McQueen D S, Noble M A H, Bond S M
Division of Neuroscience, School of Biomedical Sciences, University of Edinburgh College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
Br J Pharmacol. 2007 May;151(2):278-84. doi: 10.1038/sj.bjp.0707216. Epub 2007 Mar 12.
Endothelin-1 (ET-1) is present in murine and human skin and causes itch (pruritus) when injected in humans. This behavioural study examined the scratch reflex evoked by ET-1 in mice.
An automated detector was used to determine whether ET-1 causes reflex scratching, the behavioural correlate of itching, in BALB/c mice. Selective agonists and antagonists were used to probe the ET receptor(s) involved.
ET-1 evoked dose-related reflex scratching lasting up to 20 min following intradermal injection (0.1-100 ng; 0.04-40 pmol). The ED(50) for ET-1 induced scratching was 2.1 ng and desensitization occurred with cumulative dosing. High doses of the ET(B) receptor agonist IRL1620 (10 microg; 5.5 nmol), also caused scratching (ED(50) 1.3 microg, 0.7 nmol). The ET(A) receptor antagonist BQ123 significantly reduced scratching evoked by ET-1 and IRL 1620, suggesting that both agonists caused scratching via an ET(A) receptor-dependent mechanism. The ET(B) receptor antagonist BQ788 significantly reduced scratching evoked by IRL1620 but had no effect on scratching evoked by ET-1. This indicated that activation of ET(B) receptors by high doses of ET(B) agonist, but not ET-1, can trigger scratching.
ET-1 is a potent endogenous activator of reflex scratching (itch). Mechanisms for ET-induced scratching are considered, including direct action of ET-1 on pruriceptive nerve endings and indirect actions via release of endogenous mediators such as histamine from mast cells. ET-1 and ET(A) receptors, possibly also ET(B) receptors, are potential targets for developing specific anti-pruritic drugs to treat pruritic skin disorders such as atopic dermatitis.
内皮素 -1（ET -1）存在于小鼠和人类皮肤中，注射到人体时会引发瘙痒。本行为学研究检测了ET -1在小鼠中诱发的搔抓反射。
使用自动探测器来确定ET -1是否会在BALB/c小鼠中引发反射性搔抓，搔抓是瘙痒的行为关联指标。使用选择性激动剂和拮抗剂来探究相关的ET受体。
皮内注射ET -1（0.1 - 100 ng；0.04 - 40 pmol）后，ET -1诱发剂量相关的反射性搔抓，持续长达20分钟。ET -1诱发搔抓的半数有效剂量（ED50）为2.1 ng，累积给药会导致脱敏。高剂量的ET(B)受体激动剂IRL1620（10 μg；5.5 nmol）也会引起搔抓（ED50为1.3 μg，0.7 nmol）。ET(A)受体拮抗剂BQ123显著减少了ET -1和IRL 1620诱发的搔抓，这表明两种激动剂均通过ET(A)受体依赖性机制引起搔抓。ET(B)受体拮抗剂BQ788显著减少了IRL1620诱发的搔抓，但对ET -1诱发的搔抓无影响。这表明高剂量的ET(B)激动剂激活ET(B)受体可引发搔抓，而ET -1则不能。
ET -1是反射性搔抓（瘙痒）的强效内源性激活剂。研究了ET诱发搔抓的机制，包括ET -1对瘙痒感受神经末梢的直接作用以及通过肥大细胞释放组胺等内源性介质的间接作用。ET -1和ET(A)受体，可能还有ET(B)受体，是开发治疗特应性皮炎等瘙痒性皮肤病的特异性抗瘙痒药物的潜在靶点。
