未完全了解。在这里，我们报告一组 RVM 神经元独特地表达 G 蛋白偶联雌激素受体 (GPER)，它介导瘙痒的下行抑制。我们发现RVM 中的GPER ⁺神经元在大鼠和小鼠的慢性瘙痒条件下被激活。RVM GPER ⁺神经元的选择性消融或化学遗传学抑制导致机械异位运动和对瘙痒原的反应增加的抓挠，而 GPER ^{+ 的}化学遗传学激活神经元消除了瘙痒反应，表明 GPER ⁺神经元具有止痒作用。此外，任何性别的 GPER 缺陷小鼠和大鼠都表现出对机械和化学瘙痒的超敏反应，这种表型可通过 μ 型阿片受体 (MOR) 拮抗作用逆转。此外，在野生型慢性瘙痒模型中检测到 RVM 中显着的 MOR 磷酸化，但在 GPER ^-/-大鼠中未检测到。因此，GPER 不仅可以识别一组髓质止痒神经元，还可以通过调节 μ 阿片类信号来确定降序的止痒音。

重要性声明瘙痒的治疗选择有限，因为对瘙痒处理机制的理解尚不完全。我们的数据为正常和病理条件下瘙痒下调的细胞组织和分子机制提供了新的见解。RVM 中的 GPER ⁺神经元（主要是 GABA 能）是强效阿片能抑制下的止痒神经元，GPER 的激活促进 MOR 的磷酸化和抑制性阿片能输入的止痒 GPE​​R ⁺神经元的去抑制，并且未能动员 GPER ⁺神经元可能导致瘙痒加剧。我们的数据还阐明了该领域的一些悬而未决的问题，例如瘙痒、疼痛和阿片类药物镇痛的性别偏见背后的机制，以及吗啡对疼痛和瘙痒的反常作用。