Department of Pharmacology, Wakayama Medical University, Wakayama, Japan.
Department of Anatomy, Kansai University of Health Sciences, Osaka, Japan.
Neuropsychopharmacol Rep. 2020 Sep;40(3):287-290. doi: 10.1002/npr2.12120. Epub 2020 Jun 25.
Ample evidence indicates that gastrin-releasing peptide receptor (GRPR)-expressing neurons play a critical role in the transmission of acute itch. However, the pathophysiology of spinal mechanisms underlying intractable itch such as psoriasis remains unclear. In this study, we aimed to determine whether itch-responsive GRPR neurons contribute to the spinal transmission of imiquimod (IMQ)-induced psoriatic itch.
To generate a psoriasis model, C57BL/6J mice received a daily topical application of 5% IMQ cream on their shaved back skin for 7-10 consecutive days. GRP neurons were inhibited using Cre-dependent expression of Gi-designer receptors exclusively activated by designer drugs (DREADDs), while GRPR neurons were ablated by intrathecal administration of bombesin-saporin.
Repeated topical application of IMQ elicited psoriasis-like dermatitis and scratching behaviors. The mRNA expression levels of GRP and GRPR were upregulated in the cervical spinal dorsal horn (SDH) on days 7 and 10 after IMQ application. Either chemogenetic silencing of GRP neurons by Gi-DREADD or ablation of GRPR neurons significantly attenuated IMQ-induced scratching behaviors.
The GRP-GRPR system might be enhanced in the SDH, and itch-responsive GRPR neurons largely contribute to intractable itch in a mouse model of psoriasis.
大量证据表明，胃泌素释放肽受体（GRPR）表达神经元在急性瘙痒的传递中发挥关键作用。然而，银屑病等难治性瘙痒的脊髓机制的病理生理学仍然不清楚。在这项研究中，我们旨在确定瘙痒反应性 GRPR 神经元是否有助于咪喹莫特（IMQ）诱导的银屑病瘙痒的脊髓传递。
为了产生银屑病模型，C57BL/6J 小鼠在剃光的背部皮肤上每天接受 5% IMQ 乳膏的外用，连续 7-10 天。使用 Cre 依赖性表达的 Gi 设计受体仅被设计药物激活（DREADDs）来抑制 GRP 神经元，而通过鞘内给予脑啡肽-saporin 来消融 GRPR 神经元。
重复局部应用 IMQ 可引起类似银屑病的皮炎和搔抓行为。在 IMQ 应用后的第 7 和第 10 天，GRP 和 GRPR 的 mRNA 表达水平在颈段脊髓背角（SDH）中上调。通过 Gi-DREADD 化学遗传沉默 GRP 神经元或消融 GRPR 神经元均可显著减轻 IMQ 诱导的搔抓行为。
GRP-GRPR 系统在 SDH 中可能增强，并且瘙痒反应性 GRPR 神经元在银屑病小鼠模型中对难治性瘙痒有很大贡献。
