Gastrin-releasing peptide (GRP) receptor-expressing (GRPR)+ neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensation. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR+ neurons in the spinal dorsal horn (SDH). GRPR+ neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR+ neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP+ neurons in SDH contain glutamate, we investigated the role of GRP+ (GRP+/Glu+) neurons in regulating itch. Chemogenetic inhibition of GRP+ neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP+ neurons or ablation of GRPR+ neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR+ AMPAR+ neurons in SDH, mediating itch sensation. GRP-GRPR and the glutamate-AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.

中文翻译：

---

GRP受体和AMPA受体协同调节脊髓背角的瘙痒反应神经元。

胃泌素释放肽（GRP）受体表达（GRPR）+神经元在瘙痒的脊柱传递中具有重要作用。由于尚未了解其基本调节机制，因此确定此类神经元如何兴奋并整合痒感非常重要。在这项研究中，我们研究了脊髓背角（SDH）中瘙痒反应性GRPR +神经元激活的机制。GRPR +神经元表达了含有GluR2亚基的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）。在小鼠中，鞘内给予AMPAR拮抗剂NBQX可预防周围引起的组胺和非组胺性瘙痒，这与以下事实相符：NBQX完全阻断了在组胺和非组胺性瘙痒下SDH中GRPR +神经元的放电，但GRPR拮抗剂RC-3095却没有。由于SDH中的GRP +神经元含有谷氨酸，因此我们研究了GRP +（GRP + / Glu +）神经元在调节瘙痒中的作用。GRP +神经元的化学生成抑制作用可抑制组胺能和非组胺能止痒，而不会影响机械性疼痛阈值。在非人类的灵长类动物中，NBQX的给药也可减轻周围引起的瘙痒，而不会影响热痛阈值。在二苯环丙烯酮（DCP）诱导的接触性皮炎的小鼠模型中，GRP，GRPR和AMPAR亚基在SDH中上调。通过沉默GRP +神经元或消融GRPR +神经元可防止DCP引起的瘙痒。总而言之，这些发现表明，GRP和谷氨酸可协同调节SDH中的GRPR + AMPAR +神经元，介导瘙痒感。