皮肤干燥是许多瘙痒疾病的常见病,口服传统抗组胺药难以改善。最近,越来越多的证据表明,组胺H4受体(H4R)在瘙痒的发生、发展中起着重要作用。脊髓细胞外信号调节激酶(ERK)磷酸化激活介导组胺诱导的急性和脉络膜瘙痒。然而,组胺H4受体是否调节干性皮肤瘙痒中的ERK激活仍不清楚。在研究中,我们探讨了组胺H4受体和p-ERK在丙酮-乙醚-水(AEW)诱导的干性皮肤小鼠模型中的作用。q-PCR,蛋白质印迹,药理学和免疫荧光应用于研究。我们通过在小鼠颈项上反复应用AEW建立了干性皮肤瘙痒模型。AEW小鼠表现出典型的干燥皮肤组织学变化和持续的自发抓挠行为。组胺H4受体,而不是组胺H1受体,AEW小鼠介导的自发抓挠行为。此外,在AEW小鼠中,脊髓神经元中的c-Fos和p-ERK表达增加,并与GRPR阳性神经元共标记。此外,H4R激动剂4-甲基组胺二盐酸盐(4-MH)诱导瘙痒。AEW小鼠中4-MH诱导的瘙痒和自发性瘙痒均被p-ERK抑制剂U0126阻断。最后,鞘内注射H4R受体拮抗剂JNJ7777120抑制AEW小鼠脊髓p-ERK表达。我们的结果表明脊髓H4R在AEW诱导的干性皮肤小鼠中通过ERK激活介导瘙痒。
Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal-regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine-induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p-ERK in the spinal cord in a dry skin mouse model induced by acetone-
ether-water (AEW). q-PCR, Western blot, pharmacology and immunofluorescence were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c-Fos and p-ERK expression in the spinal cord neurons were increased and co-labelled with GRPR-positive neurons in AEW mice. Furthermore, H4R agonist 4-methyhistamine dihydrochloride (4-MH)induced itch. Both 4-MH-induced itch and the spontaneous itch in AEW mice were blocked by p-ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p-ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW-induced dry skin mice.