Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, China.
Laboratory of Sensory Neurobiology, Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, China.
Exp Dermatol. 2024 Jul;33(7):e15128. doi: 10.1111/exd.15128.
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.
干燥皮肤是许多瘙痒性疾病的常见症状，用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）在瘙痒的发生和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引起的急性和慢性瘙痒。然而，组胺 H4 受体是否调节干燥皮肤瘙痒中的 ERK 激活尚不清楚。在这项研究中，我们通过丙酮-乙醚-水（AEW）在颈部反复应用建立了干燥皮肤瘙痒模型，探讨了组胺 H4 受体和脊髓 p-ERK 在干燥皮肤瘙痒小鼠模型中的作用。研究中应用了 q-PCR、Western blot、药理学和免疫荧光技术。我们在颈部反复应用 AEW 建立了干燥皮肤瘙痒模型，发现 AEW 小鼠表现出典型的干燥皮肤组织学变化和持续的自发性搔抓行为。组胺 H4 受体而非组胺 H1 受体介导 AEW 小鼠的自发性搔抓行为。此外，AEW 小鼠脊髓神经元中 c-Fos 和 p-ERK 的表达增加，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）可引起瘙痒。4-MH 诱导的瘙痒和 AEW 小鼠的自发性瘙痒均被 p-ERK 抑制剂 U0126 阻断。最后，鞘内给予 H4R 拮抗剂 JNJ7777120 可抑制 AEW 小鼠脊髓 p-ERK 的表达。我们的研究结果表明，脊髓 H4R 通过 AEW 诱导的干燥皮肤小鼠中的 ERK 激活介导瘙痒。
