Division of Anesthesiology, Department of Cardiovascular Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
Exp Biol Med (Maywood). 2010 Nov;235(11):1300-5. doi: 10.1258/ebm.2010.010121.
Endothelin-1 (ET-1) has recently been identified to evoke pruritus/itching sensation in both humans and animals. It is most likely that the signaling is through the specific G-protein-coupled ET(A) and ET(B) receptors, but the downstream signaling mediators for ET-1 remain elusive. In the present study, we examined the potential involvement of several distinct signaling molecules in ET-1-induced pruritus in a murine model. We applied an in vivo pruritus model in C57BL/6J mice by injecting ET-1 intradermally into the scruff, and recording the number of scratching bouts within 30 min after injection. Then specific antagonists/inhibitors for distinct signaling molecules, including cell-surface ET(A) and ET(B) receptors, histamine receptor type 1 (H1 receptor), protein kinases A (PKA) and C (PKC), phospholipase C (PLC) or adenylyl cyclase (AC), were co-injected with ET-1. The results showed that ET-1 induced a vigorous scratching response in mice in a dose-dependent manner. This response was further enhanced by a specific antagonist for ET(B) receptor, BQ-788, reduced by a specific antagonist for ET(A) receptor, BQ-123, and not affected by mepyramine, the specific inhibitor for H1 receptor. In addition, the scratching response was significantly reduced by inhibitors for PKC and AC, but was significantly enhanced by PLC inhibitor, while PKA inhibitors showed no effects in the ET-1-induced scratching response. Our data suggested that ET-1 may signal through the ET(A) receptor, AC and PKC pathway to induce pruritus sensation, while ET(B) receptor and PLC may antagonize the pruritus evoked by ET-1. These results may provide a basis for the future development of antipruritic therapy.
内皮素-1（ET-1）最近被鉴定为在人类和动物中引发瘙痒/瘙痒感。很可能信号是通过特定的 G 蛋白偶联的 ET(A)和 ET(B)受体，但 ET-1 的下游信号介质仍然难以捉摸。在本研究中，我们在小鼠模型中检查了几种不同信号分子在 ET-1 诱导的瘙痒中的潜在作用。我们通过将 ET-1 皮内注射到颈背，在 C57BL/6J 小鼠中应用体内瘙痒模型，并在注射后 30 分钟内记录搔抓次数，来评估瘙痒的程度。然后，我们将特定的拮抗剂/抑制剂用于不同的信号分子，包括细胞表面的 ET(A)和 ET(B)受体、组胺受体 1（H1 受体）、蛋白激酶 A（PKA）和 C（PKC）、磷脂酶 C（PLC）或腺苷酸环化酶（AC），与 ET-1 一起注射。结果表明，ET-1 以剂量依赖的方式在小鼠中诱导强烈的搔抓反应。这种反应进一步被 ET(B)受体的特定拮抗剂 BQ-788 增强，被 ET(A)受体的特定拮抗剂 BQ-123 减弱，而不受 H1 受体的特定抑制剂甲吡拉敏的影响。此外，PKC 和 AC 的抑制剂显著减少搔抓反应，但 PLC 抑制剂显著增强搔抓反应，而 PKA 抑制剂对 ET-1 诱导的搔抓反应没有影响。我们的数据表明，ET-1 可能通过 ET(A)受体、AC 和 PKC 途径信号转导来诱导瘙痒感，而 ET(B)受体和 PLC 可能拮抗 ET-1 引起的瘙痒。这些结果可能为未来的止痒治疗提供基础。
